A bispecific CD40 agonistic antibody allowing for antibody-peptide conjugate formation to enable cancer-specific peptide delivery, resulting in improved T proliferation and anti-tumor immunity in mice.

Mebrahtu A, Laurén I, Veerman R, Akpinar GG, Lord M, Kostakis A, Astorga-Wells J, Dahllund L, Olsson A, Andersson O, Persson J, Persson H, Dönnes P, Rockberg J, Mangsbo S

Nat Commun 15 (1) 9542 [2024-11-05; online 2024-11-05]

Current antibody-based immunotherapy depends on tumor antigen shedding for proper T cell priming. Here we select a novel human CD40 agonistic drug candidate and generate a bispecific antibody, herein named BiA9*2_HF, that allows for rapid antibody-peptide conjugate formation. The format is designed to facilitate peptide antigen delivery to CD40 expressing cells combined with simultaneous CD40 agonistic activity. In vivo, the selected bispecific antibody BiA9*2_HF loaded with peptide cargos induces improved antigen-specific proliferation of CD8+ (10-15 fold) and CD4+ T cells (2-7 fold) over control in draining lymph nodes. In both virus-induced and neoantigen-based mouse tumor models, BiA9*2_HF demonstrates therapeutic efficacy and elevated safety profile, with complete tumor clearance, as well as measured abscopal impact on tumor growth. The BiA9*2_HF drug candidate can thus be utilized to tailor immunotherapeutics for cancer patients.

Drug Discovery and Development (DDD) [Service]

PubMed 39500897

DOI 10.1038/s41467-024-53839-5

Crossref 10.1038/s41467-024-53839-5

pmc: PMC11538452
pii: 10.1038/s41467-024-53839-5