HERA-GITRL activates T cells and promotes anti-tumor efficacy independent of FcγR-binding functionality.

Autor: Richards DM; Research and Development, Apogenix AG, Im Neuenheimer Feld 584, 69120, Heidelberg, Germany., Marschall V; Present address: Biotest AG, Dreieich, Germany., Billian-Frey K; Research and Development, Apogenix AG, Im Neuenheimer Feld 584, 69120, Heidelberg, Germany., Heinonen K; Research and Development, Apogenix AG, Im Neuenheimer Feld 584, 69120, Heidelberg, Germany., Merz C; Research and Development, Apogenix AG, Im Neuenheimer Feld 584, 69120, Heidelberg, Germany., Redondo Müller M; Research and Development, Apogenix AG, Im Neuenheimer Feld 584, 69120, Heidelberg, Germany., Sefrin JP; Research and Development, Apogenix AG, Im Neuenheimer Feld 584, 69120, Heidelberg, Germany., Schröder M; Research and Development, Apogenix AG, Im Neuenheimer Feld 584, 69120, Heidelberg, Germany., Sykora J; Research and Development, Apogenix AG, Im Neuenheimer Feld 584, 69120, Heidelberg, Germany., Fricke H; Present address: SOTIO, Prague, Czech Republic., Hill O; Research and Development, Apogenix AG, Im Neuenheimer Feld 584, 69120, Heidelberg, Germany., Gieffers C; Research and Development, Apogenix AG, Im Neuenheimer Feld 584, 69120, Heidelberg, Germany., Thiemann M; Research and Development, Apogenix AG, Im Neuenheimer Feld 584, 69120, Heidelberg, Germany. meinolf.thiemann@apogenix.com.
Jazyk: angličtina
Zdroj: Journal for immunotherapy of cancer [J Immunother Cancer] 2019 Jul 19; Vol. 7 (1), pp. 191. Date of Electronic Publication: 2019 Jul 19.
DOI: 10.1186/s40425-019-0671-4
Abstrakt: Background: Glucocorticoid-induced TNFR-related protein (TNFRSF18, GITR, CD357), expressed by T cells, and its ligand (TNFSF18, GITRL), expressed by myeloid populations, provide co-stimulatory signals that boost T cell activity. Due to the important role that GITR plays in regulating immune functions, agonistic stimulation of GITR is a promising therapeutic concept. Multiple strategies to induce GITR signaling have been investigated. The limited clinical efficacy of antibody-based GITR agonists results from structural and functional characteristics of antibodies that are unsuitable for stimulating the well-defined trimeric members of the TNFRSF.
Methods: To overcome limitations of antibody-based TNFRSF agonists, we have developed HERA-GITRL, a fully human hexavalent TNF receptor agonist (HERA) targeting GITR and mimicking the natural signaling concept. HERA-GITRL is composed of a trivalent but single-chain GITRL-receptor-binding-domain (scGITRL-RBD) unit fused to an IgG1 derived silenced Fc-domain serving as dimerization scaffold. A specific mouse surrogate, mmHERA-GITRL, was also generated to examine in vivo activity in respective mouse tumor models.
Results: For functional characterization of HERA-GITRL in vitro, human immune cells were isolated from healthy-donor blood and stimulated with anti-CD3 antibody in the presence of HERA-GITRL. Consistently, HERA-GITRL increased the activity of T cells, including proliferation and differentiation, even in the presence of regulatory T cells. In line with these findings, mmHERA-GITRL enhanced antigen-specific clonal expansion of both CD4+ (OT-II) and CD8+ (OT-I) T cells in vivo while having no effect on non-specific T cells. In addition, mmHERA-GITRL showed single-agent anti-tumor activity in two subcutaneous syngeneic colon cancer models (CT26wt and MC38-CEA). Importantly, this activity is independent of its FcγR-binding functionality, as both mmHERA-GITRL with a functional Fc- and a silenced Fc-domain showed similar tumor growth inhibition. Finally, in a direct in vitro comparison to a bivalent clinical benchmark anti-GITR antibody and a trivalent GITRL, only the hexavalent HERA-GITRL showed full biological activity independent of additional crosslinking.
Conclusion: In this manuscript, we describe the development of HERA-GITRL, a true GITR agonist with a clearly defined mechanism of action. By clustering six receptor chains in a spatially well-defined manner, HERA-GITRL induces potent agonistic activity without being dependent on additional FcγR-mediated crosslinking.
Databáze: MEDLINE
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