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


METHODS
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.
Culp
Patricia A
PA
Facet Biotech, Redwood City, California 94063, USA. patricia.culp@facetbiotech.com
Choi
Donghee
D
Zhang
Yongke
Y
Yin
Johnny
J
Seto
Pui
P
Ybarra
Suzanne E
SE
Su
Mian
M
Sho
Mien
M
Steinle
Roxanne
R
Wong
Melanie H L
MH
Evangelista
Ferdinand
F
Grove
Jennifer
J
Cardenas
Marie
M
James
Marjorie
M
Hsi
Eric D
ED
Chao
Debra T
DT
Powers
David B
DB
Ramakrishnan
Vanitha
V
Dubridge
Robert
R
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects*; D000074049:Cytokine TWEAK; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology* / Q000628:therapy; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D048069:Tumor Necrosis Factors / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D000074049:Cytokine TWEAK; C109743:TNFSF12 protein, human; D048069:Tumor Necrosis Factors; C578859:enavatuzumab