PF-03732010: a fully human monoclonal antibody against P-cadherin with antitumor and antimetastatic activity.
OBJECTIVE
P-cadherin is a membrane glycoprotein that functionally mediates tumor cell adhesion, proliferation, and invasiveness. We characterized the biological properties of PF-03732010, a human monoclonal antibody against P-cadherin, in cell-based assays and tumor models.


METHODS
The affinity, selectivity, and cellular inhibitory activity of PF-03732010 were tested in vitro. Multiple orthotopic and metastatic tumor models were used for assessing the antitumor and antimetastatic activities of PF-03732010. Treatment-associated pharmacodynamic changes were also investigated.


RESULTS
PF-03732010 selectively inhibits P-cadherin-mediated cell adhesion and aggregation in vitro. In the P-cadherin-overexpressing tumor models, including MDA-MB-231-CDH3, 4T1-CDH3, MDA-MB-435HAL-CDH3, HCT116, H1650, PC3M-CDH3, and DU145, PF-03732010 inhibited the growth of primary tumors and metastatic progression, as determined by bioluminescence imaging. Computed tomography imaging, H&E stain, and quantitative PCR analysis confirmed the antimetastatic activity of PF-03732010. In contrast, PF-03732010 did not show antitumor and antimetastatic efficacy in the counterpart tumor models exhibiting low P-cadherin expression. Mechanistic studies via immunofluorescence, immunohistochemical analyses, and 3'-[(18)F]fluoro-3'-deoxythymidine-positron emission tomography imaging revealed that PF-03732010 suppressed P-cadherin levels, caused degradation of membrane β-catenin, and concurrently suppressed cytoplasmic vimentin, resulting in diminished metastatic capacity. Changes in the levels of Ki67, caspase-3, and 3'-[(18)F]fluoro-3'-deoxythymidine tracer uptake also indicated antiproliferative activity and increased apoptosis in the tested xenografts.


CONCLUSIONS
These findings suggest that interrupting the P-cadherin signaling pathway may be a novel therapeutic approach for cancer therapy. PF-03732010 is presently undergoing evaluation in Phase 1 clinical trials.
Zhang
Cathy C
CC
Translational Research Group in Oncology Research Unit, Pfizer Global Research and Development, La Jolla Laboratories, San Diego, California 92121, USA. cathy.zhang@pfizer.com
Yan
Zhengming
Z
Zhang
Qin
Q
Kuszpit
Kyle
K
Zasadny
Kenneth
K
Qiu
Ming
M
Painter
Cory L
CL
Wong
Anthony
A
Kraynov
Eugenia
E
Arango
Maria E
ME
Mehta
Pramod P
PP
Popoff
Ian
I
Casperson
Gerald F
GF
Los
Gerrit
G
Bender
Steve
S
Anderes
Kenna
K
Christensen
James G
JG
VanArsdale
Todd
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D015820:Cadherins / Q000276:immunology*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000517:prevention & control; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016042:Transplantation, Heterotopic; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015820:Cadherins; C556089:PF-03732010 monoclonal antibody