Cancer therapy via neoepitope-specific monoclonal antibody cocktails

Publication date: Aug 05, 2024

Background: Cellular heterogeneity presents a significant challenge to cancer treatment. Antibody therapies targeting individual tumor-associated antigens can be extremely effective but are not suited for all patients and often fail against tumors with heterogeneous expression as tumor cells with low or no antigen expression escape targeting and develop resistance. Simultaneously targeting multiple tumor-specific proteins with multiple antibodies has the potential to overcome this barrier and improve efficacy, but relatively few widely expressed cancer-specific antigens are known. In contrast, neoepitopes, which arise from mutations unique to tumor cells, are considerably more abundant. However, since neoepitopes are not commonly shared between individuals, a patient-customized approach is necessary and motivates efforts to develop an efficient means to identify suitable target mutations and isolate neoepitope-specific monoclonal antibodies. Methods: Here, focusing on the latter goal, we use directed evolution in yeast and phage display systems to engineer antibodies from non-immune, human antibody fragment libraries that are specific for neoepitopes previously reported in the B16F10 melanoma model. Results: We demonstrate proof-of-concept for a pipeline that supports rapid isolation and functional enhancement of multiple neoepitope peptide-targeted monoclonal antibodies and demonstrate their robust binding to B16F10 cells and potent effector functions in vitro. These antibodies were combined and evaluated in vivo for anti-cancer activity in tumor-bearing mice, where they suppressed B16F10 tumor growth and prolonged survival. Conclusions: These findings emphasize the potential for clinical application of patient-customized antibody cocktails in the treatment of the many cancers poorly addressed by current therapies.

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Concepts Keywords
Cancer Antibodies
Cgagctattacaagtcttcttcagaaataagcttttgttctagaattccgga Antibody
Chicken B16f10
Efficient Binding
Biorxiv
Cocktail
Display
Fig
Neoepitope
Peptide
Peptides
Preprint
Specific
Tumor
Yeast

Semantics

Type Source Name
disease MESH Cancer
disease MESH melanoma
pathway KEGG Melanoma
disease MESH autoimmunity
disease MESH B cell lymphoma
drug DRUGBANK Spinosad
pathway REACTOME Translation
drug DRUGBANK Amino acids
disease MESH vitiligo
disease MESH lymphomas
disease MESH tumor escape
drug DRUGBANK Biotin
drug DRUGBANK Pentaerythritol tetranitrate
drug DRUGBANK Galactose
drug DRUGBANK Dextrose unspecified form
drug DRUGBANK Streptomycin
drug DRUGBANK Myricetin
pathway KEGG Homologous recombination
drug DRUGBANK Trypsin
drug DRUGBANK Flunarizine
drug DRUGBANK Human Serum Albumin
drug DRUGBANK Edetic Acid
drug DRUGBANK Sodium carbonate
drug DRUGBANK Glycine
drug DRUGBANK Tromethamine
drug DRUGBANK Immune Globulin Human

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