Pre-clinical evaluation of surovatamig (AZD0486) in comparison to CD20xCD3 bispecific antibodies

Abstract Background Surovatamig is a novel, fully human IgG4 bispecific T-cell engager (TCE) targeting CD19 and CD3. Engineered with low CD3 affinity, Surovatamig aims to broaden the clinical therapeutic window by reducing cytokine release while maintaining potent T-cell-mediated cytotoxicity. We conducted comprehensive preclinical comparisons between Surovatamig and FDA-approved CD20×CD3 bispecifics (mosunetuzumab, epcoritamab, and glofitamab) to evaluate relative efficacy and safety profiles. Methods Comparative analyses were performed using in vitro assays to evaluate T-cell activation, cytokine release, and cytotoxicity against B-cell tumor lines. In vivo studies utilized humanized murine xenograft models engrafted with CD19+ and CD20+ B-cell tumors to assess anti-tumor efficacy and pharmacodynamic responses. All CD20×CD3 comparators were tested at clinically relevant concentrations. Primary endpoints included tumor burden reduction and quantification of serum cytokines. Results Surovatamig ability to induce T cell activation in the absence of target B cells was evaluated in vitro, in a soluble and plate-bound formats, and showed minimal non-specific T cell activation in comparison to CD20xCD3 benchmarks which activated 40% to 100% of T cells. In the presence of target B cells and at clinically relevant high concentrations (4 nM-20 nM), Surovatamig demonstrated robust T-cell-mediated cytotoxicity, comparable to benchmarks, while producing significantly lower levels of cytokines. In particular, Surovatamig induced IL-6 levels on average 5-fold lower than glofitamab (~380 pg/mL vs 1950 pg/mL), with parallel reductions observed for TNF-α and IL-10 (~161 pg/mL vs 970 pg/mL and ~390 pg/mL vs 3645 pg/mL, respectively). In vivo, Surovatamig induced dose-dependent tumor regression in a Toledo-luciferase humanized disseminated mouse model from DLBCL origin. At 0.4 mg/kg, Surovatamig achieved near-complete tumor clearance (>3 log decrease in luminescence compared to PBS control group), showing comparable efficacy to benchmark TCEs. Critically, 3h post-dosing, Surovatamig triggered substantially less systemic cytokine release (mean ± SD TNF-α levels of 74 ± 21 pg/mL) compared to glofitamab (2146 ± 1329 pg/mL). Mosunetuzumab and epcoritamab induced cytokine release trending slightly higher than Surovatamig levels, albeit significantly lower than glofitamab (298 ± 184 and 349 ± 181 pg/mL, respectively). Similar profiles were observed across other cytokines evaluated (e.g. IL-10, IL-2, IL-17A). Conclusions These findings demonstrate that Surovatamig's unique low-affinity CD3 binding delivers effective anti-tumor activity while significantly reducing CRS-associated cytokine in preclinical models. This favorable profile positions Surovatamig as a promising therapeutic candidate with potential to expand the therapeutic window and improve tolerability for patients with B-cell related pathologies, supporting its advancement into clinical investigation.