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Antibodies 2016, 5(1), 6; doi:10.3390/antib5010006

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

1
Global Biotherapeutics Technologies, Pfizer Inc., 610 Main St., Cambridge, MA 02139, USA
2
Global Biotherapeutics Technologies, Pfizer Inc., Grange Castle Business Park, Clondalkin, Dublin 22, Ireland
3
MacroGenics Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA
4
Oncology Research Unit, Pfizer Inc., 401 N. Middletown Road, Pearl River, NY 10965, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Christian Klein
Received: 4 January 2016 / Revised: 14 February 2016 / Accepted: 17 February 2016 / Published: 4 March 2016
(This article belongs to the Special Issue Advances in Bispecific Antibodies)
View Full-Text   |   Download PDF [2260 KB, uploaded 10 March 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. View Full-Text
Keywords: P-cadherin; bispecific; cancer; immuno-oncology; T-cell; re-targeting P-cadherin; bispecific; cancer; immuno-oncology; T-cell; re-targeting
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Root, A.R.; Cao, W.; Li, B.; LaPan, P.; Meade, C.; Sanford, J.; Jin, M.; O’Sullivan, C.; Cummins, E.; Lambert, M.; Sheehan, A.D.; Ma, W.; Gatto, S.; Kerns, K.; Lam, K.; D’Antona, A.M.; Zhu, L.; Brady, W.A.; Benard, S.; King, A.; He, T.; Racie, L.; Arai, M.; Barrett, D.; Stochaj, W.; LaVallie, E.R.; Apgar, J.R.; Svenson, K.; Mosyak, L.; Yang, Y.; Chichili, G.R.; Liu, L.; Li, H.; Burke, S.; Johnson, S.; Alderson, R.; Finlay, W.J.J.; Lin, L.; Olland, S.; Somers, W.; Bonvini, E.; Gerber, H.-P.; May, C.; Moore, P.A.; Tchistiakova, L.; Bloom, L. Development of PF-06671008, a Highly Potent Anti-P-cadherin/Anti-CD3 Bispecific DART Molecule with Extended Half-Life for the Treatment of Cancer. Antibodies 2016, 5, 6.

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