Abstract
Tumor necrosis factor receptor superfamily member 7 (TNFRSF7, CD27), expressed primarily by T cells, and its ligand CD27L (TNFSF7, CD70) provide co-stimulatory signals that boost T cell activation, differentiation, and survival. Agonistic stimulation of CD27 is therefore a promising therapeutic concept in immuno-oncology intended to boost and sustain T cell driven anti-tumor responses. Endogenous TNFSF/TNFRSF-based signal transmission is a structurally well-defined event that takes place during cell-to-cell-based contacts. It is well-established that the trimeric-trivalent TNFSF-receptor binding domain (TNFSF-RBD) exposed by the conducting cell and the resulting multi-trimer-based receptor clustering on the receiving cell are essential for agonistic signaling. Therefore, we have developed HERA-CD27L, a novel hexavalent TNF receptor agonist (HERA) targeting CD27 and mimicking the natural signaling concept. HERA-CD27L is composed of a trivalent but single-chain CD27L-receptor-binding-domain (scCD27L-RBD) fused to an IgG1 derived silenced Fc-domain serving as dimerization scaffold. The hexavalent agonist significantly boosted antigen-specific T cell responses while having no effect on non-specific T cells and was superior over stabilized recombinant trivalent CD27L. In addition, HERA-CD27L demonstrated potent single-agent anti-tumor efficacy in two different syngeneic tumor models, MC38-CEA and CT26wt. Furthermore, the combination of HERA-CD27L and an anti-PD-1 antibody showed additive anti-tumor effects highlighting the importance of both T cell activation and checkpoint inhibition in anti-tumor immunity. In this manuscript, we describe the development of HERA-CD27L, a true CD27 agonist with a clearly defined forward-signaling mechanism of action.
Highlights
Strategies to enhance anti-tumor immune responses are among the most promising new developments in oncology due to important characteristics of the adaptive immune system; including, antigen-specificity, adaptability, and ability to generate long-lasting memory [1]
We showed that the unique molecular layout and binding mode of HERATRAIL/APG350, a prototype death receptor agonist, conferred potent biological activity that was superior to conventional agonistic antibodies and independent of additional crosslinking via Fcγ receptors (FcγR) [11, 14]
Immunotherapeutic strategies targeting stimulatory TNF receptor superfamily (TNFRSF) receptors to promote anti-tumor immune responses have tremendous potential and CD27 is an important candidate due to its unique role in both initiating as well as maintaining T cell responses
Summary
Strategies to enhance anti-tumor immune responses are among the most promising new developments in oncology due to important characteristics of the adaptive immune system; including, antigen-specificity, adaptability, and ability to generate long-lasting memory [1]. TNFRSF receptors are expressed by a wide variety of immune cells including T cells and antigen-presenting cell (APC) populations, such as dendritic cells and macrophages, as well as by tumor cells themselves [2, 3]. This diverse expression pattern highlights the critical role that they play in many locations and phases of the anti-tumor immune response. CD27 signaling, induced by its ligand CD70 (TNFSF7, CD27L), plays an important role in regulating immune responses by providing co-stimulatory signals to boost T cell activation, differentiation, survival and memory formation [3, 6, 7].
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