Abstract
3 min read<h3>Background</h3> Tumor-infiltrating regulatory T (Treg) cells aid the development and progression of tumors by inhibiting the anti-tumor immune response. This immunosuppressive effect often leads to resistance against current immunotherapies for certain cancers .<sup>1 2</sup> Although the first generation Treg-depleting CTLA-4 antibody ipilimumab has shown clinical efficacy, its use, particularly in combination with PD-1 inhibitors, has been associated with severe immune-related adverse events.<sup>3</sup> To address this difficulty, we set out to develop a next-generation Treg-depleting antibody with improved efficacy and safety. Since tumor-infiltrating Treg cells consistently exhibit higher expression levels of both CTLA-4 and OX40 compared to T cells in the periphery across multiple cancer types,<sup>4 5</sup> we developed an Fc-enhanced CTLA-4×OX40 bispecific IgG1 antibody, YH006, designed to deplete tumor-infiltrating Treg cells with better specificity. YH006 was generated from the RenLite® mouse, which contains a fully human common light chain to facilitate bispecific antibody assembly and the downstream CMC process. <h3>Methods</h3> The ability of YH006 to promote T-cell responses <i>in vitro</i> was measured by effector cytokine secretion from staphylococcal enterotoxin b-stimulated human PBMCs, and ADCC activity in the context of effector NK-92 cells (with CD16A expression) and human Treg cells, measured by flow cytometry. The <i>in vivo</i> anti-tumor activity of YH006 was evaluated in B-hCTLA-4/hOX40 humanized mice with syngeneic tumors. Transaminase and serum cytokine levels were monitored to determine the preclinical safety of YH006 <i>in vivo</i>. The physiochemical properties of YH006 were assessed by HPLC and LC-MS. <h3>Results</h3> YH006 treatment and ADCC activity over ipilimumab <i>in vitro</i>. In <i>vivo</i> syngeneic tumor studies demonstrated a superior and dose-dependent anti-tumor activity of YH006 compared to both ipilimumab analog and its Fc-enhanced parental monoclonal antibodies at low doses. Tumor-infiltrating lymphocyte analysis revealed that YH006 treatment can better increase the intra-tumoral CD8/Treg ratio compared with ipilimumab analog. YH006 also showed dose-dependent efficacy in GL261 syngeneic model. Notably, YH006 synergized with PD-1 or PD-L1 antibodies in syngeneic MC38 and B16F10-OVA models. Importantly, YH006 treatment did not elevate liver enzymes or induce production of inflammatory cytokines. Ongoing CMC process development has a titer of 6.9 g/L at the 3L scale, and the purification yield is 80.7%, suggesting excellent quality without homodimers detected. YH006 has consistent quality from research cell bank (RCB) to passage 97. <h3>Conclusions</h3> YH006 demonstrated superior anti-tumor efficacy across several tumor models and excellent physiochemical properties, which make it a promising candidate for further development as a cancer treatment. <h3>References</h3> Saleh R, Elkord E. Treg-mediated acquired resistance to immune checkpoint inhibitors. <i>Cancer Lett</i> 2019;<b>457</b>:168–79. Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? <i>Cancer Sci</i> 2019;<b>110</b>(7):2080–89. Weber J, Mandala M, Del Vecchio M, <i>et al</i>. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. <i>N Engl J Med</i> 2017;<b>377</b>(19):1824–35. Montler R, Bell RB, Thalhofer C, <i>et al</i>. OX40, PD-1 and CTLA-4 are selectively expressed on tumor-infiltrating T cells in head and neck cancer. <i>Clin Transl Immunology</i> 2016;<b>5</b>(4):e70. Arce Vargas F, Furness AJS, Litchfield K, <i>et al</i>. Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies. <i>Cancer Cell</i> 2018;<b>33</b>(4):649–63 e4. <h3>Ethics Approval</h3> All animal studies were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Biocytogen Beijing Co., Ltd.
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