A fully human afucosylated anti-GARP antibody PBA-0111 drives anti-tumor immunity through combined ADCC induction and TGF-β1 pathway blockade.
We have evaluated PBA-0111, a fully human antibody targeting Glycoprotein A Repetitions Predominant (GARP), designed to induce both antibody-dependent cellular cytotoxicity (ADCC) as well as blockage of Transforming Growth Factor Beta 1 (TGF-β1) activation. Functional assessments included in vitro cytotoxicity assays, inhibition of GARP/TGF-β1 complex formation and inhibition of TGF-β1 signaling. PBA-0111 was compared with clinically tested anti-GARP antibodies, including DS-1055a- and ABBV-151-like antibodies. Lack of significant binding to human platelets was confirmed by flow cytometry. Anti-tumor efficacy in vivo was assessed in CD34+ human stem cell humanized mice xenograft models, including models where GARP was expressed both on tumor cells and regulatory T cells as well as models where GARP was expressed exclusively on regulatory T cells. The potential of PBA-0111 to stimulate immune cell activation inside tumors was further studied in a placebo-controlled Phase 0 clinical study in soft tissue sarcoma patients receiving intra-tumoral injections.
Our findings demonstrate that PBA-0111 exhibits ADCC activity comparable to DS-1055a-like antibody, which was not observed for ABBV-151-like antibody. PBA-0111 effectively blocks TGF-β1 activation, similar to ABBV-151-like antibody but unlike DS-1055a-like antibody. In contrast to ABBV-151, which blocks TGF-β1 activation within the pre-formed GARP/TGF-β1 complex, PBA-0111 prevents GARP/TGF-β1 complex formation itself. Importantly, PBA-0111 did not demonstrate significant binding to human platelets. In humanized mice, whether GARP was expressed on tumor cells or exclusively on Tregs, PBA-0111 treatment induced robust inhibition of tumor growth, whereas DS-1055a-like antibody did not demonstrate any statistically significant anti-tumor efficacy in these models. Tumor growth inhibition by PBA-0111 was accompanied by cytotoxic T cell activation. A similar trend of T cell activation was observed in soft tissue sarcoma patients receiving intra-tumoral injections of PBA-0111 in the Phase 0 clinical trial.
These results underscore the therapeutic potential of PBA-0111 as a dual-functioning immunotherapy and a promising candidate for the treatment of GARP-positive cancers. This integrated mechanism may amplify anti-tumor immunity, improve synergy with checkpoint inhibitors, and provide more durable reprogramming of the tumor microenvironment than either approach alone.
Our findings demonstrate that PBA-0111 exhibits ADCC activity comparable to DS-1055a-like antibody, which was not observed for ABBV-151-like antibody. PBA-0111 effectively blocks TGF-β1 activation, similar to ABBV-151-like antibody but unlike DS-1055a-like antibody. In contrast to ABBV-151, which blocks TGF-β1 activation within the pre-formed GARP/TGF-β1 complex, PBA-0111 prevents GARP/TGF-β1 complex formation itself. Importantly, PBA-0111 did not demonstrate significant binding to human platelets. In humanized mice, whether GARP was expressed on tumor cells or exclusively on Tregs, PBA-0111 treatment induced robust inhibition of tumor growth, whereas DS-1055a-like antibody did not demonstrate any statistically significant anti-tumor efficacy in these models. Tumor growth inhibition by PBA-0111 was accompanied by cytotoxic T cell activation. A similar trend of T cell activation was observed in soft tissue sarcoma patients receiving intra-tumoral injections of PBA-0111 in the Phase 0 clinical trial.
These results underscore the therapeutic potential of PBA-0111 as a dual-functioning immunotherapy and a promising candidate for the treatment of GARP-positive cancers. This integrated mechanism may amplify anti-tumor immunity, improve synergy with checkpoint inhibitors, and provide more durable reprogramming of the tumor microenvironment than either approach alone.
Authors
Spee Spee, Litwin Litwin, Trojanowski Trojanowski, Burns Burns, Dudek Dudek, Gołdyn Gołdyn, Sołtys Sołtys, Sobecki Sobecki, Świderska Świderska, Matyjaszczyk Matyjaszczyk, Orłowski Orłowski, Mamczur Mamczur, Kolodziejczyk Kolodziejczyk, Piliuhin Piliuhin, Xu Xu, Krzywińska Krzywińska, Deshmukh Deshmukh, Klaus Klaus, Świderek Świderek, Gillespie Gillespie, Turner Turner, Jenkins Jenkins, Frazier Frazier, Gundle Gundle, Weinberg Weinberg, Veitonmäki Veitonmäki
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