Abstract 4532: Preclinical evaluation of JTX-1811, an anti-CCR8 antibody with enhanced ADCC activity, for preferential depletion of tumor-infiltrating regulatory T cells

Abstract

Introduction: Immune checkpoint blockade (ICB) has revolutionized the treatment of many cancers, still most patients do not respond to PD-1 or CTLA-4 inhibitors. Thus, new Immuno-Oncology (IO) therapies that could potentially benefit non-responding patients are greatly needed. Jounce has generated cell type-specific gene signatures as a means of probing The Cancer Genome Atlas and other large datasets for novel IO targets. Regulatory T cells (Tregs) are one attractive cell type for targeting as they may contribute to resistance to ICB. While Tregs are critical for immune homeostasis and preventing tissue damage, they are often present in large numbers within tumors where they may suppress anti-tumor immunity. Therapeutic strategies that specifically deplete tumor-infiltrating Tregs (TITRs) while sparing peripheral and normal tissue Tregs are highly desirable. Using a Treg gene signature, we have a found a strong correlation with TITRs and CCR8 (C-C motif chemokine receptor 8) across multiple tumor types. CCR8 may be differentiated from other known Treg targets in this regard, as its expression was found to be highly selective to TITRs. Methods and Results: We first assessed CCR8 levels on TITRs across multiple tumor types and compared expression to Tregs in normal colon tissue or peripheral blood. On average, peripheral blood Tregs had nearly undetectable CCR8 expression and normal colon tissue Tregs showed 4 to 5-fold lower levels of CCR8 than TITRs. We then generated a panel of monoclonal antibodies (mAbs) that bind specifically to CCR8, but not other family members, and block CCR8 signaling induced by its ligand CCL1. The ability of these mAbs to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) of target cells expressing CCR8 was tested. When target cells expressed CCR8 at levels equivalent to normal tissue Tregs no ADCC activity was observed. In contrast, when cells expressed CCR8 at levels equivalent to TITRs, robust ADCC was observed, but only using antibodies in which the human IgG1 Fc was afucosylated. Thus, afucosylated anti-CCR8 antibodies demonstrated a therapeutic window whereby TITRs but not normal tissue Tregs could be depleted. An Fc competent, mouse-specific, anti-CCR8 antibody showed single agent tumor growth inhibition across several murine tumor models - including models in which anti-PD-1 was ineffective. Anti-CCR8 was a potent combination partner with anti-PD-1 resulting in 50% complete tumor regressions in PD-1 resistant models. Conclusions: Based on these pre-clinical data JTX-1811, a high affinity CCR8-specific humanized monoclonal antibody with enhanced ADCC activity, is being developed for the selective depletion of tumor-infiltrating Tregs. JTX-1811 may be useful in PD-1 resistant settings and may restore the activity of PD-1 inhibitors in the setting of primary or acquired resistance to ICB. Citation Format: Fabien Dépis, Changyun Hu, Jessica Weaver, Lara McGrath, Boris Klebanov, Joshua Buggé, Ben Umiker, Christine Fregeau, Dhruvkumar Upadhyay, Anirudh Singh, Chang-Ai Xu, Vikki Spaulding, Michelle Priess, Masie Wong, Seema Naheed, Yan Zhang, Kristin Legendre, Edward C. Stack, Alessandro Mora, Margaret Willer, Kristan Meetze, Monica Gostissa, Michael A. Meehl, Donald R. Shaffer. Preclinical evaluation of JTX-1811, an anti-CCR8 antibody with enhanced ADCC activity, for preferential depletion of tumor-infiltrating regulatory T cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4532.

Preclinical and translational pharmacology of afucosylated anti‐CCR8 antibody for depletion of tumour‐infiltrating regulatory T cells

“…q3w was well tolerated (Kolben, 2021). CCR8 has a more restricted expression profile (lower copy number per cell and more selective expression in tumour) than CCR4 and CD25, both of which have been used as targets for Treg‐cell depletion (Campbell et al, 2021; Dépis et al, 2020). Furthermore, the average RO over the first dosing interval of 21 days in the tumour (target site) is predicted to be about 80% based on the mPBPK–PD model simulations, at the proposed starting dose.…”

“…In contrast, CCR8 is expressed at a lower level and only on a small fraction of Treg cells in circulation and normal tissues, including the intestine, skin and lung. In tumours, only a small subset of CD4 + and CD8 + effector T cells expresses CCR8 (Campbell et al, 2021; Dépis et al, 2020). Additionally, the expression of CCR8 on effector T cells is substantially lower than that of CCR4 and CD25, two other targets evaluated in clinical trials for Treg‐cell depletion (Campbell et al, 2021).…”

Recruitment and Expansion of Tregs Cells in the Tumor Environment—How to Target Them?

“…JTX-1811, recently developed by Jounce Therapeutics (Cambridge, MA, USA) in collaboration with Gilead (Foster City, CA, USA), is a humanized mAb with enhanced ADCC activity to selectively deplete immunosuppressive CCR8 + TA-Tregs. Experiments with a surrogate mAb specific for murine CCR8 showed good activity as a single agent or in combination with PD-1 inhibitors in anti-PD-1-resistant murine tumor models [ 333 ], suggesting that JTX-1811 would be efficient to deplete CCR8 + Tregs in human solid tumors in favor of the antitumor immune response. Its evaluation in a clinical trial is planned.…”

Integrated BATF transcriptional network regulates suppressive intratumoral regulatory T cells

“…An elevated frequency of T regs within a tumor is associated with an adverse prognosis across many cancers (5)(6)(7)(8)(9). The current methods of targeting T regs in the clinic are direct T reg depletion, targeting costimulatory or coinhibitory receptors, halting T reg migration into the TME, and inducing T reg fragility (10)(11)(12)(13)(14). However, immune-related adverse effects such as pneumonitis and colitis were seen in clinical studies of T reg -targeted therapies (15)(16)(17).…”