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Development of CDX-527: a bispecific antibody combining PD-1 blockade and CD27 costimulation for cancer immunotherapy.
- Source :
-
Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2020 Oct; Vol. 69 (10), pp. 2125-2137. Date of Electronic Publication: 2020 May 25. - Publication Year :
- 2020
-
Abstract
- CD27 is a costimulatory molecule that provides a complementary target to the PD-1/PD-L1 checkpoint axis on T cells. Combining a CD27 agonist antibody with PD-1/PD-L1 blockade has shown synergistic antitumor activity in preclinical models, which led to clinical studies of the combination in cancer patients. We theorized that coupling CD27 costimulation with PD-1/PD-L1 blockade in a bispecific antibody (BsAb) may provide greater immune activating properties than combining the individual mAbs due to enhanced CD27 activation by cross-linking through PD-L1 and Fc receptors. To test this approach, we developed CDX-527, a tetravalent PD-L1xCD27 IgG1-scFv BsAb. CDX-527 potently inhibits PD-1 signaling and induces CD27-mediated T cell costimulation through PD-L1 cross-linking. In mixed lymphocyte reaction assays, CDX-527 is more potent than the combination of the parental antibodies, suggesting that cross-linking through both Fc receptors and PD-L1 results in enhanced CD27 agonist activity. CDX-527 was shown to mediate effector function against tumor cells overexpressing either CD27 or PD-L1. In human CD27 transgenic mice, we observed that antigen-specific T cell responses to a vaccine are greatly enhanced with a surrogate PD-L1xCD27 BsAb. Furthermore, the BsAb exhibits greater antitumor activity than the combination of the parental antibodies in a syngeneic lymphoma model. A pilot study of CDX-527 in cynomolgus macaques confirmed a mAb-like pharmacokinetic profile without noted toxicities. These studies demonstrate that CDX-527 effectively combines PD-1 blockade and CD27 costimulation into one molecule that is more potent than combination of the parental antibodies providing the rationale to advance this BsAb toward clinical studies in cancer patients.
- Subjects :
- Animals
Antibodies, Bispecific chemistry
Humans
Lymphoma, B-Cell immunology
Lymphoma, B-Cell metabolism
Lymphoma, B-Cell pathology
Macaca fascicularis
Male
Mice
Mice, Transgenic
Antibodies, Bispecific pharmacology
Antibody Formation
Immunotherapy methods
Lymphoma, B-Cell therapy
Programmed Cell Death 1 Receptor antagonists & inhibitors
Tumor Necrosis Factor Receptor Superfamily, Member 7 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0851
- Volume :
- 69
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cancer immunology, immunotherapy : CII
- Publication Type :
- Academic Journal
- Accession number :
- 32451681
- Full Text :
- https://doi.org/10.1007/s00262-020-02610-y