Abstract 3132: Innovative development of IMB-201, an anti-HLA-G antibody-drug conjugate (ADC), for enhanced tumor immunotherapy

Abstract Human leukocyte antigen-G (HLA-G), a non-classical MHC class I molecule, is expressed only in the placenta, where it functions as an immune suppressor to protect the fetus from maternal immune recognition. Recent studies have demonstrated that HLA-G is enriched in various malignant cells, providing evidence that HLA-G is strongly associated with tumor immune escape. HLA-G, a tumor-specific antigen, mediates immune suppression in tumor-infiltrating immune cells, including T cells, natural killer (NK) cells, and macrophages, by engaging inhibitory receptors such as Ig-like transcript 2 (ILT2) and 4 (ILT4). Therefore, the development of an HLA-G-targeting ADC can be a novel therapeutic strategy not only to induce direct tumor cell killing through payload delivery upon binding to HLA-G, but also to take advantage of the fact that HLA-G is minimally expressed on normal cells and predominantly restricted to tumor cells. This selective expression pattern makes HLA-G a promising target compared to other cancer antigens, in which off-target effects on normal tissues are expected to be minimal. Moreover, by disrupting the interaction between HLA-G and inhibitory receptors such as ILT2, this approach enhances anti-tumor immunity, followed by boosting immune activation and improving therapeutic outcomes. We developed an antibody-drug conjugate (ADC) targeting HLA-G (IMB-201) to selectively deliver cytotoxic drugs to HLA-G-expressing tumor cells, thereby overcoming immune suppression and promoting tumor regression. We generated a monoclonal antibody specific to HLA-G and conjugated it with a potent cytotoxic drug via a stable linker. The IMB-201 demonstrated high binding affinity and selectivity for HLA-G-positive tumor cells. In vitro serum and preliminary stability assays confirmed that the stability of IMB-201 is comparable to that of other developed ADCs. In vitro studies revealed significant dose-dependent cytotoxicity when treated to HLA-G-expressing cell lines, with minimal off-target effects on HLA-G-negative cells. In vivo studies employing mouse models demonstrated significant tumor regression and prolonged survival. Collectively, the IMB-201 could be a promising therapeutic approach for the treatment of HLA-G-positive solid tumors, such as gastric and pancreatic cancers. As HLA-G is a tumor-specific antigen, it has the potential to widen the therapeutic index (TI) compared to other conventional therapies. This strategy selectively targets tumor cells, delivering cytotoxic agents and enhancing immune response, thereby overcoming immune evasion mechanisms. Citation Format: Hyeonju Kang, Inyoung Lee, Joseph Kim, Yoojin Kim, Sungmuk Kang, Yongjun Kang, Hongjai Lee, Chungmin Lee, Chihye Park, Gyongsik Ha. Innovative development of IMB-201, an anti-HLA-G antibody-drug conjugate (ADC), for enhanced tumor immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3132.