Antibodies to TWEAK receptor inhibit human tumor growth through dual mechanisms.

Abstract

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 x G1) exhibited significantly less ADCC than 19.2.1. However, 19.2. 1x 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.

• Authors: Patricia A Culp, Donghee Choi, Yongke Zhang, Johnny Yin, Pui Seto, Suzanne E Ybarra, Mian Su, Mien Sho, Roxanne Steinle, Melanie H L Wong, Ferdinand Evangelista, Jennifer Grove, Marie Cardenas, Marjorie James, Eric D Hsi, Debra T Chao, David B Powers, Vanitha Ramakrishnan, Robert Dubridge
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 2 Pg. 497-508 (Jan 15 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20068083 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Cancer Vaccines
• Cytokine TWEAK
• TNFSF12 protein, human
• Tumor Necrosis Factors
• enavatuzumab

Topics

• Animals
• Antibodies, Monoclonal, Humanized (pharmacology, therapeutic use)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cancer Vaccines (therapeutic use)
• Cell Proliferation (drug effects)
• Cytokine TWEAK
• Dose-Response Relationship, Drug
• Humans
• Immunotherapy (methods)
• Mice
• Mice, Inbred BALB C
• NIH 3T3 Cells
• Neoplasm Metastasis
• Neoplasms (pathology, therapy)
• Signal Transduction (drug effects, physiology)
• Tumor Burden (drug effects)
• Tumor Cells, Cultured
• Tumor Necrosis Factors (immunology)
• Xenograft Model Antitumor Assays