Science

Angiex is developing antibody-based therapeutics against a novel target, TM4SF1 (Transmembrane-4 L Six Family member 1).  TM4SF1 is a membrane glycoprotein of tetraspanin topology that was originally discovered as a protein expressed on many human epithelial tumor cells. [1] In tumor cells, TM4SF1 supports growth, invasion, and metastasis. [2, 3] Angiex founders Hal Dvorak and Shou-Ching Jaminet identified TM4SF1 as an endothelial cell biomarker [4] with critical roles in support of angiogenesis, thereby establishing TM4SF1 as a dual (tumor vessel and tumor cell) therapeutic target in cancer. [5] TM4SF1 clusters in cell surface microdomains [6] and internalizes [7], making it a candidate target of antibody-drug conjugate therapy. 

The potential of anti-TM4SF1 antibody-drug conjugates (ADCs) was tested in a preclinical collaboration between Pfizer and Angiex founders at Beth Israel Deaconess Medical Center. Anti-TM4SF1 ADCs effectively regressed xenograft tumors in mice. [8] 

An improved anti-TM4SF1 ADC would have potential to effectively treat all solid tumors. Creating such an agent is Angiex’s mission.

References

[1] Hellström I, Beaumier PL, Hellström KE. Antitumor effects of L6, an IgG2a antibody that reacts with most human carcinomas. Proc Natl Acad Sci U S A. 1986 Sep;83(18):7059-63. PMID: 3462743.

[2] Kao YR, Shih JY, Wen WC, Ko YP, Chen BM, Chan YL, Chu YW, Yang PC, Wu CW, Roffler SR. Tumor-associated antigen L6 and the invasion of human lung cancer cells. Clin Cancer Res. 2003 Jul;9(7):2807-16. PMID: 12855661.

[3] Gao H, Chakraborty G, Zhang Z, Akalay I, Gadiya M, Gao Y, Sinha S, Hu J, Jiang C, Akram M, Brogi E, Leitinger B, Giancotti FG. Multi-organ Site Metastatic Reactivation Mediated by Non-canonical Discoidin Domain Receptor 1 Signaling. Cell. 2016 Jun 30;166(1):47-62. PMID: 27368100.

[4] Shih SC, Zukauskas A, Li D, Liu G, Ang LH, Nagy JA, Brown LF, Dvorak HF. The L6 protein TM4SF1 is critical for endothelial cell function and tumor angiogenesis. Cancer Res. 2009 Apr 15;69(8):3272-7. PMID: 19351819.

[5] Lin CI, Merley A, Sciuto TE, Li D, Dvorak AM, Melero-Martin JM, Dvorak HF, Jaminet SC. TM4SF1: a new vascular therapeutic target in cancer. Angiogenesis. 2014 Oct;17(4):897-907. PMID: 24986520.

[6] Zukauskas A, Merley A, Li D, Ang LH, Sciuto TE, Salman S, Dvorak AM, Dvorak HF, Jaminet SC. TM4SF1: a tetraspanin-like protein necessary for nanopodia formation and endothelial cell migration. Angiogenesis. 2011 Sep;14(3):345-54. PMID: 21626280.

[7] Sciuto TE, Merley A, Lin CI, Richardson D, Liu Y, Li D, Dvorak AM, Dvorak HF, Jaminet SC. Intracellular distribution of TM4SF1 and internalization of TM4SF1-antibody complex in vascular endothelial cells. Biochem Biophys Res Commun. 2015 Sep 25;465(3):338-43. PMID: 26241677.

[8] Visintin A, Knowlton K, Tyminski E, Lin CI, Zheng X, Marquette K, Jain S, Tchistiakova L, Li D, O’Donnell CJ, Maderna A, Cao X, Dunn R, Snyder WB, Abraham AK, Leal M, Shetty S, Barry A, Zawel L, Coyle AJ, Dvorak HF, Jaminet SC. Novel Anti-TM4SF1 Antibody-Drug Conjugates with Activity against Tumor Cells and Tumor Vasculature. Mol Cancer Ther. 2015 Aug;14(8):1868-76. PMID: 26089370.