TCR-like antibody duocarmycin conjugates promote cytotoxicity of tumor cells expressing low peptide/HLA targets

Abstract

Abstract Immunotherapeutic strategies such as unmodified antibodies have significantly advanced treatment options for individuals with cancer. Yet, to further improve the efficacy of this approach, engineered platforms such as antibody drug conjugates (ADCs) are under development. Current FDA-approved ADC designs incorporate tubulin inhibitors that abate cancer growth and mediate clinical protection for patients. However, successful ADC treatment typically requires high tumor antigen (TA) surface expression to bind/internalize ADC material, destabilize cytoskeletal networks, and suppress tumorigenesis. Unfortunately, few known TAs are localized on cancer cells at elevated densities, potentially minimizing the therapeutic index and widespread application of current ADC regimens. Our group sought to overcome this ADC limitation of TA expression by crosslinking the DNA alkylating compound duocarmycin with T cell receptor (TCR)-like antibodies, which specifically bind TA peptide/human leukocyte antigen (HLA) complexes analogous to a TCR. In select assays, a panel of TCR-like ADCs were capable of distinguishing human breast and colon cancer lines and promoting potent cell cytotoxicity even under common scenarios of low TA peptide/HLA densities. Additionally, TCR-like antibody TA peptide/HLA binding appeared to play an important role in ADC-mediated cytotoxicity, supporting the notion that spatial TA ligand interactions influence ADC function. Overall, our data highlight the proof-of-principle that TCR-like ADCs induce cancer cell death under physiologically-relevant TA expression profiles and support their translational development, particularly alongside agents that disrupt DNA replication.