Exploring the anti-tumor potential of HLA-G-targeted therapeutics through diverse preclinical approaches

HLA-G, a non-classical MHC class I molecule with potent immunosuppressive properties, is aberrantly expressed in various solid tumors and plays a critical role in immune evasion. This immune suppression is primarily mediated through its interaction with inhibitory receptors such as ILT-2 on immune cells, which dampens anti-tumor responses and facilitates tumor progression. As such, HLA-G functions as an immune checkpoint molecule, making it a promising target for cancer immunotherapy. Monoclonal antibodies and CAR-T therapies targeting HLA-G have been previously explored; however, further optimization of therapeutic formats, incorporation of novel modalities such as antibody-drug conjugates (ADCs) and multi-specific antibodies, and preclinical validation are needed to advance their clinical potential. In this study, we present a preclinical evaluation of HLA-G-targeting biologics, including ADCs and bispecific antibodies, with emphasis on pharmacokinetics, efficacy, and biomarker-guided tumor selectivity. Notably, in a choriocarcinoma xenograft model, one complete response was observed following ADC monotherapy, suggesting the therapeutic potential of HLA-G-targeted ADCs in specific tumor contexts. To further assess clinical relevance, MiniPDX platforms derived from patient tumors were employed for target validation and biomarker correlation. These studies indicate HLA-G expression may serve as a predictive marker for therapeutic response and revealed differential efficacy across tumor types. In parallel, bispecific antibodies targeting HLA-G and co-expressed tumor antigens were evaluated for binding affinity and cytotoxicity. Bispecific formats demonstrated enhanced tumor cell engagement and potent anti-tumor activity, suggesting their utility in overcoming antigen heterogeneity and resistance mechanisms. Collectively, these findings provide preclinical evidence supporting the development of HLA-G-targeting therapeutics using diverse modalities. ADCs are particularly appealing as they can enhance potency through cytotoxic payloads while minimizing off-target toxicity due to the tumor-specific antigen nature of HLA-G. In addition, bispecific antibodies may offer further tumor selectivity and augment immune activation. This study presents additional efficacy data from in vivo xenograft and MiniPDX models, contributing to the ongoing preclinical evaluation of HLA-G-targeting strategies. Importantly, HLA-G has emerged as a potential therapeutic target capable of delivering robust efficacy through diverse therapeutic modalities and may serve as a predictive biomarker. These findings underscore the potential of HLA-G-targeted therapeutics, particularly ADCs and bispecific formats, as investigational treatment options for cancers with limited effective therapies, such as ovarian cancer.