Supplementary Figures S1-S6 from Novel Anti-TM4SF1 Antibody–Drug Conjugates with Activity against Tumor Cells and Tumor Vasculature

Visintin, Alberto; Knowlton, Kelly; Tyminski, Edyta; Lin, Chi-Iou; Zheng, Xiang; Marquette, Kimberly; Jain, Sadhana; Tchistiakova, Lioudmila; Li, Dan; O'Donnell, Christopher J.; Maderna, Andreas; Cao, Xianjun; Dunn, Robert; Snyder, William B.; Abraham, Anson K.; Leal, Mauricio; Shetty, Shoba; Barry, Anthony; Zawel, Leigh; Coyle, Anthony J.; Dvorak, Harold F.; Jaminet, Shou-Ching

doi:10.1158/1535-7163.22505884.v1

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Supplementary Figures S1-S6 from Novel Anti-TM4SF1 Antibody–Drug Conjugates with Activity against Tumor Cells and Tumor Vasculature

journal contribution

posted on 2023-04-03, 15:20 authored by Alberto Visintin, Kelly Knowlton, Edyta Tyminski, Chi-Iou Lin, Xiang Zheng, Kimberly Marquette, Sadhana Jain, Lioudmila Tchistiakova, Dan Li, Christopher J. O'Donnell, Andreas Maderna, Xianjun Cao, Robert Dunn, William B. Snyder, Anson K. Abraham, Mauricio Leal, Shoba Shetty, Anthony Barry, Leigh Zawel, Anthony J. Coyle, Harold F. Dvorak, Shou-Ching Jaminet

Supplementary Figures S1-S6. Supplementary Figure S1. Liquid chromatography electrospray ionization tandem mass spectrometry analysis; Supplementary Figure S2. TM4SF1 expression in human breast and colon cancers; Supplementary Figure S3A. Clearance of anti-TM4SF1 antibody from HUVEC surface; Supplementary Figure S3B. Uptake of anti-TM4SF1 antibody in HUVEC; Supplementary Figure S4A. NSCLC killing by anti-TM4SF1 ADC; Supplementary Figure S4B. Tumor cell killing by anti-TM4SF1 ADC; Supplementary Figure S5. Expression level of TM4SF1 and other endothelial cell markers in tumor xenografts; Supplementary Figure S6. Clearance of anti-TM4SF1 ADCs; tolerance in mice.

History

ARTICLE 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 anti-mouse 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. Mol Cancer Ther; 14(8); 1868–76. ©2015 AACR.