Abstract 3813: Development of JNJ-64164711, a low fucose anti-GITR antibody for enhanced depletion of tumor regulatory T cells (Tregs)
Authors: Cam V. Holland, John Kehoe, Judith Hailey, Rupesh Nanjunda, Eilyn Lacy, Robin Ernst, Di Zhang, Sam Wu, Alexey Teplyakov, Weimin Li, Michelle Kinder, Edward W. Thompson, Patrick Wilkinson, Jackson Wong, Gerald Chu, Linda Okonkwo, John D. Alvarez, Anhco Nguyen, Iqbal S. Grewal, Moitreyee Chatterjee-Kishore, Mark Salvati, Marco Gottardis
Journal: Cancer Research (2018)

Abstract Background: Checkpoint blockade of PD-1/PDL-1 or CTLA-4 has demonstrated clinical benefit in a subset of cancer patients (pts). To further improve the outcome, approaches to deplete immunosuppressive Tregs are being developed. Emerging evidence supports that the TNF receptor superfamily member 18 (TNFRSF18 or GITR) is highly expressed on intratumoral (i.t.) Tregs with limited expression on effector T cells or circulating immune cells (1,2). This differential expression allows for development of monoclonal antibody (mAb) therapies that eliminate this population while sparing other immune subsets. Herein we characterize JNJ-64164711 (JNJ-711), a fully human anti-GITR mAb being developed to selectively deplete GITR+ Tregs and expand the population of pts that may respond to immunotherapy. Methods: Treg frequency and GITR expression on human cancer specimens was performed by IHC and multicolor flow cytometric analysis (FC). JNJ-711 was assessed for binding to GITR (human and cyno) and human Fcγ receptors, and inhibition of hGITRL binding to hGITR. The JNJ-711 binding epitope was mapped by hydrogen-deuterium exchange. JNJ-711 functional activity was determined by 1) an NF-kB reporter assay, 2) antibody dependent cellular cytotoxicity (ADCC) on GITR+ cell lines, and 3) JNJ-711 mediated Treg depletion in primary pts tumor samples. Results: GITR expression prevalence was evaluated by IHC in multiple solid tumors. Immune cell GITR expression was observed in head and neck (HN), esophageal (ESO), non-small cell lung carcinoma (NSCLC), colorectal (CRC) and prostate cancers. GITR was moderately expressed on HN and ESO tumor cells. GITR expression (by FC) was higher on tumor Tregs versus other T cell populations in the tumor and periphery across NSCLC, CRC, ovarian and renal cell carcinoma samples. GITR was differentially higher on i.t. effector Tregs (eTreg) whereas CCR4 was highest on CD4+ T cells in circulation. JNJ-711 binds to hGITR on cells with high affinity [KD= 180 pM], has a log greater affinity to FcγRIIIa [KD= 37 nM on 158V; KD= 180 nM on 158F], a slower dissociation rate than most GITR agonist (Ag) mAb tested [Koff= 5.47 x 10-4 s-1 for Fab], and binds to the CRD1 of GITR. Unlike other GITR Ag mAbs tested, JNJ-711 does not block GITR interaction with GITRL. JNJ-711 demonstrates higher ADCC mediated cell depletion than other GITR Ag mAbs in clinical development on 1) GITR+ hematologic tumor cell lines (HuT102, KMS-12-BM, RPMI 8226, JJN-3), 2) primary activated GITR+ T cells, and 3) in vitro expanded Tregs. Using dissociated primary pts samples, JNJ-711 selectively depleted i.t. eTregs. Conclusion: JNJ-64164711 selectively depletes hGITR+ cells including Tregs and has potential to enhance antitumor immune response. This antibody is being evaluated for clinical development. References: 1. Asma et al. Tumor Biol 2015;36:3727-34. 2. Pedroza-Gonzalez et al. OncoImmunology 2015;4:12, e1051297. Citation Format: Cam V. Holland, John Kehoe, Judith Hailey, Rupesh Nanjunda, Eilyn Lacy, Robin Ernst, Di Zhang, Sam Wu, Alexey Teplyakov, Weimin Li, Michelle Kinder, Edward W. Thompson, Patrick Wilkinson, Jackson Wong, Gerald Chu, Linda Okonkwo, John D. Alvarez, Anhco Nguyen, Iqbal S. Grewal, Moitreyee Chatterjee-Kishore, Mark Salvati, Marco Gottardis. Development of JNJ-64164711, a low fucose anti-GITR antibody for enhanced depletion of tumor regulatory T cells (Tregs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3813.