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Abstract
Background CCR8-expressing CD4 and Foxp3 positive Treg (CCR8+ Treg) has been demonstrated to be a major driver for immunosuppression in solid tumors1 <1> Superscript. Clinical studies have shown that CCR8 is selectively up-regulated by tumor resident Tregs in several tumor types including clear cell renal cell carcinoma (ccRCC)2 <2> Superscript and breast cancer3 <3> Superscript. In these tumor types, CCR8 exhibit strong expression on tumor resident Tregs while it is rarely observed on Tregs in peripheral blood mononuclear cells (PBMCs). High expression of the CCR8 in tumor-infiltrating lymphocytes-Treg cells (TIL-Tregs) was associated with poor prognosis in breast cancer patients. These results suggest CCR8 as a promising therapeutic target; and anti-CCR8 mAbs could selectively inhibit a subpopulation of tumor resident Tregs in the tumor microenvironment (TME), to augment antitumor immunity.
Methods In vitro assay:HBM1022 binding on human, cynomolgus CCR8 and TIL-Tregs are evaluated via flow cytometry. Blocking and ADCC functional assay are all based on CCR8 overexpressing cell lines.In vivo efficacy study:HBM1022 anti-CCR8 antibody was administered after implantation (≈ 100 mm3 <3>Superscript tumor volume) alone and in combination with anti−PD-1.
Results Anti-CCR8 antibody HBM1022 specifically binds to cell lines that over-express human or cynomolgus CCR8, as well as TIL-Tregs in multiple cancer types with the high affinity. HBM1022 potently blocks CCL1 binding to both human and cynomolgus CCR8. HBM1022 inhibits CCL1-induced migration and related GPCR signaling pathways. Furthermore, with enhanced antibody-dependent cell-mediated cytotoxicity (eADCC) activity, HBM1022 exhibits potent in vitro killing activity on CCR8-expressing cells. HBM1022 shows tumor growth inhibition as monotherapy in preclinical mouse syngeneic and humanized models. Moreover, HBM1022 shows enhanced antitumor activity with the combination of Keytruda® in preclinical efficacy models.
Conclusions Our finding reveals HBM1022 as an innovative immunotherapy targeting intra-tumoral suppressive Treg cells to change suppressive tumor to hot tumor. HBM1022 presents its great potential as exciting mono or combo anti-tumor therapies.
References
Yiftah B, Gizi W, Eran L, et al. CCR8+FOXp3+ Treg cells as master drivers of immune regulation. Proc Natl Acad Sci U S A 2017;114 (23):6086–6091.
Tetsuya Y, Yujiro K, Mitsunobu M, et al. Method of treating cancer with an anti-CCR8 having antibody-dependent cell-mediated cytotoxicity (ADCC) activity against cells expressing CCR8. US10550191B2. 2020.
George P, Catherine K, Kenmin W, et al. Regulatory T cells exhibit distinct features in human breast cancer. Immunity 2016;45:1122–1134.
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