Patent landscape analysis of neuroblastoma immunotherapy: trends and opportunities

Gabriela Sánchez-Esgua1 iD, Marisol Sánchez-Esgua2 iD, Maricruz Anaya-Ruiz3 iD, Cecilia Soberanes-Barabata4, Martín Pérez-Santos5* iD

1Dirección de Innovación y Transferencia de Conocimiento, Benemérita Universidad Autónoma de Puebla, Puebla CP 72570, México. 2Biotecnología productiva, Centro de Investigación en Biotecnología Aplicada del Instituto Politécnico Nacional, Santa Inés Tecuexcomac, Tlaxcala, CP 90700, México. 3Laboratorio de Biología Celular, Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Metepec, Puebla CP 74360, México. 4Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, Puebla CP 72570, México. 5Dirección de Innovación y Transferencia de Conocimiento, Benemérita Universidad Autónoma de Puebla, Puebla CP 72570, México. *martin.perez@correo.buap.mx

http://doi.org/10.5281/zenodo.23898896

Bajar cita (RIS): Sánchez-Esgua et al., 2026 AyTBUAP 11(43):67-100

Editado por: Jesús Muñoz-Rojas (Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla).

Recibido: 30 de abril 2026. Aceptado: 22 de septiembre 2026. Fecha de publicación: 30 de septiembre de 2026

URI: https://hdl.handle.net/20.500.12371/34517

Referencia: Sánchez-Esgua G, Sánchez-Esgua M, Anaya-Ruiz M, Soberanes-Barabata C, Pérez-Santos M. Patent landscape analysis of neuroblastoma immunotherapy: trends and opportunities. Alianzas y Tendencias BUAP. 2026;11(43):67–100. Available from: https://www.aytbuap.mx/aytbuap-1143/patent-landscape-analysis-of-neuroblastoma-immunotherapy

ABSTRACT

The analysis based on databases from the European Patent Office and the World Intellectual Property Organization encompasses a total of 33 key patent families focused on the development of immunotherapies for neuroblastoma. Patenting activity shows a marked polarization toward antibodies and cellular immunotherapy, leaving significant "white spaces" in other modalities. Antibodies account for nearly 70% of the analyzed intellectual property, with the tumor-associated antigen GD2 standing out as the most mature and commercially explored therapeutic target (10 patents), while cellular immunotherapy ranks second with 7 patents (21.2%), primarily covering chimeric antigen receptors (CARs) targeting GD2 and PHOX2B. Under-represented modalities, such as vaccines (6.1%) and immune checkpoint inhibitors (3.0%)—along with a complete absence of patents for immunomodulators and oncolytic viruses for neuroblastoma—highlight opportunities for future pharmaceutical research and development. Patent innovation is heavily concentrated in developed economies, with the United States leading decisively by accounting for more than half of all registered patents (57.6%), followed by China (12.1%) and notable contributions from European countries including Germany, France, Italy, and the Netherlands. Furthermore, an examination of the types of claims reveals that virtually 100% of the analyzed patents include claims regarding the active principle, methods of use, and production processes, whereas there is a relative scarcity of patents focused exclusively on new pharmaceutical formulations and optimized dosage regimens, indicating that a large portion of the portfolio remains in early or intermediate stages of protecting the molecule and its general application.

Palabras clave: Neuroblastoma; patents; cancer; immunotherapy; GD2.

RESUMEN

El análisis, basado en bases de datos de la Oficina Europea de Patentes y la Organización Mundial de la Propiedad Intelectual, abarca un total de 33 familias de patentes clave centradas en el desarrollo de inmunoterapias para el neuroblastoma. La actividad de patentamiento muestra una marcada polarización hacia los anticuerpos y la inmunoterapia celular, dejando “espacios vacíos” importantes en otras modalidades. Los anticuerpos representan cerca del 70 % de la propiedad intelectual analizada; en este ámbito, el antígeno asociado a tumores GD2 destaca como la diana terapéutica más madura y explorada comercialmente (10 patentes), mientras que la inmunoterapia celular ocupa el segundo lugar con 7 patentes (21,2 %), centradas principalmente en receptores de antígenos quiméricos (CAR, por sus siglas en inglés) dirigidos contra GD2 y PHOX2B. Modalidades con menor representación, como las vacunas (6,1 %) y los inhibidores de puntos de control inmunitario (3,0 %) —sumado a una ausencia total de patentes relativas a inmunomoduladores y virus oncolíticos para el neuroblastoma—, ponen de relieve oportunidades para la futura investigación y desarrollo farmacéutico. La innovación en materia de patentes se concentra mayoritariamente en economías desarrolladas: Estados Unidos lidera de forma decisiva, al aglutinar más de la mitad de todas las patentes registradas (57,6 %), seguido por China (12,1 %) y con contribuciones notables de países europeos como Alemania, Francia, Italia y los Países Bajos. Asimismo, el examen de los tipos de reivindicaciones revela que prácticamente el 100 % de las patentes analizadas incluyen reivindicaciones sobre el principio activo, los métodos de uso y los procesos de producción; por el contrario, existe una relativa escasez de patentes centradas exclusivamente en nuevas formulaciones farmacéuticas o regímenes de dosificación optimizados, lo que indica que una gran parte de la cartera se encuentra aún en etapas iniciales o intermedias, centradas en la protección de la molécula y su aplicación general.

Palabras clave: Neuroblastoma; patentes; cáncer; inmunoterapia; GD2.

INTRODUCCIÓN

Neuroblastoma is a type of extracranial solid tumor occurring in children. Its incidence, during the period 1990–2021 in children aged 0–14 years, accounted for 5,560 cases, 1,977 deaths, and 174,186.3 disability-adjusted life years (DALYs) [1]. Neuroblastoma arises from fetal neuroblasts that, instead of maturing into nerve cells or brainstem cells, fail to mature and continue to proliferate as the child grows, eventually developing into a cancerous tumor [2]. Neuroblastomas are generally observed in the adrenal, abdominal/retroperitoneal, neck, and thoracic and pelvic regions, among others [3]. Several genetic alterations are linked to the immaturity of neuroblasts, including amplification of the MYCN gene, mutations in ALK and PHOX2B, rearrangements in the ATRX and TERT loci, and overexpression of MYCN, ALK, PHOX2B, and LIN28B [4-10]. The various treatments approved by the U.S. Food and Drug Administration (FDA) for neuroblastoma include injectable cyclophosphamide, doxorubicin, vincristine, eflornithine, antibodies binding to the glycolipid GD2 (such as naxitamab-gqgk and dinutuximab), and combination regimens including busulfan/melphalan and carboplatin/etoposide/melphalan [11-14]. Naxitamab-gqgk, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), is indicated for the treatment of patients with relapsed or refractory high-risk neuroblastoma; however, treatment with naxitamab-gqgk can cause cardiac arrest, anaphylaxis, hypotension, bronchospasm, stridor, severe neuropathic pain, transverse myelitis, and posterior reversible encephalopathy syndrome [15]. Dinutuximab, indicated for intravenous administration in pediatric patients with high-risk neuroblastoma, is associated with capillary leak syndrome, hypotension, ocular neurological disorders, severe neuropathic pain, and atypical hemolytic uremic syndrome [16]. Due to these adverse reactions, the continuous development of new immunotherapeutic alternatives for neuroblastoma treatment is crucial. Therefore, this study aims to conduct a patent landscape analysis encompassing patent trends for immunotherapies directed against various targets expressed in neuroblastoma.

METHODOLOGY

Patent search strategy

To obtain patent documents relating to immunotherapy against neuroblastoma, a search strategy based on keywords related to neuroblastoma immunotherapy was designed. This strategy included all patents published, up to August 2025, in the patent databases of the world's main patent offices, United States Patent and Trademark Office, European Patent Office (Espacenet), and World Intellectual Property Organization (Patentscope). The patent search was performed using keywords in the title, abstract, and claims sections of the patent databases.

The search strategy was designed for the following mechanisms of action (MoA): i) antibodies, ii) cellular immunotherapy, iii) vaccines, iv) checkpoint inhibitors, v) immunomodulators, vi) oncolytic viruses. Each MoA included a particular search strategy that included keywords related to the MoA.

The following strategy was used to search for patents related to antibodies: (ti = "neuroblastoma" OR ab = "neuroblastoma") AND claims = "neuroblastoma" AND (ctxt = "antigen bind*" OR ctxt = "target bind*" OR ctxt any "bispec*,multispec*,trispec*,antibod*,immunoglobul*,fab,fab2" AND (cpc = "C07K16/low" OR cpc = "A61K39/395/low" OR cpc = "C07K2317/low" OR cpc = "C07K2318/low" OR cpc any "A61K2039/505,A61K2039/507") AND (ctxt = "cancer*" OR cl = "A61P35/low").

The following strategy was used to search for patents related to vaccines: (ti = "neuroblastoma" OR ab = "neuroblastoma") AND claims = "neuroblastoma" AND (claims any "vaccin*" OR claims = "immunogenic composition?" OR claims = "antigenic composition?" OR claims = "immunogen* pr?parat*" OR claims = "medical preparation") AND (cpc = "A61K39/0011/low" AND cpc = "A61K2039/53") for nucleic acid vaccines; (ti = "neuroblastoma" OR ab = "neuroblastoma") AND claims = "neuroblastoma" AND (((claims any "vaccin*" OR claims = "immunogenic composition?" OR claims = "antigenic composition?" OR claims = "immunogen* pr?parat*" OR claims = "medical preparation") AND cpc = "A61K39/0011/low") NOT cpc any "A61K2039/5256,A61K2039/523,A61K2039/521,A61K2039/5252,A61K2039/5254,A61K2039/522") for proteins vaccines; and (ti = "neuroblastoma" OR ab = "neuroblastoma") AND claims = "neuroblastoma" AND (claims any "vaccin*" OR claims = "immunogenic composition?" OR claims = "antigenic composition?" OR claims = "immunogen* pr?parat*" OR claims = "medical preparation") AND (cpc = "A61K39/0011/low" AND cpc any "A61K2039/523,A61K2039/5256,C12N2710/24143,C12N2710/10343,C12N2740/15043,C12N2710/10043,C12N2740/16043,C12N2710/24043,C12N2740/13043,C12N2770/36143,C12N2760/20243") for vectored vaccines.

The following strategy was used to search for patents related to checkpoints immune: (ti = "neuroblastoma" OR ab = "neuroblastoma") AND claims = "neuroblastoma" AND (ctxt = "antigen bind*" AND (ctxt any "ipilimumab,yervoy,nivolumab,opdivo,pembrolizumab,keytruda,atezolizumab,tecentriq,avelumab,bavencio,durvalumab, imfinzi,cemiplimab,libtayo" OR ctxt = "pd l1" OR ctxt = "pd 1" OR ctxt = "pd l2" OR ctxt = "hpd 1" OR ctxt = "hupd 1" OR ctxt = "ctla 4" OR ctxt = "lag 3" OR ctxt = "tim 3" OR ctxt any "TIGIT,cd223,havcr2,wucam,vstm3,vsig9,cd272,btla,cd272" OR ctxt = "b7 h4" OR ctxt any "FPA150,a2ar,cd73,Mupadolimab,NKG2A,Monalizumab,PVRIG,PVRL2" OR ctxt = "COM 701" OR ctxt = "CEACAM 1" OR ctxt = "cm24" OR ctxt = "CEACAM 5" OR ctxt = "CEACAM 6" OR ctxt = "NEO 201" OR ctxt any "CCL2,CCR2,LIF" OR ctxt = "MSC 1" OR ctxt = "LAG 525" OR ctxt = "IMP 701" OR ctxt = "REGN 3767" OR ctxt = "RN 3767" OR ctxt = "RG 3767" OR ctxt = "BI 754 091" OR ctxt any "tebotelimab,mGD013" OR ctxt = "b7 h3" OR ctxt any "CD276,VISTA" OR ctxt = "B7 H5" OR ctxt any "IMP321,relatlimab" OR ctxt = "PD 1H" OR ctxt = "domain Ig suppressor T cell activation" OR ctxt = "IMP 321" OR ctxt = "Relatlimab" OR ctxt = "BMS 986 016" OR ctxt = "LAG 525" OR ctxt = "MK 4280" OR ctxt = "REGN 3767" OR ctxt = "REGN 2810" OR ctxt = "RG 2810" OR ctxt = "RN 2810" OR ctxt = "TSR 033" OR ctxt = "Hu5F9" OR ctxt = "LY 3022855" OR ctxt = "SNDX 6352" OR ctxt = "BI 754111" OR ctxt = "BI_754091" OR ctxt = "Sym_022" OR ctxt any "Sym021,Sym023" OR ctxt = "Syn 22" OR ctxt = "Sym 21" OR ctxt = "Sym 23" OR ctxt = "MGD 013" OR ctxt = "TSR 022" OR ctxt = "TSR 22" OR ctxt = "MBG 453" OR ctxt = "TSR 042" OR ctxt = "TSR 42" OR ctxt = "dostarlimab" OR ctxt = "tsr 033" OR ctxt = "TSR 33" OR ctxt = "MBG 453" OR ctxt = "sabatolimab" OR ctxt = "PDR 001" OR ctxt = "spartalizumab" OR ctxt = "INCAGN 2390" OR ctxt = "LY 3321367" OR ctxt = "LY 3300054" OR ctxt = "Lodapolimab" OR ctxt = "SHR 1702" OR ctxt = "Camrelizumab" OR ctxt = "RO 7121661" OR ctxt = "RG 7769" OR ctxt = "MK 7684" OR ctxt = "Etigilimab" OR ctxt = "OMP 313" OR ctxt = "Tiragolumab" OR ctxt = "MTIG 7192 A" OR ctxt = "RG 6058" OR ctxt = "BMS 986207" OR ctxt = "Zimberelimab,aB122,Domvanalimab,AB154" OR ctxt = "JNJ 61610588" OR ctxt = "CA 170" OR ctxt = "Enoblituzumab" OR ctxt = "MGA 271" OR ctxt = "MGD009" OR ctxt = "I 8H9" OR ctxt = "omburtamab" OR ctxt = "immune checkpoint?" OR ctxt = "checkpoint inhibitor?" OR ctxt = "ICP" OR ctxt = "b7 h1" OR ctxt any "cd274,cd152,hvem,tnfrsf14,cd160,cd66a" OR ctxt = "galectin 9" OR ctxt any "lgals9,2b4,cd244,vstm3,indoleamine,ido" OR ctxt = "lymphocyte activation antigen 3" OR ctxt any "cd155,pvr")).

The following strategy was used to search for patents related to cellular immunotherapy: (ti = "neuroblastoma" OR ab = "neuroblastoma") AND claims = "neuroblastoma" AND ((cpc = "A61K39/0011/low" AND cpc = "A61K2039/5156" AND cpc = "C07K14/7051" AND cpc = "C07K2319/03") OR ((ta any "CAR,CART" OR ta = "chimeric antigen receptor?") AND (cpc = "A61K39/0011/low" OR cpc any "C12N5/0636, C12N5/0638, C12N5/0646, A61K35/17, C07K14/7051"))).

The following strategy was used to search for patents related to immunomodulators: (ti = "neuroblastoma" OR ab = "neuroblastoma") AND claims = "neuroblastoma" AND (ta=("Cereblon" prox/distance<=6 "inhibit??") OR ta=("Cereblon" prox/distance<=6 "block???") OR ta=("Cereblon" prox/distance<=6 "antagoni???") OR ta=("CRBN?" prox/distance<=6 "inhibit??") OR ta=("CRBN?" prox/distance<=6 "block???") OR ta=("CRBN?" prox/distance<=6 "antagoni???") OR ta any "iberdomid?, avadomid?, iberdomid?, eragidomid?" OR ta any "thalidomid?,Synovir,Talizer,Thaled" OR ta any "lenalidomide,Revimid,Revlimid" OR ta any "pomalidomid?,Actimid,Imnovid,Pomalyst") for cereblon; (ti = "neuroblastoma" OR ab = "neuroblastoma") AND claims = "neuroblastoma" AND (ta any "nabilon?,cesamet" OR ta = "cannabi* recept*" OR ta any "dexanabinol,dexanabinon?" OR ta = "tetrahydro cannabinol" OR (ta = "dronabinol" OR ta = "delta 9 tetrahydro cannabinol" OR ta = "Compassia Deltanyne" OR ta any "Ladavru,Marinol" OR ta = "MedChew Namisol" OR ta any "Reduvo,Relivar,Tetranabinex,caumz" OR ta = "cannabidiolic acid" OR ta = "cannabinoid?" OR ta = "hemp? extract?") OR (ta = "nabiximols" OR ta=("cannabis sativa" prox/distance<=3/ordered "extract") OR ta = "Sativex") OR (ta = "cannabidiol" OR ta = "DehydraTECH CBD" OR ta = "CanChew Plus" OR ta any "Epidiolex,Epidyolex,Nabidiolex,Xalex,Zygel")) for cannabinoids; (ti = "neuroblastoma" OR ab = "neuroblastoma") AND claims = "neuroblastoma" AND ((ta=("tlr?" prox/distance<=4 "agonis??") OR ta=("tlr?" prox/distance<=4 "stimul*") OR ta=("tlr?" prox/distance<=4 "signal*") OR ta=("toll like recept*" prox/distance<=4 "agonis??") OR ta=("toll like recept*" prox/distance<=4 "stimul*") OR ta=("toll like recept*" prox/distance<=4 "signal*")) OR ta any "telratolimod" OR ta = "BDC 1001" OR ta = "ono 4007" OR ta = "resiquimod" OR ta = "vidutolimod" OR ta any "Immuvac,Leprovac" OR ta any "imiquimod,Aldara,Beselna,Vesimune,Vyloma,Zartra,Zyclara,limtop") for TRLs; (ti = "neuroblastoma" OR ab = "neuroblastoma") AND claims = "neuroblastoma" AND (((ti=("indoleamin?" prox/distance<=3/ordered "dioxygenas??") OR ti = "ido" OR ti = "ido 1" OR ti = "CD107B") AND ti any "inhibit???, block????, antagoni????") OR (ab=("indoleamin?" prox/distance<=3/ordered "dioxygenas??") OR ab = "ido" OR ab = "ido 1" OR ab = "CD107B") AND ab any "inhibit???, block????, antagoni????") OR ta any "tenatoprazole,benatoprazol?,Protop,Ulsacare" OR ta = "navoximod" OR ta = "linrodostat" OR ta = "indole 3 carbinol" OR ta = "beta-lapachon?" OR (ta = "epigallocatechin gallat?" OR ta = "EGCG" OR ta = "epigallocatechin 3 gallat?" OR ta any "Sunphenon,Teavigo") OR (ta = "indoximod" OR ta = "1 methyl D tryptophan" OR ta = "l methyl D tryptophan" OR ta = "i methyl D tryptophan") OR (ta = "3 deazaguanin?" OR ta = "dezaguanin?") OR (ta = "di indolylmethan?" OR ta = "BR DIM" OR ta = "Bio Response DIM" OR ta = "Blo_Response_DIM" OR ta = "B1o_Response_DIM" OR ta = "diindolylmethan?") OR ta = "epacadostat" OR ta any "sertaconazol?,Dermofix,Dermoseptic,Ertaczo,Extens,Fisderm,Ginedermofix,Onabet,Zalain") for IDO; (ti = "neuroblastoma" OR ab = "neuroblastoma") AND claims = "neuroblastoma" AND (((ti all "adenosin? A2? receptor??" OR ti = "adenosin? A2a receptor??" OR ti = "adenosin? A2b receptor??" OR ti = "adenosin? receptor??") AND ti any "inhibit???, block????, antagoni????") OR ((ab all "adenosin? A2? receptor??" OR ab = "adenosin? A2a receptor??" OR ab = "adenosin? A2b receptor??" OR ab = "adenosin? receptor??" OR ab = "ADORA?") AND ab any "inhibit???, block????, antagoni????") OR ta = "preladenant" OR ta = "imaradenant" OR ta = "ciforadenant" OR ta = "taminadenant" OR ta = "etrumadenant" OR (ta=("ergotamine" prox/distance<=2 " caffein?") OR ta = "Cafergot") OR (ta = "aspirin" AND ta=("caffein?" prox/distance<=2/ordered "dihydrocodein")) OR ta = "Synalgos DC")) for adenosine receptors.

The following strategy was used to search for patents related to oncolytic viruses: (ti = "neuroblastoma" OR ab = "neuroblastoma") AND claims = "neuroblastoma" AND (ctxt=("oncoly*" prox/distance<=5 "virus*") OR ctxt = "viro thera*" OR ctxt = "viral therap*") AND (cpc any "C12N2710/10332,C12N2710/16632,C12N2710/24132,C12N2720/12232,C12N2760/18132,C12N2760/20232,C12N2770/32332" OR cpc = "A61K35/761/same" OR cpc = "A61K35/763/same" OR cpc = "A61K35/765/same" OR cpc = "A61K35/766/same" OR cpc = "A61K35/768/same" OR ctxt any "talimogene,Oncovex,echo") AND (cpc = "A01K2267/0331" OR cpc = "A61P35/low" OR ctxt=("cancer" prox/distance<=3 "model?")).

After patents were obtained, they were grouped according to the patent family (patent applications related to the same invention and with the same priority date) and categorized according to their MoA. Through the analysis of the claims, the patents were classified according to the following: 1) patents of active pharmaceutical ingredients (molecule responsible for the therapeutic effect of the drug), 2) method of use patents (novel therapeutic applications discovered for existing drugs), 3) process patents (methods for manufacturing the drug), 4) formulation patents (formulating the drug), 5) dosage regimen patents (specific dosing schedules or treatment regimens). The following data were obtained from the patent databases: 1) applicant, 2) country of origin, and 3) scope (countries where each patent was claimed).

Inclusion criteria

• Family grouping: patents belonging to a patent family (patent applications related to the same invention and sharing the same priority date).

• Mechanism of action (MoA): patents categorized and associated with a specific therapeutic mechanism of action.

• Classification by claim type: patents falling into any of the following categories: 1) Active pharmaceutical ingredient patents (the molecule responsible for the drug's therapeutic effect); 2) Method-of-use patents (novel therapeutic applications discovered for existing drugs); 3) Process patents (methods for manufacturing the drug); 4) Formulation patents (drug formulation); and 5) dosing regimen patents (specific dosing schedules or treatment regimens).

• Metadata availability: patents from which the following essential data can be extracted from the databases: 1) applicant, 2) country of origin, and 3) scope (countries where each patent was claimed).

Exclusion criteria

• Non-family duplication: duplicate patent applications that do not belong to the same patent family (defined by invention and priority date).

• Lack of characterization: patents for which the mechanism of action (MoA) cannot be identified or categorized according to the study parameters.

• Claims outside the pharmaceutical scope: Patents that do not fit into any of the established classification categories (active ingredients, methods of use, processes, formulation, or dosing regimens).

• Incomplete information: Patents or database records lacking the minimum metadata required for analysis (applicant, country of origin, or geographic scope).

RESULTS

Immunotherapy

Anti-Ganglioside GD2 antibodies

Gangloside GD2 is a tumor-associated antigen that is highly expressed in tumor cells, including neuroblastoma, osteosarcoma, melanoma, glioma, retinoblastoma, and breast cancer, among others [17-21]. The key enzyme of ganglioside GD2 synthesis is the enzyme GD2 synthase, whose expression is higher in neuroblastoma, retinoblastoma, and breast cancer [22-24].

3F8 is anti-GD2 antibody described in the US9315585 patent family claim in 2010 (Table 1) [25]. This Memorial Sloan Kettering Cancer Center patent family consists of twenty patents granted in various countries, including three patents granted in the United States: US9315585 and its continuations in part US9688772, and US10287365 [26, 27]. Patent US9315585 was granted claims of the type of a humanized or chimeric antibody and the pharmaceutical composition having the same, a bispecific antibody that binds to GD2 and CD3, and the composition having the same. Patent US9688772 relates to the isolated DNA that encodes the monospecific andanti-GD2 and bispecific anti-GD2/CD3 antibodies, as well as the vector having the DNA, the host cell for the vector, and the method for producing said antibodies. Patent US10287365 describes the method of treating neuroblastoma, melanoma, sarcoma, brain tumor, or carcinoma. This family of patents describes a chimeric antibody (ch3F8-IgG1) and two humanized antibodies (hu3F8-IgG1 and hu3F8-IgG4) derived from the murine antibody 3F8. These antibodies inhibited tumor cell growth in vitro, as well as a highly efficient antibody-dependent cell-mediated cytotoxicity of LAN-1 cells in the presence of PBMC [28]. Naxitamab (hu3F8-IgG1) is approved, in combination with granulocyte-macrophage colony-stimulating factor, for the treatment of patients with relapsed or refractory high-risk neuroblastoma [15].

Patent US10167341, owned by Memorial Sloan Kettering Cancer Center and claimed in 12 countries, describes monospecific and bispecific antibodies, derived from hu38F, with D32H and E1K mutations in its light chain. The bispecific antibody binds GD2 and CD3. These antibodies showed a 20-fold greater potency in antibody-dependent cell-mediated cytotoxicity of LAN-1 cells in the presence of PBMC, compared to the hu3F8-IgG1 antibody [29].

Patent US2021198379, also owned by Memorial Sloan Kettering Cancer Center and claimed only in the United States and China, describes a method of treating neuroblastoma that includes the administration of the hu3F8-IgG1 antibody together with a hematopoietic growth factor (granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor), and one chemotherapeutic agent (irinotecan or temozolomide) [30].

Patent WO2024073525, owned by Memorial Sloan Kettering Cancer Center, describes a method of companion diagnostics of a cancer patient who received a GD2-based vaccine to detect anti-GD2 antibody levels [31].

Ch14.18 (dinutuximab) is a chimeric antibody that binds to GD2, protected by patents owned by Apeiron Biologics. Several patents protect treatment regimens for GD2 positive cancer, including neuroblastoma. These regimens include: i) continuous intravenous administration for 24 hours of the ch14.18/CHO antibody at a daily dose of 1-250 mg/m2 described in patent US9777068 [32]; ii) continuous intravenous administration for 24 hours of the ch14.18/CHO antibody at a daily dose of 1-250 mg/m2, but without concomitant administration of IL-2 (US9840566) [33]; iii) administration of the antibody in at least one treatment cycle at a dose of 10-20 mg/m2 continuously intravenously for 10-40 hours per day without administration of IL-2 within the same treatment cycle (US10294305) [34]; iv) administration of the antibody at a dose of 17.5 mg/m2 daily continuously intravenously for 10 or up to 20 hours for four consecutive days in a 24-32 day cycle, with at least 1 cycle and up to 5 cycles (US10995147) [35]; v) administration of the antibody continuously intravenously for 24 hours at a dose of 10 mg/m2 for 10 consecutive days with administration of IL-2 preceding or during administration of the antibody (US11447565) [36]; vi) administration of the antibody at a dose of 17.5 mg/m2/day over at least 10 hours per day and over 4 consecutive days in a 24-32 day cycle, wherein administration of the antibody in cycles 1, 3 or 5 is carried out between the fourth and seventh day with an administration of retinoic acid between the eleventh and twenty-fourth, and where administration in cycles 2 and 4 is carried out between the eighth and eleventh day, with an administration of retinoic acid between the fifteenth and twenty-eighth days (US11492412) [37]; (vii) administration of the antibody at a dose of 10 mg/m2/day for 10 consecutive days, or at a dose of 25 mg/m2 for 4 consecutive days, without concomitant administration of IL-2 (US11597775) [38]; viii) administration of the antibody, without concomitant administration of IL-2, at a dose of 25 mg/m2/day for 4 consecutive days for 1, 2, 3, 4, 5 or more cycles (US2020055953) [39]; ix) administration of the antibody at a daily dose of 1-25 mg/m2 intravenously continuously for 24 hours for at least 7 consecutive days, or at a dose of 50-150 mg/m2/cycle [US2023340148) [40]; and x) administration of the antibody at a dose of 60-75 mg/m2 over 4 consecutive days in a 24-32 hour cycle, for at least 1 cycle and up to 5 cycles (US2024158530) [41]

Hu14.18K322A is a humanized antibody from ch14.18 described in the patent family US7432357. This patent family, owned by Merck, consists of thirteen patents granted in various countries, including four United States patents: US7432357, US8835606, US9617349, and US10633452 [42-45]. Patent US7432347, claimed on January 22, 2004, gave rise to continuations in part of patents US8835606 and US9617349, as well as divisional patents US10017579 and US10633452. According to their priority dates, each of the thirteen patents has expired. Patents US7432347, US8835606 and US9617349 were granted an anti-GD2 antibody with antibody-dependent cytotoxic activity in cells expressing GD2 that may or may not present the Lys322Ala mutation in their heavy chain, while patent US10017579 was granted claims relating to methods for the treatment of cancer, including neuroblastoma. Patent US10633452 granted claims relating to the cell producing the anti-GD2 antibody. Phase 1 clinical trial NCT00743496, designed to determine the maximum-tolerated dose (MTD), safety profile, and pharmacokinetics in 38 pediatric patients with neuroblastoma, showed that this antibody had an MTD of 60 mg/m(2) per day for 4 days, where the most common grade 3 or 4 toxicities were pain (68%) and fever (21%) [46-48]. In phase 2 clinical trial (NCT01857934), treatment of neuroblastoma with this antibody prior to chemotherapy (cyclophosphamide/topotecan, irinotecan/temozolomide, or ifosfamide/carboplatin/etoposide) showed a median time to progression was 274 days, and 10 of 13 patients (77%) survived 1 year, no patients experienced progression, and two-year event-free survival (EFS) was 85.7% [49-52].

Another anti-GD2 antibody is described in patents US11866511 and US2021179732, owned by UMC Utrecht [53, 54] and claimed in 11 countries. This antibody is reformatted ch14.18 into IgA1 isotype, with mutations in CH1 domain (N45.2G and P124), CH2 domain (C92S, N120T, I121L and T122S) and a deletion in CH3 domain (P131-Y148). This antibody showed a similar or slightly better therapeutic effect compared with ch14.18, without inducing neuropathic pain [55]. Ektomun is a patent-pending bispecific antibody directed against GD2 and CD3 from Trion Research (US2024239916), whose GD2-binding arm is derived from ch14.18/CHO [56]. This antibody induced cytotoxicity of neuroblastoma cell lines, and in vitro activation of effector cells (CD4+ and CD8+ T cells, and NK cells) [57]. Patent WO2023168241, claimed by The Penn State Research Foundation, describes a method of treating neuroblastoma by administering dinutuximab and tipifarnib, through tipifarnib-mediated inhibition of tumor-derived sEV (small extracellular vesicles) secretion; however, this patent was not claimed in national phases in any country [58, 59].

Patent CN118416062, claimed by Tianjin Cancer Hospital, describes the combination of chidamide with an anti-GD2 monoclonal antibody for the treatment of neuroblastoma, based on the inhibition of tumor growth in a subcutaneous tumor model of C57 mice inoculated with SK-N-AS, SK-N-MC, SK-N-BE(2), SH-SY5Y, and SK-N-SH cells, without apparent toxic effects [60].

An antibody directed against Signal regulatory protein-alpha (SIRPα) is described in patent WO2022219076, which was claimed in Europe and the United States by Institut National de la Santé et de la Recherche Médicale, OGD2 Pharma, and Nantes Université. This patent claims the combination of two antibodies, anti-SIRPα and anti-OAcGD2 (O-acetylated disialoganglioside) for the treatment of cancer, including neuroblastoma, by restoring antibody-dependent cellular phagocytosis of macrophages treated with the antibody 8B6 (anti-OAcGD2), and increasing antitumor activity in an in vivo model (A/J mice inoculated with NXS2 cells) [61].

A bispecific antibody directed against GD2 and CD3, claimed and granted in 9 countries, including the United States, by Memorial Sloan-Kettering Cancer Center, is described in patent US9802995 [62]. This bispecific antibody arises from an anti-GD2 antibody 5F11-scFv and the anti-CD3 huOKT3-scFv (5F11-scBA), in which 5F11-scFv is replaced by hu3F8-scBA. This substitution resulted in a 5000-fold increase in potency in cytotoxic assays, as well as increased tumor growth suppression in a mouse model of neuroblastoma [63].

Anti-Glypican 2 Antibodies

Glypican 2 (GPC2) is an oncofetal protein considered as a tumor antigen in several types of cancer, including prostate cancer, colorectal cancer, and neuroblastoma [64-66]. GPC2 is a potential therapeutic target, including immunotherapy, for neuroblastoma [67]. US11066479, owned by the United States Department of Health and Human Services and claimed in Australia, Canada, Europe and the United States, describes six antibodies that bind to GPC2. Patent US11066479 was granted claims for antibodies that bind to GPC2, immunoconjugates, chimeric antigen receptor (CAR) including the monoclonal antibody, CAR T cells, antibody-drug conjugate, and method of inhibiting tumor growth or metastasis of a GPC2-positive cancer, among others. The patent describes six antibodies that bind to GPC2, of which three (LH1, LH4, and LH7) inhibited the growth of GPC2-positive neuroblastoma tumor lines (LAN1 and IMR5) with IC50 values of 0.5-1.2 nM, and one of them (LH7-PE38) significantly inhibited the growth of neuroblastoma xenograft in nude mice, with no apparent side effects or toxicity [68]. LH7 CAR T cells show potent activity in mice bearing human neuroblastomas [69].

US12012463, and its continuation-in-part US2024301084, owned by the United States Department of Health and Human Services and claimed in Australia, Canada, China, Europe and the United States, describes two humanized antibodies (CT3 and CT5) that bind to GPC2. US12012463 was granted claims in the type of monoclonal antibodies, chimeric antigen receptor, CAR-T cells, multispecific antibodies, nucleic acid molecules, vectors, pharmaceutical compositions, and methods of inhibiting tumor growth or metastasis of a GPC2-positive cancer. CAR-T cells expressing CT3 exhibited activity to kill GPC2 positive tumor cells (G10, IMR5, and F8) and regressed the neuroblastoma tumor growth in model mice [70]. CAR-T cells derived from these antibodies mediated, without evident toxicity, a potent activity in NOD-SCID xenograft model [71].

Antibodies against other targets

The family patents US8946388, US9216218, and US10596256, owned by Ganymed Pharmaceutical and granted in Australia, Brazil, Canada, China, Europe, Spain, Israel, South Korea, and Mexico, among others, describes antibodies that bind to the GT468 protein. These antibodies were able to recognize GT468 in western blot assays in the LA1-55n cell line. However, even when the antibody was not tested in an in vivo model of neuroblastoma, it was effective in reducing metastatic tumor load in the lungs of nude mice. Patent US10596256 was granted claims for the type of method of inhibiting tumor growth in GT468 positive patients [72-74].

Patent WO2023235767, claimed by the University of Colorado in Australia and Europe, describes an antibody against CD99, a marker overexpressed in various cases of neuroblastoma. The patent claims the anti-CD99 antibody, as well as a pharmaceutical composition containing it, and a method for the treatment of cancer, including neuroblastoma [75]. However, patent WO2023235767 does not present preclinical and/or clinical data that allow for an evaluation.

An antibody directed against anaplastic lymphoma kinase (ALK) is described in patent WO2023147292, claimed in Australia, China, Europe, Japan, Korea South, Mexico, and the United States, by Children’s Hospital of Philadelphia and the University of Pittsburgh. This patent claims the anti-ALK antibody, an antibody-drug conjugate, a CAR, a CAR-T cell, a bispecific T-cell engager, and a method for treating cancer, including neuroblastoma, based on the fact that the anti-ALK antibody, as well as the bispecific T cell engager and chimeric CAR, showed cytolytic activity in neuroblastoma’s cells. (SK-N-AS, IMR-32, and SH-SY5Y cells) [76].

Patent WO2023278391, claimed only in the United States by the University of Texas, describes an antibody that binds to Nel-like molecule, type 2 (NELL-2). This patent claims the antibody, as well as the pharmaceutical composition containing it, and the method for the treatment of cancer, including neuroblastoma, which includes the administration of said antibody. However, the patent does not present preclinical or clinical data that allow evaluating the potential of the antibody [77].

A Neuroblastoma-RAS (“NRAS”) binding polypeptide is described in patent WO2023192915, claimed by New York University. The affinity of the polypeptide for NRAS is described. However, the patent does not present in vitro, preclinical, and clinical data that would allow analyzing its potential [78].

Patent WO2021202885, claimed in Australia, Europe, Japan, and the United States by Baylor College of Medicine, describes a method of treating neuroblastoma that includes administering to the patient TNF-α inhibitors, including etanercept, infliximab, certolizumab, golimumab, adalimumab, thalidomide, lenalidomide, pomalidomide, a xanthine derivative, bupropion, and 5-HT2A agonist hallucinogen. Etanercept inhibited tumor growth in NSG mice inoculated with NB cells (SK-N-AS) [79], derived from the fact that the interaction of TNFR2 with TNF-α triggers tumorigenic inflammation [80].

Patent WO2018223140, claimed only at the Patent Cooperation Treaty level, by Prothena Biosciences, describes a method of treating neuroblastoma that includes the administration of antibodies directed against the melanoma cell adhesion molecule (MCAM). However, the patent does not present preclinical or clinical data that would allow analysis of the potential of such antibodies in the treatment of neuroblastoma [81].

A bispecific anti-AFP caTCR-1 and anti-GPC-3 antibody is described in patent WO2018200586, granted to Eureka Therapeutics in Australia, China, Israel, Japan, South Korea, and the United States, among others. Administration of the bispecific antibody inhibited tumor growth in a mouse model implanted with Hep G2 cells [82].

Patent CN105695418, claimed and granted only in China by Chengdu Zen Bioscience, describes an antibody directed against flap endonuclease 1 (FEN1), a protein highly expressed in stage IV neuroblastoma [83, 84]. However, the patent only describes the method of obtaining the monoclonal antibody, without providing preclinical or clinical data on its application in the treatment of neuroblastoma.

An antibody directed against ADAM10, as well as a method of treating various types of cancer, including neuroblastoma, are described in the patent family US10023653 and US11160873, claimed in the United States, Australia and Europe by Lackmann Beate, Monash University, Memorial Sloan-Kettering Cancer Centre, Ludwig Institute for Cancer Research Ltd, and Olivia Newton-John Cancer Research Institute. However, the patent only presents data on an in vitro model of breast cancer, so the potential of said antibody in the treatment of neuroblastoma cannot be analyzed [85].

Patents KR101630225 and KR101769320, claimed and granted only in South Korea by Sejong University and the National Cancer Centre, describes two antibodies directed against PGRMC1 (progesterone receptor membrane component 1), 4A68 and 108-B6, respectively. These antibodies can bind to cancer cells, including neuroblastoma cells (SH-SY5Y cells), which can be interpreted as a potential antibody for the diagnosis of neuroblastoma; however, no preclinical or clinical data are presented to analyze its potential in the treatment of neuroblastoma [86-88].

An anti-NLRR1 (neuronal leucine-rich repeat protein 1) antibody is described in patent WO2014175444, claimed only in Japan by Chiba-Prefecture. This antibody reduces tumor cell proliferation in vitro and tumor growth in a mouse model inoculated with SH-SY5Y cells [89, 90]. Unfortunately, the patent was rejected.

Cellular immunotherapy

Patent application US2025144214, also claimed by the United States Department of Health and Human Services and claimed in Australia, Canada, China, Europe, Japan, and the United States, describes and claims a CAR that binds to GPC2 and includes a CT3 domain, a CD28 hinge region, a CD28 transmembrane domain, an intracellular co-stimulatory domain, and an intracellular signaling domain [91]. A construct derived from patent US2025144214 with a single-chain variable fragment of CT3 integrated in a CAR with a CD28 hinge region, and 4-1BB co-stimulatory domain showed a longer survival in murine models of neuroblastoma mediated by CD8+ effector cells in the tumor microenvironment [92].

A CAR directed against the peptide QYNPIRTTF, derived from the PHOX2B protein in neuroblastoma, is described in patent WO2024178354, claimed by the Children's Hospital of Philadelphia and Myrio Therapeutics [93]. This patent claims a CAR, as well as a method for diagnosing and treating neuroblastoma that includes the use of the antibody; however, no results are presented on the efficacy of this CAR in preclinical or clinical models.

Patent CN114685683, claimed in China by Bosengji Medical Science & Tech Suzhou, describes CAR-T cells having a CAR construct based on an scFv fragment of an anti-GD2 antibody, an Fc fragment, an ICOS transmembrane region, human 4-1BB intracellular region sequence, and a CD3ζ sequence. These cells inhibited tumor growth, through an increase in T cell infiltration into the tumor microenvironment of tumor model mice subcutaneously inoculated with the neuroblastoma cell line SK-N-AS [94].

Another CAR is described in the patent family US10975162 and US11879016, owned by Autolus and granted in eighteen countries. This chimeric receptor has a GD2-binding domain, a hydrophobic alpha helical transmembrane domain, and a CD28-CD3Zeta endodomain. The results of a phase 1 clinical trial (NCT02761915) suggest that this CAR induces rapid regression of neuroblastoma with no observed neurotoxicity [95, 96].

Patent WO2024246965, claimed only in Italy by Ospedale Pediatrico Bambino Gesu, describes CAR effector cells for use in the treatment of cancer, including neuroblastoma. The patent claims CAR, as well as CAR cells, nucleic acid sequences and vectors that allow their production. CAR consists of a signal peptide, an anti-GD2 single chain antibody domain, a hinge, a trans membrane domain, at least two co-stimulatory signaling domains, and a CD3Zeta chain sequence [97]. In the clinical trial NCT03373097, a maximum tolerated dose of 10 × 106 CAR+ cells per kg, an overall response rate of 66%, a complete remission rate of 37%, 34% and 40% at 6 weeks, 3 months and 6 months, respectively, and a 5-year overall survival of 42.6% were obtained [98].

Peptide-Centric-CAR is described in patent US2024352130, claimed by The Children's Hospital of Philadelphia & Myrio Therapeutics, in United States, Australia, Canada, China, Europe, Japan, Israel, and South Korea. Patent US2024352130 claims CAR, CAR-T cell, pharmaceutical compositions, and methods of diagnosis and treatment of neuroblastoma, based on this CAR recognizing PHOX2B epitopes displayed by human leukocyte. CAR cells showed complete tumor cell killing in neuroblastoma cell lines (SKNAS, NBSD, and SKNFI) at 5:1 effector to target ratio [99, 100].

The patent family US2021220403 and US2024277764, claimed by Baylor College Medicine in five countries, including the United States, describes a method of treating neuroblastoma that includes administering to the patient engineered natural killer T-cells containing a CAR that targets GD2 and an expression construct that encodes IL-2, IL-4, IL-7, IL-15 [101]. The clinical trial NCT03294954 evaluated autologous NKTs co-expressing a GD2-specific CAR with IL-15, where one of twelve patients experienced grade 2 cytokine release syndrome (resolved by tocilizumab), and where maximum tolerated dose was not reached [102].

In patent CN114763381, claimed in China and Europe by Persongen Biotherapeutics Suzhou, a CAR having a scFv targeting B7-H3 is described. B7-H3 CAR-T cells inhibited tumor cell proliferation in NSG mice using the SK-N-AS neuroblastoma cell strain [103, 104].

Vaccines

Patent US7902328, owned by Abbott and granted in Australia, Canada, China, Europe, Spain, Japan, Mexico, South Africa, and United States, describes oligomers of the amyloid protein β (1-42) that have molecular weights between 15-48 kDa. These oligomers had neurotoxic activity in murine cortical neuron cultures. Patent US9176150, also granted in Australia, Canada, China, Europe, Spain, Japan, Mexico, and South Africa, describes antibodies that bind to oligomers of the amyloid protein β; however, CDRs of said antibodies are not described, nor are assays that allow us to suppose their effectiveness. Likewise, patent US10464976 was granted claims for the type of vaccine based on the oligomers described in US patent 7902328; however, patent US10464976 does not provide data on the effectiveness of the vaccine in any in vivo model [105-107].

An mRNA vaccine is described in patent CN110448689, claimed and withdrawn by Thera MAB Bioscience [108]. This vaccine independently has an epitope antigen gene sequence of three genes of tumor-associated antigens (KRas, survivin and CEA), which are associated with high-risk neuroblastoma [109-111]. However, despite claiming the application of this vaccine in neuroblastoma, no preclinical or clinical data about efficacy or safety are presented.

Checkpoints inhibitors

Patent WO2022219080, claimed in Europe and the United States by the Institut National de la Santé et de la Recherche Médicale, describes a pharmaceutical combination having retinoic acid, an anti-OAcGD2 antibody and an anti-PD-L1 antibody, which increases the infiltration of NK cells into neuroblastoma tumors. Patent WO2022219080 also describes an anti-OAcGD2/PD-L1 bispecific antibody that shows greater efficacy in an A/J mice model inoculated with NXS2 Cells, compared to anti-PD-L1 treatment [112, 113].

Meta-analysis

The analysis based on databases from the European Patent Office and the World Intellectual Property Organization encompasses a total of 33 key patent families focused on the development of immunotherapies for neuroblastoma. Patenting activity shows a marked polarization toward antibodies and cellular immunotherapy, leaving significant "white spaces" in other modalities. Antibodies: these account for nearly 70% of the analyzed intellectual property, with the tumor-associated antigen GD2 standing out as the most mature and commercially explored therapeutic target (10 patents). Cellular Immunotherapy: this ranks second with 7 patents (21.2%), primarily covering chimeric antigen receptors (CARs) targeting GD2 and PHOX2B. Under-represented Modalities: vaccines (6.1%) and immune checkpoint inhibitors (3.0%)—along with a complete absence of patents for immunomodulators and oncolytic viruses for neuroblastoma—highlight opportunities ("white spaces") for future pharmaceutical research and development. Patent innovation in neuroblastoma immunotherapy is heavily concentrated in developed economies, with the United States leading decisively by accounting for more than half of all registered patents (57.6%); the U.S. spearheads research across both the academic sector (institutions such as Memorial Sloan Kettering Cancer Center, the NIH, etc.) and the industrial sector. China accounts for 12.1% of applications, reflecting its growing activity in the field, followed by notable contributions from European countries such as Germany, France, Italy, and the Netherlands. An examination of the types of claims presented in the 33 patents reveals structural patterns regarding the state of technological maturity: i) virtually 100% of the analyzed patents include claims regarding the active principle (therapeutic molecule), methods of use, and production processes; ii) there is a relative scarcity of patents focused exclusively on new pharmaceutical formulations and optimized dosage regimens (with the exception of certain specific filings for anti-GD2 antibodies such as dinutuximab/ch14.18). This indicates that a large portion of the portfolio is in the early or intermediate stages of protecting the molecule and its general application.

DISCUSSION

Given the unmet medical need for neuroblastoma treatment, the aim of this study was to analyze the trend of patents for immunotherapy directed against different targets expressed in neuroblastoma. The patent trend analysis was performed, by setting up seven MoAs (antibodies, vaccines, checkpoint inhibitors, cellular immunotherapy, immunomodulators, oncolytic viruses), to find the patents related to each MoA. This strategy served to find the “white spaces” where neuroblastoma treatment has not been addressed.

According to the results obtained, it can be observed that tumor-associated antigen GD2 is the most often addressed target for antibody development. The development of antibodies against GD2 is in a mature phase, due to the multiple antibody options, including bispecific antibodies, as well as the number of applicants involved, the countries of origin of such patents, and the legal scope (countries where each patent was claimed). Specifically, the development of antibodies against GD2 has thirteen patents, nine of which originate in academia and four from pharmaceutical companies. This translates into commercial maturity, also supported by the fact that these patents have been protected in major economies (United States, Europe, Japan, and China).

Antibody development is not exclusive to GD2; other targets have also been addressed to a lesser extent, including GPC2, GT468, CD99, ALK, NELL-2, NRAS, MCAM, AFP caTCR-1, FEN1, ADAM10, PGRMC1, and NLRR1. However, with the exception of GPC2, the other targets only have one patent. The small number of patents on these targets represents a potential opportunity for future approaches to new neuroblastoma treatment strategies.

The second most patented MoA was cellular immunotherapy, with eight patents, including CARs against GD2 (four patents), followed by PHOX2B (two patents), GPC2, and B7-H3. This scarcity of targets for CAR and CAR T cell development is a space white for pharmaceutical approaches. Vaccines were the third MoA, with only two patents targeting oligomers of amyloid protein β, KRas, survivin, and CEA. Finally, the MoA "Checkpoints inhibitors" had only one patent, which targeted GD2 and PD-L1. The MoAs for immunomodulators and oncolytic viruses had no patents.

The analysis of the present study included an analysis of the claims of each patent, classifying them as follows: 1) patents of active pharmaceutical ingredients (molecule responsible for the therapeutic effect of the drug), 2) method of use patents (novel therapeutic applications discovered for existing drugs), 3) process patents (methods for manufacturing the drug), 4) formulation patents (formulating the drug), 5) dosage regimen patents (specific dosing schedules or treatment regimens). With few exceptions, all patents included claims for active pharmaceutical ingredients, method of use patents, and process patents. The latter is that immunotherapeutic development against neuroblastoma is at an early stage, lacking patents that involve new formulation and dosage regimen.

From these results except for the MoA for antibodies, the remaining MoAs have not been adequately addressed, so addressing them is an opportunity for the development of new modalities for the treatment of neuroblastoma. In this way, public policy developers, as well as those responsible for research and development at pharmaceutical companies, will be able to decide, considering this study, the opportunities for new pharmaceutical developments against neuroblastoma.

CONCLUSION

Therapeutic dominance and technological maturity

The GD2 antigen has clearly consolidated its position as the cornerstone of the intellectual property landscape, reflecting a level of technological maturity focused primarily on monoclonal antibodies and CAR-T cell therapies. The high concentration of claims regarding the active ingredient and production processes suggests that the field is at a stage where protecting the "core molecule" and its mechanism of action takes precedence over optimizing second-generation formulations.

Identification of opportunities (white spaces)

A significant technological gap has been identified in emerging therapeutic modalities. The underrepresentation of vaccines and immune checkpoint inhibitors—coupled with a complete absence of patents targeting oncolytic viruses and immunomodulators—presents a strategic window of opportunity for innovation. These unexplored niches could prove crucial in overcoming therapeutic resistance in patients with high-risk or refractory neuroblastoma.

Geographic concentration and R&D dynamics

The concentration of intellectual property within developed economies—led by the United States—highlights a systemic reliance on high-profile academic and industrial hubs. However, the rise in patent applications from China and active European participation point to a global diversification of research efforts that could, in the medium term, decentralizes the development of future immunotherapies.

Implications for pharmaceutical development

The current landscape suggests that, while the efficacy of anti-GD2 antibodies is both clinically and commercially validated, the future of neuroblastoma treatment will depend on the industry's ability to shift from protecting single molecules to protecting combination regimens, novel delivery platforms, and multimodal strategies capable of overcoming the immunosuppressive tumor microenvironment.

HIGHLIGHTS

• Antibody development is the mechanism of action with the greatest number of patents

• The second most patented mechanism of action was cellular immunotherapy

• Tumor-associated antigen GD2 is the most often addressed target for antibody development

• United States is the leading country in patent applications for immunotherapies for neuroblastoma.

FUNDING

This paper was not funded.

DECLARATION OF INTEREST

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

REFERENCES

[1]. Nong J, Su Ch, Li Ch, Wang C, Li W, Li Y, et al. Global, regional, and national epidemiology of childhood neuroblastoma (1990–2021): a statistical analysis of incidence, mortality, and DALYs. eClinicalMedicine, 2024; 79: 102964. Available from: https://europepmc.org/article/MED/39720601

[2]. Katta SS, Nagati V, Paturi AS, Murakonda SP, Pandey MK, Gupta SC, et al. Neuroblastoma: Emerging trends in pathogenesis, diagnosis, and therapeutic targets. Journal of Controlled Release, 2023; 357: 444-59. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0168365923002511

[3]. Vo KT, Matthay KK, Neuhaus J, London WB, Hero B, Ambros PF et al. Clinical, biologic, and prognostic differences on the basis of primary tumor site in neuroblastoma: a report from the international neuroblastoma risk group project. J Clin Oncol, 2014; 32: 3169-76. Available from: https://ascopubs.org/doi/10.1200/JCO.2014.56.1621

[4]. Epp S, Chuah SM, Halasz M. Epigenetic Dysregulation in MYCN-Amplified Neuroblastoma. Int J Mol Sci. 2023; 24(23):17085. Available from: https://www.mdpi.com/1422-0067/24/23/17085

[5]. Trigg RM, Turner SD. ALK in Neuroblastoma: Biological and Therapeutic Implications. Cancers (Basel). 2018; 10(4): 113. Available from: https://www.mdpi.com/2072-6694/10/4/113

[6]. Higashi M, Sakai K, Fumino S, Aoi S, Furukawa T, Tajiri T. The roles played by the MYCN, Trk, and ALK genes in neuroblastoma and neural development. Surg Today. 2019; 49(9): 721-727. Available from: https://link.springer.com/article/10.1007/s00595-019-01790-0

[7]. Chen D, Schnepp RW. RNA Binding Protein LIN28B: a prime time player shaping neuroblastoma aggression and metastasis. Oncoscience. 2020; 7(7-8): 52-56. Available from: https://www.oncoscience.us/article/512/text

[8]. Trochet D, Bourdeaut F, Janoueix-Lerosey I, Deville A, de Pontual L, Schleiermacher G, et al. Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. The American Journal of Human Genetics. 2004; 74(4): 761-764. Available from: https://www.cell.com/ajhg/fulltext/S0002-9297(07)61902-8

[9]. Duan XF, Zhao Q. TERT-mediated and ATRX-mediated Telomere Maintenance and Neuroblastoma. J Pediatr Hematol Oncol. 2018; 40(1): 1-6. Available from: https://www.ovid.com/jnls/jpho-online/abstract/10.1097/mph.0000000000000840~tert-mediated-and-atrx-mediated-telomere-maintenance-and

[10]. Kerkar AN, Chinnam D, Verma A, Peters NJ, Kakkar N, Trehan A, et al. MYCN amplification, TERT rearrangements and ATRX mutations in neuroblastoma: clinicopathological correlates- an Indian perspective. Virchows Arch. 2023; 483(4): 477-486. Available from: https://link.springer.com/article/10.1007/s00428-023-03604-8

[11]. Nevakar Injectables announces FDA approval of cyclophosphamide RTD solution. News release. Nevakar Injectables. July 3, 2023. https://nevakarpharm.com/nevakar-injectables-announces-fda-approval-of-cyclophosphamide-rtd-solution/

[12]. Markham A. Naxitamab: First Approval. Drugs. 2021; 81(2): 291-296. Available from: https://link.springer.com/article/10.1007/s40265-021-01467-4

[13]. Dhillon S. Dinutuximab: first global approval. Drugs. 2015; 75(8): 923-7. Available from: https://link.springer.com/article/10.1007/s40265-015-0399-5

[14]. Duke ES, Bradford D, Sinha AK, Mishra-Kalyani PS, Lerro CC, Rivera D, et al. US Food and Drug Administration Approval Summary: Eflornithine for High-Risk Neuroblastoma After Prior Multiagent, Multimodality Therapy. J Clin Oncol. 2024; 42(25): 3047-3057. Available from: https://ascopubs.org/doi/10.1200/JCO.24.00546

[15]. Danyelza could make a difference. United States; YmAbs Therapeutics; August 2024. Available from: https://danyelza.com

[16]. Unituxin. The first antibody therapy FDA-approved for children with high-risk neuroblastoma. United States; United Therapeutics oncology; 2025. Available from: https://www.unituxin.com

[17]. Wei X, Li S, Wang Y. Expression of GD2 and GD3 in peripheral neuroblastic tumors. Indian J Pathol Microbiol. 2025; 68(1): 17-22. Available from: https://www.ovid.com/jnls/ijpm/fulltext/10.4103/ijpm.ijpm_618_23~expression-of-gd2-and-gd3-in-peripheral-neuroblastic-tumors

[18]. Dobrenkov K, Ostrovnaya I, Gu J, Cheung IY, Cheung N-KV. Oncotargets GD2 and GD3 are highly expressed in sarcomas of children, adolescents, and young adults. Pediatr Blood Cancer. 2016; 63(10): 1780-5. Available from: https://onlinelibrary.wiley.com/doi/10.1002/pbc.26097

[19]. Nazha B, Inal C, Owonikoko TK. Disialoganglioside GD2 Expression in Solid Tumors and Role as a Target for Cancer Therapy. Front Oncol. 2020; 10: 1000. Available from: https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.01000/full

[20]. Higashi C, Saito K, Kozuka Y, Yuasa H, Nakamura K, Ishitobi M et al. Ganglioside GD2 Expression Is Associated With Unfavorable Prognosis in Early Triple-negative Breast Cancer. Anticancer Res. 2023; 43(9): 4045-4053. Available from: https://ar.iiarjournals.org/content/43/9/4045.long

[21]. Mansoori M, Mirzaei A, Abdi Rad I, Mahmodloud R, Mansouri F, Saeednejad Zanjani L, et al. Upregulation of Ganglioside GD2 Synthase (GD2S), as a New Putative Cancer Stem Cell Marker in Breast Carcinomas. Med J Islam Repub Iran. 2021; 35: 148. Available from: https://mjiri.iums.ac.ir/article-1-5637-en.html

[22]. Lo Piccolo MS, Cheung NK, Cheung IY. GD2 synthase: a new molecular marker for detecting neuroblastoma. Cancer. 2001; 92(4): 924-31. Available from: https://europepmc.org/article/MED/11550167

[23]. Sethu Nagarajan R, Kim U, Shanthi R, Vanniarajan A. Investigation of GD2 synthase as a potential marker for retinoblastoma poor prognosis. Mol Biol Rep. 2025; 52(1): 372. Available from: Available from: https://link.springer.com/article/10.1007/s11033-025-10475-6

[24]. Machy P, Mortier E, Birklé S. Biology of GD2 ganglioside: implications for cancer immunotherapy. Front Pharmacol. 2023; 14-2023; 14: 1249929. Available from: https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1249929/full

[25]. Cheung N-K, Ahmed M, Xu M. Memorial Sloan Kettering Cancer Center, United States. Anti-GD2 antibodies. United States patent US9315585. 2016 Apr 19. Available from: https://patents.justia.com/patent/9315585

[26]. Cheung N-K, Ahmed M, Xu M. Memorial Sloan Kettering Cancer Center, United States. Anti-GD2 antibodies. United States patent US9688772. 2017 Jun 27. Available from: https://patents.justia.com/patent/9688772

[27]. Cheung N-K, Ahmed M, Xu M. Memorial Sloan Kettering Cancer Center, United States. Anti-GD2 antibodies. United States patent US10287365. 2019 May 14. Available from: https://pubchem.ncbi.nlm.nih.gov/patent/US-10287365-B2

[28]. Cheung NK, Guo H, Hu J, Tassev DV, Cheung IY. Humanizing murine IgG3 anti-GD2 antibody m3F8 substantially improves antibody-dependent cell-mediated cytotoxicity while retaining targeting in vivo. Oncoimmunology. 2012; 1(4): 477-486. Available from: https://www.tandfonline.com/doi/full/10.4161/onci.19864

[29]. Cheung N-K, Ahmed M, Zhao O. Memorial Sloan Kettering Cancer Center, United States. High affinity anti-GD2 antibodies. United States patent US10167341. 2016 feb 04. Available from: https://patentimages.storage.googleapis.com/f7/4f/3a/c38068efb42667/US10167341.pdf

[30]. Modak Sh. Memorial Sloan Kettering Cancer Center, United States. Methods for treating neuroblastoma with combination therapy. United States patent US2021198379. 2021 Jul 01. Available from: https://worldwide.espacenet.com/patent/search/family/069591261/publication/US2021198379A1?q=US2021198379

[31]. Cheung N-K, Cheung I. Memorial Sloan Kettering Cancer Center, United States. Prognostic and therapeutic methods including Anti-GD2 IGA. Worldwide patent WO2024073525. 2024 Apr 04. Available from: https://worldwide.espacenet.com/patent/search/family/090479263/publication/WO2024073525A2?q=WO2024073525

[32]. Loibner Hm Schuster M, Janzek-Hawlat E. Apeiron Biologics, Austria. Method for treating a GD2 positive cancer. United States patent US9777068. 2017 Oct 03. Available from: https://worldwide.espacenet.com/patent/search/family/046639481/publication/US9777068B2?q=US9777068

[33]. Loibner H, Mutschlechner O, Ladenstein R, Klier I. Apeiron Biologics, Austria. Preparations and methods for treating a GD2 positive cancer. United States patent US9840566. 2017 Dec 12. Available from: https://worldwide.espacenet.com/patent/search/family/057129615/publication/US9840566B2?q=US9840566

[34]. Loibner H, Mutschlechner O, Ladenstein R, Klier I. Apeiron Biologics, Austria. Method for treating a GD2 positive cancer. United States patent US10294305. 2019 May 21. Available from: https://worldwide.espacenet.com/patent/search/family/046317406/publication/US10294305B2?q=US10294305B2

[35]. Loibner H, Mutschlechner O, Ladenstein R, Klier I. Apeiron Biologics, Austria. Preparations and methods for treating a GD2 positive cancer. United States patent US10995147. 2021 May 04. Available from: https://worldwide.espacenet.com/patent/search/family/053179006/publication/US10995147B2?q=US10995147

[36]. Loibner H, Schuster M, Janzek-Hawlat E, Wiederkum S, Peball B, Stranner S, et al. Apeiron Biologics, Austria. Method for treating a GD2 positive cancer. United States patent US11447565. 2022 Sep 20. Available from: https://worldwide.espacenet.com/patent/search/family/046317406/publication/US11447565B2?q=US11447565

[37]. Loibner H, Mutschlechner O, Ladenstein R, Klier I. Apeiron Biologics, Austria. Preparations and methods for treating a GD2 positive cancer. United States patent US11492412. 2022 Nov 08. Available from: https://worldwide.espacenet.com/patent/search/family/053179006/publication/US11492412B2?q=US11492412

[38]. Loibner H, Mutschlechner O, Ladenstein R, Klier I. Apeiron Biologics, Austria. Preparations and methods for treating a GD2 positive cancer. United States patent US11597775. 2023 Mar 07. Available from: https://worldwide.espacenet.com/patent/search/family/057129615/publication/US11597775B2?q=US11597775

[39]. Loibner H, Mutschlechner O, Ladenstein R, Klier I. Apeiron Biologics, Austria. Method for Treating a GD2 Positive Cancer. United States patent US2020055953. 2020 Feb 20. Available from: https://worldwide.espacenet.com/patent/search/family/046317406/publication/US2020055953A1?q=US2020055953A1

[40]. Loibner H, Schuster M, Janzek-Hawlat E, Wiederkum S, Peball B, Stranner S, et al. Apeiron Biologics, Austria. Method for Treating a GD2 Positive Cancer. United States patent US2023340148. 2023 Oct 26. Available from: https://worldwide.espacenet.com/patent/search/family/046317406/publication/US2023340148A1?q=US2023340148

[41]. Loibner H, Mutschlechner O, Ladenstein R, Klier I. Apeiron Biologics, Austria. Preparations and methods for treating a GD2 positive cancer. United States patent US2024158530. 2024 May 16. Available from: https://worldwide.espacenet.com/patent/search/family/053179006/publication/US20240158530A1?q=US2024158530

[42]. Gillies SD. Merck, Germany. Anti-cancer antibodies with reduced complement fixation. United States patent US7432357. 2008 Oct 07. Available from: https://worldwide.espacenet.com/patent/search/family/034807180/publication/US7432357B2?q=US7432357

[43]. Gillies SD. Merck, Germany. Anti-cancer antibodies with reduced complement fixation. United States patent US8835606. 2014 Sep 16. Available from: https://worldwide.espacenet.com/patent/search/family/034807180/publication/US8835606B2?q=US8835606B2

[44]. Gillies SD. Merck, Germany. Anti-cancer antibodies with reduced complement fixation. United States patent US9617349. 2017 Apr 11. Available from: https://worldwide.espacenet.com/patent/search/family/034807180/publication/US9617349B2?q=US9617349B2

[45]. Gillies SD. Merck, Germany. Anti-cancer antibodies with reduced complement fixation. United States patent US10633452. 2020 Apr 28. Available from: https://worldwide.espacenet.com/patent/search/family/034807180/publication/US10633452B2?q=US10633452

[46]. Navid F, Sondel PM, Barfield R, Shulkin BL, Kaufman RA, Allay JA, et al. Phase I trial of a novel anti-GD2 monoclonal antibody, Hu14.18K322A, designed to decrease toxicity in children with refractory or recurrent neuroblastoma. J Clin Oncol. 2014; 32(14): 1445-52. Available from: https://ascopubs.org/doi/10.1200/JCO.2013.50.4423

[47]. Bishop MW, Hutson PR, Hank JA, Sondel PM, Furman WL, Meagher MM, et al. A Phase 1 and pharmacokinetic study evaluating daily or weekly schedules of the humanized anti-GD2 antibody hu14.18K322A in recurrent/refractory solid tumors. MAbs. 2020; 12(1): 1773751. Available from: https://www.tandfonline.com/doi/full/10.1080/19420862.2020.1773751

[48]. Anghelescu DL, Goldberg JL, Faughnan LG, Wu J, Mao S, Furman W, et al. Comparison of pain outcomes between two anti-GD2 antibodies in patients with neuroblastoma. Pediatr Blood Cancer. 2015; 62(2): 224-228. Available from: https://onlinelibrary.wiley.com/doi/10.1002/pbc.25280

[49]. Federico SM, McCarville MB, Shulkin BL, Sondel PM, Hank JA, Hutson P, et al. Pilot Trial of Humanized Anti-GD2 Monoclonal Antibody (hu14.18K322A) with Chemotherapy and Natural Killer Cells in Children with Recurrent/Refractory Neuroblastoma. Clin Cancer Res. 2017; 23(21): 6441-6449. Available from: https://aacrjournals.org/clincancerres/article/23/21/6441/260123/A-Pilot-Trial-of-Humanized-Anti-GD2-Monoclonal

[50]. Furman WL, Federico SM, McCarville MB, Shulkin BL, Davidoff AM, Krasin MJ, et al. A Phase II Trial of Hu14.18K322A in Combination with Induction Chemotherapy in Children with Newly Diagnosed High-Risk Neuroblastoma. Clin Cancer Res. 2019 Nov 1;25(21):6320-6328. Available from: https://aacrjournals.org/clincancerres/article/25/21/6320/82291/A-Phase-II-Trial-of-Hu14-18K322A-in-Combination

[51]. Furman WL, McCarville B, Shulkin BL, Davidoff A, Krasin M, Hsu C-W, et al. Improved outcome in children with newly diagnosed high-risk neuroblastoma treated with chemoimmunotherapy: Updated Results of a Phase II Study Using hu14.18K322A. J Clin Oncol. 2022; 40(4): 335-344. Available from: https://ascopubs.org/doi/10.1200/JCO.21.01375

[52]. Thomas M, Nguyen TH, Drnevich J, D’Souza AM, de Alarcon PA, Gnanamony M. Hu14.18K.322A Causes Direct Cell Cytotoxicity and Synergizes with Induction Chemotherapy in High-Risk Neuroblastoma. Cancers (Basel). 2024; 16(11): 2064. Available from: https://www.mdpi.com/2072-6694/16/11/2064

[53]. Leusen JHW, Evers JGM. UMC Utrecht Holding, Netherlands. Anti-GD2 antibody for the treatment of neuroblastoma. United States patent US11866511. 2020 Sep 10. Available from: https://worldwide.espacenet.com/patent/search/family/059955406/publication/US11866511B2?q=US11866511

[54]. Leusen JHW, Evers JGM. UMC Utrecht Holding, Netherlands. Anti-GD2 antibody for the treatment of neuroblastoma. United States patent US2021179732. 2021 Jun 17. Available from: https://worldwide.espacenet.com/patent/search/family/059955406/publication/US2021179732A1?q=US2021179732

[55]. Stip MC, Evers M, Nederend M, Chan C, Reiding KR, Damen MJ, et al. IgA antibody immunotherapy targeting GD2 is effective in preclinical neuroblastoma models. J Immunother Cancer. 2023; 11(7): e006948. Available from: https://jitc.bmj.com/content/11/7/e006948

[56]. Lindhofer H, Ruf P. Trion Research, Germany. Multispecific antibodies binding to tumor-associated antigens causing no or reduced nerve pain in the treatment of cancer. United States US2024239916. 2024 Jul 18. Available from: https://worldwide.espacenet.com/patent/search/family/082656531/publication/US20240239916A1?q=US2024239916

[57]. Zirngibl F, Ivasko SM, Grunewald L, Klaus A, Schwiebert S, Ruf P, et al. GD2-directed bispecific trifunctional antibody outperforms dinutuximab beta in a murine model for aggressive metastasized neuroblastoma. J Immunother Cancer. 2021; 9(7): e002923. Available from: https://jitc.bmj.com/content/9/7/e002923

[58]. Wang H-G, Liu X, Wills CA. The Penn State Research Foundation, United States. Combination immunotherapy compositions and methods of use thereof. Worldwide patent WO2023168241. 2023 Sep 07. Available from: https://worldwide.espacenet.com/patent/search/family/087884329/publication/WO2023168241A1?q=WO2023168241

[59]. Liu X, Wills CA, Chen L, Zhang j, Zhao Y, Zhou M, et al. Small extracellular vesicles induce resistance to anti-GD2 immunotherapy unveiling tipifarnib as an adjunct to neuroblastoma immunotherapy. J Immunother Cancer. 2022; 10(4): e004399. Available from: https://jitc.bmj.com/content/10/4/e004399

[60]. Jin Y, Zhao Q, Liu J, Gong B, Chen C, Li Z, et al. Tianjin Cancer Hospital, China. Application of chidamide combined with GD2 monoclonal antibody in neuroblastoma. China patent CN118416062. 2024 Aug 02. Available from: https://worldwide.espacenet.com/patent/search/family/092334114/publication/CN118416062A?q=CN118416062

[61]. Birkle S, Vermeulen S, Fougeray S, Bahr M. Institut National de la Santé et de la Recherche Médicale, OGD2 Pharma, and Nantes Université, France. New method to improve the anti-tumoral activity of macrophages. Worldwide patent WO2022219076. 2022 Oct 20. Available from: https://worldwide.espacenet.com/patent/search/family/076059832/publication/WO2022219076A1?q=WO2022219076

[62]. Ahmed M, Cheung N-K V. Memorial Sloan-Kettering Cancer Center, United States. Antibody multimerization technologies. United States patent US9802995. 2017 Oct 31. Available from: https://worldwide.espacenet.com/patent/search/family/051538343/publication/US9802995B2?q=US9802995B2

[63]. Cheng M, Santich BH, Xu H, Ahmed M, Huse M, Cheung NK. Successful engineering of a highly potent single-chain variable-fragment (scFv) bispecific antibody to target disialoganglioside (GD2) positive tumors. Oncoimmunology. 2016; 5(6): e1168557. Available from: https://www.tandfonline.com/doi/full/10.1080/2162402X.2016.1168557

[64]. Chen S, Liao J, Li J, Wang S. GPC2 promotes prostate cancer progression via MDK-mediated activation of PI3K/AKT signaling pathway. Funct Integr Genomics. 2024; 24(4): 127. Available from: https://link.springer.com/article/10.1007/s10142-024-01406-y

[65]. Wang R, Lin X. GPC2 as a diagnostic and prognostic marker regulated progression of colorectal cancer. Arab J Gastroenterol. 2024; 25(1): 51-57. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1687197923001053

[66]. Li N, Spetz MR, Li D, Ho M. Advances in immunotherapeutic targets for childhood cancers: A focus on glypican-2 and B7-H3. Pharmacol Ther. 2021; 223: 107892. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0163725821000942?via%3Dihub

[67]. DuBois SG, Moreno L, Anderson J, Asgharzadeh S, Bagatell R, Beck-Popovic M, et al. Accelerating drug development for neuroblastoma: consensus statement from the third neuroblastoma drug development strategy forum. Pediatr Blood Cancer. 2025; 72: e31831. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/pbc.31831

[68]. Ho M, Li N, Dimitrov DS. US HEALTH. Monoclonal antibodies targeting glypican-2 (GPC2) and use thereof. United States. United States US11066479. Available from: https://worldwide.espacenet.com/patent/search/family/059501607/publication/US11066479B2?q=US11066479

[69]. Li N, Fu H, Hewitt SM, Dimitrov DS, Ho M. Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma. Proc Natl Acad Sci USA. 2017; 114(32): E6623-E6631. Available from: https://www.pnas.org/doi/full/10.1073/pnas.1706055114

[70]. Ho M, Li N, Fleming BD. High affinity monoclonal antibodies targeting glypican-2 and uses thereof. United States patent US12012463. 2024 Jun 18. Available from: https://worldwide.espacenet.com/patent/search/family/067777401/publication/US12012463B2?q=US12012463

[71]. Heitzeneder S, Bosse KR, Zhu Z, Zhelev D, Majzner RG, Radosevich MT, et al. GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity. Cancer Cell. 2022; 40(1): 53-69.e9. Available from: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00658-9

[72]. Sahin U, Tureci O, Koslowski M, Mitnacht-Kraus R. Ganymed Pharmaceuticals, Germany. Monoclonal antibodies for treatment of cancer. United States patent US8946388. 2015 Feb 03. Available from: https://worldwide.espacenet.com/patent/search/family/040589589/publication/US8946388B2?q=US8946388

[73]. Sahin U, Tureci O, Koslowski M, Mitnacht-Kraus R. Ganymed Pharmaceuticals, Germany. Monoclonal antibodies for treatment of cancerUnited States patent US9216218. 2015 Dec 22. Available from: https://worldwide.espacenet.com/patent/search/family/042244345/publication/US9216218B2?q=US9216218

[74]. Sahin U, Tureci O, Koslowski M, Mitnacht-Kraus R. Ganymed Pharmaceuticals, Germany. Monoclonal anti-GT 468 antibodies for treatment of cancer. United States patent US10596256. 2020 Mar 24. Available from: https://worldwide.espacenet.com/patent/search/family/042244345/publication/US10596256B2?q=US10596256

[75]. Venkataraman S, Vibhakar R. University of Colorado, United States. Development of a novel therapeutic CD99 antibody to treat aggressive solid tumor in children. Worldwide patent WO2023235767. 2023 Dec 07. Available from: https://worldwide.espacenet.com/patent/search/family/089025665/publication/WO2023235767A2?q=WO2023235767

[76]. Chen C, Sun Z, Wang Z, Shin S, Berrios A, Mellors JW, et al. Identification of a Fully Human Antibody VH Domain Targeting Anaplastic Lymphoma Kinase (ALK) with Applications in ALK-Positive Solid Tumor Immunotherapy. Antibodies (Basel). 2024; 13(2): 39. Available from: https://www.mdpi.com/2073-4468/13/2/39

[77]. Shiio Y. University of Texas, United States. Antibodies specific to NELL2 and methods of use. Worldwide patent WO2023278391. 2023 Jan 05. Available from: https://worldwide.espacenet.com/patent/search/family/084692045/publication/WO2023278391A1?q=WO2023278391

[78]. Koide S, Koide A. New York University, United States, Monobodies selective to NRAS. Worldwide patent WO2023192915. 2023 Oct 05. Available from: https://worldwide.espacenet.com/patent/search/family/088203464/publication/WO2023192915A1?q=WO2023192915

[79]. Metelitsa LS, Tomolonis J. Baylor College of Medicine, United States. TNFα Signaling triggers tumor-promoting inflammation that can be targeted to therapy. Worldwide patent WO2021202885. 2021 Oct 07. Available from: https://worldwide.espacenet.com/patent/search/family/077930416/publication/WO2021202885A1?q=WO2021202885

[80]. Tomolonis JA, Xu X, Dholakia KH, Zhang C, Guo L, Courtney AN, et al. Interaction between tumor cell TNFR2 and monocyte membrane-bound TNF-α triggers tumorigenic inflammation in neuroblastoma. J Immunother Cancer. 2023; 11(3): e005478. Available from: https://jitc.bmj.com/content/11/3/e005478

[81]. Flanagan K, Yednock T. Prothena Biosciences, United States. Worldwide patent WO2018223140. 2018 Dec 06. Available from: https://worldwide.espacenet.com/patent/search/family/064455589/publication/WO2018223140A1?q=WO2018223140

[82]. Zhang P, Xu Y, Morales J, Nakano Y, Liu H, Xiang J, et al. Eureka Therapeutics, United States. Constructs specifically recongnizing glypican 3 and uses thereof. United States patent US2021107992. 2021 Apr 15. Available from: https://worldwide.espacenet.com/patent/search/family/063920003/publication/US2021107992A1?q=US2021107992

[83]. Nie Z, Qiu J, Zhang T, Jiang H. Chengdu Zen Bioscience, China. Monoclonal antibody of structure specific nuclease FEN1 and application. China patent CN105695418. 2016 Jun 22. Available from: https://worldwide.espacenet.com/patent/search/family/056221823/publication/CN105695418A?q=CN105695418

[84]. Hu Y, Luo Y, Xie T, Chen Y, Zhao J, Ji W, et al. Correlation of senescence-related gene FEN1 on neuroblastoma progression and cisplatin chemotherapy sensitivity. Oncol Res. 2025; 33(7): 1695-1708. Available from: https://www.techscience.com/or/v33n7/62627

[85]. Lackmann M, Janes PW, Mudiyanselage LA, Scott AM, Nikolov DB, Saha N. Lackmann Beate, Monash University, Memorial Sloan-Kettering Cancer Centre, Ludwig Institute for Cancer Research, & Olivia Newton-John Cancer Research Institute, United States. Anti-metalloprotease antibody for diagnosis and treatment of cancers. United States patent US2019105405. 2019 Apr 11. Available from: https://worldwide.espacenet.com/patent/search/family/065992832/publication/US2019105405A1?q=US2019105405

[86]. Ryu Ch-J, Kim Y, Choi HS, Hwang HJ, Chang HJ. Sejong University & National Cancer Centre, South Korea. Monoclonal antibody 4A68 specific to PGRMC1 expressed on the surface of human embryonic stem cells and various cancer cells. South Korea patent KR20150062507. 2015 Jun 08. Available from: https://worldwide.espacenet.com/patent/search/family/053500510/publication/KR20150062507A?q=KR20150062507

[87]. Ryu Ch-J, Kim Y, Choi HS, Jang HJ. Sejong University & National Cancer Centre, South Korea. Monoclonal antibody 108-B6 specific to PGRMC1 expressed on the surface of human embryonic stem cells and various cancer cells. South Korea patent KR101769320. 2017 Aug 18. https://worldwide.espacenet.com/patent/search/family/053500509/publication/KR101769320B1?q=KR101769320

[88]. Kim JY, Kim SY, Choi HS, An S, Ryu CJ. Epitope mapping of anti-PGRMC1 antibodies reveals the non-conventional membrane topology of PGRMC1 on the cell surface. Sci Rep. 2019; 9(1): 653. Available from: https://www.nature.com/articles/s41598-018-37441-6

[89]. Nakagawara A, Takatori A. Chiba Prefecture, Japan. Anti-NLRR1 antibody. WO2014175444. 2014 Oct 30. Available from: https://worldwide.espacenet.com/patent/search/family/051792004/publication/WO2014175444A1?q=WO2014175444

[90]. Takatori A, Hossain MS, Ogura A, Akter J, Nakamura Y, Nakagawara A. NLRR1 Is a Potential Therapeutic Target in Neuroblastoma and MYCN-Driven Malignant Cancers. Front Oncol. 2021; 11: 669667. Available from: https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.669667/full

[91]. Ho M, Thiele CJ, Li N, Nguyen R, Kaplan RN. US HEALTH, United States. CD28 hinge and transmembrane containing chimeric antigen receptors targeting GPC2 and use thereof. United States patent US2025144214. 2025 May 08. Available from: https://worldwide.espacenet.com/patent/search/family/085569792/publication/US20250144214A1?q=US2025144214

[92]. Sun M, Cao Y, Okada R, Reyes-González JM, Stack HG, Qin H, et al. Preclinical optimization of a GPC2-targeting CAR T-cell therapy for neuroblastoma. J Immunother Cancer. 2023; 11(1): e005881. Available from: https://jitc.bmj.com/content/11/1/e005881

[93]. Maris J, Sgourakis N, Beasley M, Kiefel B, Gracey F, Gupta S, et al. The Children’s Hospital of Philadelphia & Myrio Therapeutics, United States. Improved PHOX2B PC-CAR generation based on structure and saturation mutagenesis. Worldwide patent WO2024178354. 2024 Aug 29. Available from: https://worldwide.espacenet.com/patent/search/family/092501823/publication/WO2024178354A2?q=WO2024178354

[94]. Yang L, You F, Ji C. Bosenji Medical science & Suzhou, China. GD2-targeted CAR-T cell as well as preparation and application thereof. China patent CN114685683. 2022 Jul 01. Available from: https://worldwide.espacenet.com/patent/search/family/082134825/publication/CN114685683A?q=CN114685683

[95]. Pulé M, Anderson J, Thomas S. Autolus, Great Britain. Chimeric antigen receptor. United States patent US11879016. 2024 Jan 2023. Available from: https://worldwide.espacenet.com/patent/search/family/050554626/publication/US11879016B2?q=US11879016

[96]. Straathof K, Flutter B, Wallace R, Jain N, Loka T, Depani S, et al. Antitumor activity without on-target off-tumor toxicity of GD2-chimeric antigen receptor T cells in patients with neuroblastoma. Sci Transl Med. 2020; 12(571): eabd6169. Available from: https://www.science.org/doi/10.1126/scitranslmed.abd6169

[97]. Locatelli F, Quintarelli C, De Angelis B. Ospedale Pediatrico Bambino Gesu, Italy. GD2-specific chimeric antigen receptor effector cells for use in the treatment of solid tumors, possibly in combination with enhancer of Zeste homolog 2 (EZH2) inhibitors. Worldwide patent WO2024246965. 2024 Dec 05. Available from: https://worldwide.espacenet.com/patent/search/family/087890007/publication/WO2024246965A1?q=WO2024246965

[98]. Locatelli F, Pagliara D, De Ioris MA, Becilli M, Del Baldo G, Serra A, et al. GD2-targeting CAR T cells in high-risk neuroblastoma: a phase 1/2 trial. Nat Med. 2025; 31: 3689-99. Available from: https://www.nature.com/articles/s41591-025-03874-6

[99]. Beasley M, Kiefel B, Maris J, Yarmarkovich M, Gracey F, Sgourakis N, et al. The Children’s Hospital of Philadelphia & Nyrio Therapeutics, United States. Peptide-centric chimeric antigen receptors to cancer self-peptides. United States patent US2024352130. 2024 Oct 24. Available from: https://worldwide.espacenet.com/patent/search/family/085322181/publication/US20240352130A1?q=US2024352130

[100]. Sun Y, Florio TJ, Gupta S, Young MC, Marshall QF, Garfinkle SE, et al. Structural principles of peptide-centric chimeric antigen receptor recognition guide therapeutic expansion. Sci Immunol. 2023; 8(90): eadj5792. Available from: https://www.science.org/doi/10.1126/sciimmunol.adj5792

[101]. Metelitsa L, Liu D, Dotti G, Heczey A. Baylor College Medicine, United States. Targeting the Tumor Microenvironment Using Manipulated NKT Cells. United States patent US2024277764. 2024 Aug 22. Available from: https://worldwide.espacenet.com/patent/search/family/047883983/publication/US20240277764A1?q=US2024277764

[102]. Heczey A, Xu X, Courtney AN, Tian G, Barragan GA, Guo L, et al. Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results. Nat Med. 2023; 29(6): 1379-1388. Available from: https://pubmed.ncbi.nlm.nih.gov/37188782/

[103]. Yang L, You F, Li F. Persongen Biotherapeutics Suzhou, China. B7-H3 chimeric antigen receptor-modified T cell and use thereof. China patent CN114763381. 2022 Jul 19. Available from: https://worldwide.espacenet.com/patent/search/family/082364073/publication/CN114763381A?q=CN114763381

[104]. Jiang L, You F, Wu H, Qi C, Xiang S, Zhang P, et al. B7-H3-Targeted CAR-Vδ1T Cells Exhibit Potent Broad-Spectrum Activity against Solid Tumors. Cancer Res. 2024; 84(23): 4066-4080. Available from: https://aacrjournals.org/cancerres/article/84/23/4066/750179/B7-H3-Targeted-CAR-V-1T-Cells-Exhibit-Potent-Broad

[105]. Hillen H, Stribinger A. Abbott, United States. Amyloid beta (1-42) oligomers, derivatives thereof and antibodies thereto, methods of preparation thereof and use thereof. United States patent US7902328. 2011 Mar 08. Available from: https://worldwide.espacenet.com/patent/search/family/032667945/publication/US7902328B2?q=US7902328

[106]. Hillen H, Stribinger A, Krantz C, Moeller A, Mueller R. Abbvie, Germany. Amyloid beta (1-42) oligomers, derivatives thereof and antibodies thereto, methods of preparation thereof and use thereof. United States patent US9176150. 2015 Nov 03. Available from: https://worldwide.espacenet.com/patent/search/family/032667945/publication/US9176150B2?q=US9176150

[107]. Hillen H, Stribinger A, Krantz C, Moeller A, Mueller R. Abbvie, Germany. Amyloid beta (1-42) oligomers, derivatives thereof and antibodies thereto, methods of preparation thereof and use thereof. United States patent US10464976. 2019 Nov 05. Available from: https://worldwide.espacenet.com/patent/search/family/032667945/publication/US10464976B2?q=US10464976

[108]. Wu C. Thera MAB Biosciene, China. mRNA vaccine and kit and application thereof. China patent CN110448689. 2019 Nov 15. Available from: https://worldwide.espacenet.com/patent/search/family/068485107/publication/CN110448689A?q=CN110448689

[109]. Xie L, Luo D, Chen X, Zhang M, Zhang W, Chang J, et al. RAS gene polymorphisms confer the risk of neuroblastoma in Chinese children from Jiangsu province. Pediatr Surg Int. 2025; 41(1): 130. Available from: https://link.springer.com/article/10.1007/s00383-025-06025-7

[110]. Meleshko A, Kushniarova L, Shinkevich V, Mikhaleuskaya T, Valochnik A, Proleskovskaya I. Expression Pattern of Tumor-associated Antigens in Neuroblastoma: Association with cytogenetic features and survival. Cancer Diagn Progn. 2023; 3(6): 695-705. Available from: https://www.cancerdiagnosisprognosis.org/article/275/expression-pattern-of-tumor-associated-antigens-in-neuroblastoma-association-with-cytogenetic-features-and-survival

[111]. Hao J, Sang J, Xu X, Bao A. Diagnostic value of CT and MRI combined with serum LDH, NSE, CEA, and MYCN in pediatric neuroblastoma. World J Surg Oncol. 2023; 21(1): 251. Available from: https://link.springer.com/article/10.1186/s12957-023-03131-5

[112]. Birkle S, Bahri M, Fougeray S. Institut National de la Santé et de la Recherche Médicale, OGD2 Pharma, and Nantes Université, France. New method to improve NK cells cytotoxicity. Worldwide patent WO2022219080. 2022 Oct 20. Available from: https://worldwide.espacenet.com/patent/search/family/076059833/publication/WO2022219080A1?q=WO2022219080

[113]. Terme M, Dorvillius M, Cochonneau D, Chaumette T, Xiao W, Diccianni MB, et al. Chimeric antibody c.8B6 to O-acetyl-GD2 mediates the same efficient anti-neuroblastoma effects as therapeutic ch14.18 antibody to GD2 without antibody induced allodynia. PLoS One. 2014; 9(2): e87210. Available from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087210