162P - Exploiting gp100-specific antibodies isolated from immune checkpoint inhibitor-responsive melanoma patients to target tumor cells

Background

The emergence of immune checkpoint inhibitor (ICI) therapy has led to enhanced survival outcomes for patients with melanoma. While T cell responses have been extensively investigated, the contribution of the humoral immune response remains elusive.

Methods

We analyzed 141 patients with stage IV melanoma treated with ICI focusing on IgG responses against melanocyte differentiation antigens (MDAs) including gp100, TRP1, TRP2, and Melan-A. Baseline and evolving antibody levels were assessed using ELISAs. Immunofluorescence and immunoprecipitation were used to confirm the specificity of these antibodies. Single gp100-specific memory B cells were isolated from selected patients, and the variable regions of the heavy and light chains were sequenced.

Results

Elevated baseline levels of IgG targeting gp100, TRP2, and Melan-A correlated with improved progression-free survival (PFS) and overall survival (OS) in stage IV patients. IgG1 and IgG2 isotypes against gp100 were significantly higher (p=0.022) in responders (n=59) versus non-responders (n=82). Immunofluorescence revealed MDA-specific IgG binding to melanoma metastases, with co-localization observed in gp100-positive tumors. Serum IgGs from responders induced antibody-dependent cellular cytotoxicity (ADCC) against gp100-positive melanoma cells in vitro. Monoclonal gp100-specific antibody clones isolated from responders mediated ADCC against melanoma cells.

Conclusions

Our findings highlight the predictive potential of MDA-specific IgGs, particularly against gp100, in identifying ICI responders and correlating with survival outcomes. These antibodies show direct binding to melanoma antigens and mediate cytotoxic effects via ADCC, suggesting a role for humoral immunity in ICI efficacy. Monoclonal antibodies derived from ICI responders provide a basis for novel tumor targeting therapies. Further exploration of MDA-specific antibodies could improve melanoma treatment, potentially complementing ICI benefits.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Deutsche Forschungsgemeinschaft.

Disclosure

L. Flatz: Financial Interests, Personal, Full or part-time Employment, Section Head of Dermato-oncology: University Hospital of Tübingen; Financial Interests, Personal, Stocks/Shares, Founder: Hookipa Pharma, Humion AG; Financial Interests, Personal, Ownership Interest, Founder: Abtherix GmbH, Schmelzberg GmbH; Financial Interests, Personal, Royalties, IP owner together with University of Zurich: Hookipa Pharma; Non-Financial Interests, Advisory Role: Philogen. S. Forchhammer: Financial Interests, Personal, Invited Speaker, Speakers Honoraria: Recordati Rare Disease, Kiowa Kirin; Financial Interests, Institutional, Research Grant, institutional research grant: Biontech SE, Neracare, Skyline DX. L. Risch: Financial Interests, Personal, Ownership Interest: Labor Risch. U. Leiter-Stoppke: Financial Interests, Personal, Advisory Board, and speaker's honoraria: Sun Pharma, Regeneron, Sanofi; Financial Interests, Personal, Advisory Board: Pierre Fabre, Novartis, Almirall Hermal; Financial Interests, Institutional, Research Grant: MSD. A. Forschner: Financial Interests, Institutional, Advisory Board: Novartis, MSD, BMS, Pierre-Fabre, Immunocore; Financial Interests, Institutional, Invited Speaker: Immunocore, Novarits, BMS, Pierre Fabre; Financial Interests, Institutional, Research Grant: BMS Immunoncology; Non-Financial Interests, Member: ADO, DKG, PSO, DDG; Non-Financial Interests, Leadership Role: ADO Komitee Survivorship; Other, congress participation including travel and hotel: Pierre Fabre. T.M.S. Amaral: Financial Interests, Personal, Writing Engagement: CeCaVa; Financial Interests, Personal, Invited Speaker: BMS, Novartis, Pierre Fabre, Neracare; Financial Interests, Personal, Advisory Board: Delcath; Financial Interests, Institutional, Funding: Novartis, Neracare, Sanofi, Skyline-Dx, Pascoe, MNI - Naturwissenschaftliches und Medizinisches Institut; Financial Interests, Institutional, Research Grant: Novartis, iFIT; Financial Interests, Institutional, Local PI: IO Biotech, MSD, University Hospital, Essen, Roche, BMS, Biontech, Philogen, Pfizer, Immunocore, HUYA Bioscience, AstraZeneca, Agenus Inc, Regeneron; Financial Interests, Institutional, Coordinating PI: Unicancer; Non-Financial Interests, Member: Portuguese Society for Medical Oncology, ASCO; Other, Clinical expert in the area of medical oncology: INFARMED - PT. R. Dummer: Financial Interests, Personal, Other, Consulting and/or advisory role: Novartis, Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, MaviVAX SA, T3 Pharma, Pfizer, Simcere. M. Joerger: Financial Interests, Institutional, Coordinating PI, Clinical study activity: Basilea, Bayer, BMS, Immunophotonics, MSD, Novartis, Roche; Financial Interests, Institutional, Other, Clinical study activity: Daiichi Sankyo; Financial Interests, Institutional, Local PI, Clinical study activity: Innomedica; Financial Interests, Institutional, Coordinating PI: Anaveon; Non-Financial Interests, Advisory Role: Novartis, AstraZeneca, Basilea, Bayer, BMS, Debiopharm, MSD, Roche, Sanofi. All other authors have declared no conflicts of interest.