Format

Send to

Choose Destination
Mol Cancer Ther. 2015 Aug;14(8):1868-76. doi: 10.1158/1535-7163.MCT-15-0188. Epub 2015 Jun 18.

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

Author information

1
Pfizer Inc., Centers for Therapeutic Innovation (CTI), Boston, Massachusetts.
2
The Center for Vascular Biology Research and the Departments of Pathology, Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, Boston, Massachusetts.
3
Pfizer Inc., Global Biotherapeutic Technologies (GBT), Cambridge, Massachusetts.
4
Pfizer Inc., Worldwide Medicinal Chemistry, Groton, Connecticut.
5
Pfizer Inc., Centers for Therapeutic Innovation (CTI), San Diego, California.
6
Pfizer Inc., Pharmacokinetics, Dynamics and Metabolism (PDM), Pearl River, New York.
7
Pfizer Inc., Drug Safety R&D, Investigative Toxicology, Groton, Connecticut.
8
Pfizer Inc., Biotherapeutics Pharmaceutical Sciences, Andover, Massachusetts.
9
The Center for Vascular Biology Research and the Departments of Pathology, Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, Boston, Massachusetts. sjaminet@bidmc.harvard.edu hdvorak@bidmc.harvard.edu.

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.

PMID:
26089370
DOI:
10.1158/1535-7163.MCT-15-0188
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center