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

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 an...

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Veröffentlicht in:Antibodies (Basel) 2016-03, Vol.5 (1), p.6
Hauptverfasser: Root, Adam, Cao, Wei, Li, Bilian, LaPan, Peter, Meade, Caryl, Sanford, Jocelyn, Jin, Macy, O’Sullivan, Cliona, Cummins, Emma, Lambert, Matthew, Sheehan, Alfredo, Ma, Weijun, Gatto, Scott, Kerns, Kelvin, Lam, Khetemenee, D’Antona, Aaron, Zhu, Lily, Brady, William, Benard, Susan, King, Amy, He, Tao, Racie, Lisa, Arai, Maya, Barrett, Dianah, Stochaj, Wayne, LaVallie, Edward, Apgar, James, Svenson, Kristine, Mosyak, Lidia, Yang, Yinhua, Chichili, Gurunadh, Liu, Liqin, Li, Hua, Burke, Steve, Johnson, Syd, Alderson, Ralph, Finlay, William, Lin, Laura, Olland, Stéphane, Somers, William, Bonvini, Ezio, Gerber, Hans-Peter, May, Chad, Moore, Paul, Tchistiakova, Lioudmila, Bloom, Laird
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Sprache:eng
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Zusammenfassung: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.
ISSN:2073-4468
2073-4468
DOI:10.3390/antib5010006