Antibodies to TWEAK Receptor Inhibit Human Tumor Growth through Dual Mechanisms

• Published in: Clinical cancer research Vol. 16; no. 2; pp. 497 - 508
• Main Authors: Culp, Patricia A, Choi, Donghee, Zhang, Yongke, Yin, Johnny, Seto, Pui, Ybarra, Suzanne E, Su, Mian, Sho, Mien, Steinle, Roxanne, Wong, Melanie H L, Evangelista, Ferdinand, Grove, Jennifer, Cardenas, Marie, James, Marjorie, Hsi, Eric D, Chao, Debra T, Powers, David B, Ramakrishnan, Vanitha, Dubridge, Robert
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 15-01-2010
• Subjects: Animals; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; antibody; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cancer Vaccines - therapeutic use; Cell Proliferation - drug effects; Cytokine TWEAK; Dose-Response Relationship, Drug; Humans; Immunotherapy - methods; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neoplasms - pathology; Neoplasms - therapy; NIH 3T3 Cells; Signal Transduction - drug effects; Signal Transduction - physiology; Tumor Burden - drug effects; Tumor Cells, Cultured; Tumor Necrosis Factors - immunology; TWEAK receptor; xenograft; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-09-1929

Purpose: Targeted therapeutics have significantly changed the outcome for patients diagnosed with cancer. Still, effective therapeutic
intervention does not exist for many cancers and much remains to be done. The objective of this study was to identify novel
genes that potentially regulate tumor growth, to target these gene products with monoclonal antibodies, and to examine the
therapeutic potential of these antibodies.
Experimental Design: Using cDNA microarray analysis, we identified genes overexpressed in several solid malignancies. We generated a mouse monoclonal
antibody, 19.2.1, and its humanized counterpart, PDL192, to one such target, TweakR (TWEAK receptor, Fn14, TNFRSF12A, CD266),
and characterized the antitumor activities in vitro and in mouse xenograft models.
Results: Both 19.2.1 (mouse IgG2a) and PDL192 (human IgG1), like TWEAK, the natural ligand of TweakR, inhibited the growth of several
TweakR-expressing cancer cell lines in anchorage-dependent and anchorage-independent assays in vitro . Both antibodies showed significant antitumor activity in multiple mouse xenograft models. PDL192 and 19.2.1 also induced
antibody-dependent cellular cytotoxicity (ADCC) of cancer cell lines in vitro . A chimeric version of 19.2.1 containing the mouse IgG1 Fc region (19.2.1×G1) exhibited significantly less ADCC than 19.2.1.
However, 19.2.1×G1 showed differential activity in vivo , with activity equivalent to 19.2.1 in one model, but significantly less efficacy than 19.2.1 in a second model. These results
indicate that PDL192 and 19.2.1 mediate their antitumor effects by signaling through TweakR, resulting in reduced tumor cell
proliferation, and by ADCC. Clin Cancer Res; 16(2); 497–508