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.
Highlights
Antibody blockade of PD-1/PD-L1 interactions has resulted in regulatory approvals in at least 14 different cancer indications, demonstrating the broad utility of this approach [1, 2]
The 9H9 mAb and avelumab demonstrated a similar concentration dependence in binding to PD-L1, inhibition of PD-1 binding to PD-L1, and inhibition of CD80 binding to PD-L1 (Fig. 2a–c)
To generate the bispecific antibody (BsAb), we initially developed and characterized novel fully human antibodies to CD27 and PD-L1 that were primarily selected for CD27 agonist activity and inhibition of PD-1 signaling, respectively
Summary
Antibody blockade of PD-1/PD-L1 interactions has resulted in regulatory approvals in at least 14 different cancer indications, demonstrating the broad utility of this approach [1, 2]. The TNFR superfamily member CD27 is a T cell costimulatory molecule with an important and non-redundant role in their activation, proliferation and survival [7,8,9,10]. This point is best illustrated in individuals with deficiency of either CD27 or its ligand CD70 that results in sometimes fatal EBV-driven lymphoproliferation, hypogammaglobulinemia and lymphoma development [11,12,13,14,15]. Among the costimulatory molecules 4-1BB (CD137), OX40 (CD134) and ICOS (CD278), CD27 is uniquely expressed at high levels on naïve T cells making it especially well-suited to help prime and promote new T cell responses [7, 16,17,18]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
