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Abstract
Background Despite significant advancements in cancer immunotherapy with immune checkpoint inhibitors, there remains a need for more effective strategies to enhance anti-tumor immune responses. This study introduces the development and characterization of OriA631-B, a first-in-class CD39/PD-L1bispecific antibody, designed to simultaneously target two key immunosuppressive pathways. CD39, highly expressed by tumor-infiltrating immune cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and PD-L1, commonly over expressed on tumor cells, play crucial roles in immune evasion and suppression within the tumor microenvironment.
Methods OriA631-B was engineered using state-of-the-art antibody engineering techniques, ensuring optimal binding affinity and specificity for both of its target antigens CD39 and PD-L1. Through meticulous design and refinement, OriA631-B was developed to possess high affinity binding capabilities to both targets, allowing for simultaneous and specific recognition (figures 1,2). The utilization of advanced antibody engineering techniques enabled the creation of OriA631-B as a powerful tool with enhanced binding properties, facilitating its potential applications in various therapeutic settings.
Results In vitro studies demonstrated that OriA631-B, based on the backbone of a clinically validated in-house generated PD-L1 antibody (YN035), effectively blocked CD39-mediated adenosine production (figure 3), leading to enhanced effector T cell function and proliferation (figure 4). In vivo efficacy studies employing syngeneic tumor models demonstrated the remarkable efficacy of OriA631, the CD39 monoclonal antibody (mAb), in effectively controlling tumor growth (figure 4). Furthermore, the impact of OriA631-B, the CD39/PD-L1 bispecific antibody, was even more profound, as it significantly inhibited tumor growth surpassing the effects observed with single-target treatments or combination therapies (figure 5). These findings highlight the potent therapeutic potential of OriA631-B and its ability to exert robust anti-tumor activity by targeting both CD39 and PD-L1 simultaneously. Moreover, safety profiling demonstrated an acceptable toxicity profile for OriA631-B, with no significant adverse events observed during the study.
Conclusions Overall, our findings highlight the potential of OriA631-B as a novel immunotherapeutic approach for cancer treatment. By simultaneously targeting CD39-mediated immune suppression and PD-L1-mediated T cell exhaustion, this bispecific antibody holds promise for overcoming resistance mechanisms and acting as a T cell-tumor cell engager, thus improving patient outcomes (figure 6). Further investigations, including clinical trials, are warranted to fully explore the therapeutic potential of this innovative bispecific antibody in the context of cancer immunotherapy.
CD39/PD-L1 BsAb (OriA631-B) relative to CD39 mAb (OriA36) and PD-L1 mAb (YN035) exhibited comparable binding strengths to human CD39 and PD-L1. Assessment of Binding Affinities of CD39 mAb (OriA631), CD39/PD-L1 BsAb (OriA631-B), and Benchmark CD39 mAb H5L5 to Human CD39 (A, B) and OriA631-B and PD-L1 mAb (YN035) to human PD-L1 (C). Evaluation performed using human CD39 or PD-L1 over-expressing CHO cells
CD39/PD-L1 BsAb (OriA631-B) exhibited similar affinity to human CD39 and PD-L1, comparable to that of CD39 mAb(OriA631) and PD-L1 mAb (YN035). Affinity Assessment of CD39 mAb (OriA631), CD39/PD-L1 BsAb (0ri631-B), and Benchmark H5L5 to CD39 (A, B, and C); PD-L1 mAb (YN035) and OriA631-B to PD-L1 (D and E) using ForteBio Octet
Comparative Assessment of Enzymatic Inhibition Ability and Internalization of CD39: OriA631-B versus CD39 mAb (OriA631) and/or Benchmark H5L5. (A) CD39 enzymatic inhibition assay was performed using soluble CD39. (B) CD39 enzymatic inhibition assay was conducted using SK-MEL-28 cells. (C) Internalization of CD39 with CD39 mAb (OriA631) and CD39/PD-L1 BsAb (OriA631-B) was clearly observed in hCD39 over-expressing CHO cells. The cells were incubated at 37°C for 1.5 hours with the indicated concentrations of CD39 mAb (OriA631) and CD39/PD-L1 BsAb (OriA631-B)
CD39 mAb (OriA631) exhibited significant anti-tumor efficacy in a mouse liver cancer model
CD39/PD-L1 BsAb (OriA631-B) demonstrated the highest anti-tumor efficacy among the tested agents
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