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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
- 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.
- Subjects :
- lcsh:Immunologic diseases. Allergy
0301 basic medicine
Phage display
CD3
T cell
Immunology
P-cadherin
bispecific
cancer
immuno-oncology
T-cell
re-targeting
Biology
Peripheral blood mononuclear cell
Article
03 medical and health sciences
In vivo
Drug Discovery
medicine
Immunology and Allergy
Cytotoxic T cell
Potency
Molecular biology
CTL
030104 developmental biology
medicine.anatomical_structure
biology.protein
lcsh:RC581-607
Subjects
Details
- ISSN :
- 20734468
- Volume :
- 5
- Database :
- OpenAIRE
- Journal :
- Antibodies
- Accession number :
- edsair.doi.dedup.....5727dc94b5642ceafb627d901f3b8117
- Full Text :
- https://doi.org/10.3390/antib5010006