A first-in-class bifunctional anti-TRPV6 antibody turns "cold" tumors "hot"

Context : The classification between “hot” and “cold” tumors has emerged as a central paradigm in immuno-oncology. In particular “cold” tumors - including prostate, sarcoma and pancreatic cancers - exhibit poor immune cell infiltration and remain refractory to current immunotherapies. This situation highlights the need of alternative and transformative therapeutic approaches that target underexplored receptors such as ion channels. Among these, TRPV6 calcium channel has emerged as a key oncogenic driver in multiple solid malignancies. While TRPV6-targeting peptides have reached clinical stage, their limitations underscore the potential of a first-in-class antibody that would be able to modulate and reshape the TME. Methods. We recently identified MQI-201, a fully developable naked anti-TRPV6 antibody. After validating affinity, specificity and safety, we pursued in vivo characterization to explore its mode of action and we demonstrated MQI-201 efficacy on 6 cancer models, including 5 classified as “cold”. Results. Firstly, we validated MQI-201 efficacy in 4 xenografted models: including 2 mPC models (LNCaP and VCaP), 1 pancreatic cancer model (BxPc3) and 1 lymphoma model (L-540). In all models tested, MQI-201 at low dose (1-8 mg/kg) induces a tumor growth inhibition ranging from 71% (VCaP) to 93% (BxPc3 and L-540). Interestingly, in BxPc3 model, MQI-201 proved its superiority over Gemcitabine (TGI 93% vs 45%). Secondly, we evaluated MQI-201 efficacy in 2 syngeneic models described as “cold”: a fibrosarcoma model (MCA-205) and an hormono-resistant prostate cancer model (RM-1). In both aggressive models, we demonstrated that MQI-201 induces potent cytotoxicity (TGI > 80%) and a superiority over SOCs. Interestingly, the efficacy was mediated by paratopic and Fc region with a clear increase of efficacy in Fc-WT as compared to Fc-silent format. Finally, we fully explored the impact of MQI-201 treatment on TME using RM-1 model. MQI-201 induces potent tumor apoptosis and increases the recruitment of T-CD8+ cells, NK cells and Granzyme B+ cells. In addition, total macrophage population was stable whereas M2 pro-tumoral subpopulation decreased by 50% following treatment. The exploration of MQI-201 in afucosylated format is now under exploration. Conclusion. MQI-201 is a first-in-class anti-TRPV6 antibody able to turn “cold” tumors “hot” by reshaping the tumor microenvironment. These unique properties open new therapeutic avenues for solid cancer treatment to unlock durable responses across immunotherapy-resistant cancers.