Download MendeleyDevelopment of PF-06671008, a Highly Potent Anti-P-cadherin/Anti-CD3 Bispecific DART Molecule with Extended Half-Life for the Treatment of Cancer.
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.(2016) Antibodies (Basel) 5
- PubMed: 31557987
- DOI: https://doi.org/10.3390/antib5010006
- Primary Citation of Related Structures:
5FCS - PubMed 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 (T m 1 > 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.
Organizational Affiliation:
Global Biotherapeutics Technologies, Pfizer Inc., 610 Main St., Cambridge, MA 02139, USA. adam.root@pfizer.com.
