Abstract 1246: Development of an agonistic antibody against the human T-cell costimulatory receptor CD27 as a potential immunotherapeutic tool

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-04, Vol.73 (8_Supplement), p.1246-1246
• Main Authors: van Eenennaam, Hans, Veraar, Elise, Mulder, Winfried, Bastiaanssen, Ellen, Driessen, Lilian, Lutje Hulsik, David, Vink, Paul, van der Horst, Gerda, Xiao, Yanling, Borst, Jannie, van Elsas, Andrea
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2013-1246

Immunotherapy of cancer has reached a mature and exciting stage. Clinical activity of monoclonal antibodies (mAb) against the T-cell inhibitory receptors CTLA-4 and PD-1 indicate that cancer patients often have latent tumour-specific T cells that can be mobilized by blocking these receptors. Activation of the T-cell costimulatory receptor CD27, a member of the TNF receptor family, provides another opportunity to promote cytotoxic T cell (CTL)-based anti-tumor immunity. To generate agonistic mAb against human (h)CD27, we used our unique B-cell selection and immortalization technology. Various novel anti-hCD27 mAb were generated and tested for their agonistic properties. We used in vitro read-out systems detecting CD27 (co-)stimulatory function on the basis of NF-κB activity, T cell division and survival. One mAb hCD27.15 (KD ∼1 nM), induced CD27 receptor activation (EC50 ∼1 nM) without the need of cross-linking. Similar to its natural ligand CD70, our hCD27.15 mAb showed bona fide costimulatory properties. hCD27.15 strongly promoted CD8+ T cell expansion under conditions of suboptimal T-cell receptor (TCR) stimulation. hCD27.15 did not stimulate T cell function in absence of TCR engagement. hCD27.15 mAb demonstrated different binding kinetics and a unique epitope, compared to other antibodies that depend on cross-linking to activate CD27. Importantly, hCD27.15 retained its agonistic properties when expressed as a human IgG1 or IgG4 chimera. hCD27.15 was shown to bind and activate primate CD27 with similar potency, providing a rationale for pre-clinical safety testing. In conclusion, to our knowledge we have developed the first mAb to hCD27 that mimics ligand function without the need for cross-linking. Data from mouse models strongly support the application of CD27 agonism to enhance CTL-based anti-tumor immunity, by promoting the generation and survival of CTL, as well as their memory function. We propose therefore that hCD27.15 mAb is a promising tool for cancer immunotherapy. Citation Format: Hans van Eenennaam, Elise Veraar, Winfried Mulder, Ellen Bastiaanssen, Lilian Driessen, David Lutje Hulsik, Paul Vink, Gerda van der Horst, Yanling Xiao, Jannie Borst, Andrea van Elsas. Development of an agonistic antibody against the human T-cell costimulatory receptor CD27 as a potential immunotherapeutic tool. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA):