Novel Anti-TM4SF1 Antibody–Drug Conjugates with Activity against Tumor Cells and Tumor Vasculature

Abstract

Antibody-drug conjugates (ADC) represent a promising therapeutic modality for managing cancer. Here, we report a novel humanized ADC that targets the tetraspanin-like protein TM4SF1. TM4SF1 is highly expressed on the plasma membranes of many human cancer cells and also on the endothelial cells lining tumor blood vessels. TM4SF1 is internalized upon interaction with antibodies. We hypothesized that an ADC against TM4SF1 would inhibit cancer growth directly by killing cancer cells and indirectly by attacking the tumor vasculature. We generated a humanized anti-human TM4SF1 monoclonal antibody, v1.10, and armed it with an auristatin cytotoxic agent LP2 (chemical name mc-3377). v1.10-LP2 selectively killed cultured human tumor cell lines and human endothelial cells that express TM4SF1. Acting as a single agent, v1.10-LP2 induced complete regression of several TM4SF1-expressing tumor xenografts in nude mice, including non-small cell lung cancer and pancreas, prostate, and colon cancers. As v1.10 did not react with mouse TM4SF1, it could not target the mouse tumor vasculature. Therefore, we generated a surrogate antimouse TM4SF1 antibody, 2A7A, and conjugated it to LP2. At 3 mpk, 2A7A-LP2 regressed several tumor xenografts without noticeable toxicity. Combination therapy with v1.10-LP2 and 2A7A-LP2 together was more effective than either ADC alone. These data provide proof-of-concept that TM4SF1-targeting ADCs have potential as anticancer agents with dual action against tumor cells and the tumor vasculature. Such agents could offer exceptional therapeutic value and warrant further investigation.

TM4SF1 Regulates Pancreatic Cancer Migration and Invasion In Vitro and In Vivo

“…This antibody lost its attachment with the membranes when it passed through the nuclear pores and entered the nucleoplasm. These results demonstrate that TM4SF1 is an important target in ADC cancer therapy [30][31][32].…”

Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature

“…The initial anti-CD276 ADC we generated used the tubulin binding anti-mitotic drug MMAE, attached to m276 through a cathepsin B cleavable valine-citrulline linker (Figure S3C). We chose vcMMAE because the same drug-linker technology is used in the US FDA-approved brentuximab vedotin and several other ADCs in clinical development, and previous reports suggest that tumor vessels may be particularly sensitive to auristatin-like compounds (Visintin et al, 2015). Upon target binding and internalization the dipeptide linker can be cleaved by lysosomal proteases releasing cell-permeable MMAE which can then freely diffuse into nearby cells in a target-independent manner resulting in substantial bystander killing (Li et al, 2016).…”

Label free quantitative proteomics reveals the role of miR-200b in androgen-independent prostate cancer cells

“…A recent study showed that RTN4 was regulated by AR in AIPC; however, its function was not clarified [25]. TM4SF1, originally described as "TAAL6", is a tumor-associated antigen found in various human epithelial malignancies including breast, ovarian, lung, and colon carcinomas [26,27]. Recent studies indicated that TM4SF1 plays a critical role in cancer cell migration and invasion [28]; it was also shown to be an androgen-responsive protein [29].…”