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Development of PF-06671008, a Highly Potent Anti-P-cadherin/Anti-CD3 Bispecific DART Molecule with Extended Half-Life for the Treatment of Cancer

Authors :
Kristine Svenson
Ezio Bonvini
Alfredo Darmanin Sheehan
William J.J. Finlay
Paul A. Moore
Jocelyn Sanford
Chad May
Kelvin M. Kerns
Liqin Liu
Susan Benard
Aaron M. D’Antona
Steve Burke
Scott Gatto
Hua Li
Syd Johnson
Hans-Peter Gerber
Yinhua Yang
Edward R. Lavallie
Gurunadh Reddy Chichili
Lioudmila Tchistiakova
Tao He
Peter LaPan
Stephane Olland
William Brady
Khetemenee Lam
Cliona M. O'Sullivan
Wei Cao
Laura Lin
Adam Root
William S. Somers
Bilian Li
Ralph Alderson
Macy Jin
Lisa Racie
Lily Zhu
Weijun Ma
Caryl L. Meade
Lidia Mosyak
Wayne Stochaj
Amy King
Emma Cummins
Matthew Allister Lambert
Laird Bloom
Dianah Barrett
James R. Apgar
Maya Arai
Source :
Antibodies, Vol 5, Iss 1, p 6 (2016), Antibodies; Volume 5; Issue 1; Pages: 6, Antibodies
Publication Year :
2016
Publisher :
MDPI AG, 2016.

Abstract

Bispecific antibodies offer a promising approach for the treatment of cancer but can be challenging to engineer and manufacture. Here we report the development of PF-06671008, an extended-half-life dual-affinity re-targeting (DART®) bispecific molecule against P-cadherin and CD3 that demonstrates antibody-like properties. Using phage display, we identified anti-P-cadherin single chain Fv (scFv) that were subsequently affinity-optimized to picomolar affinity using stringent phage selection strategies, resulting in low picomolar potency in cytotoxic T lymphocyte (CTL) killing assays in the DART format. The crystal structure of this disulfide-constrained diabody shows that it forms a novel compact structure with the two antigen binding sites separated from each other by approximately 30 Å and facing approximately 90° apart. We show here that introduction of the human Fc domain in PF-06671008 has produced a molecule with an extended half-life (-4.4 days in human FcRn knock-in mice), high stability (Tm1 > 68 °C), high expression (>1 g/L), and robust purification properties (highly pure heterodimer), all with minimal impact on potency. Finally, we demonstrate in vivo anti-tumor efficacy in a human colorectal/human peripheral blood mononuclear cell (PBMC) co-mix xenograft mouse model. These results suggest PF-06671008 is a promising new bispecific for the treatment of patients with solid tumors expressing P-cadherin.

Details

ISSN :
20734468
Volume :
5
Database :
OpenAIRE
Journal :
Antibodies
Accession number :
edsair.doi.dedup.....5727dc94b5642ceafb627d901f3b8117
Full Text :
https://doi.org/10.3390/antib5010006