Background T cell redirecting bispecific antibodies, a class of molecules which work by redirecting T cells into close contact with tumor cells, and therefore promoting T cell activation and tumor cell killing, have shown great promise in oncology, even in heavily refractory patients.¹ However, as with many immunotherapies, there is a risk of toxicity associated with this class of drugs.² Various approaches are often explored to reduce this risk, including pre-dosing with anti-inflammatory agents, subcutaneous administration, step-up dosing, and attenuation of the CD3-binding arm.³ This type of attenuation has successfully reduced toxicity and increased therapeutic index for several other classes of drugs⁴ and is expected to be beneficial for certain T cell redirectors. The objectives of this study are to investigate the impact of attenuation of CD3 binding on (tumor-antibody-T cell) trimer formation and to computationally assess the potential benefits and limitations of this approach.

Methods We developed a mechanism-based quantitative systems pharmacology (QSP) model to assess differential activity of T cell redirectors. The model reasonably characterizes preclinical and clinical dynamics of several T cell redirectors and was used for detailed exploration of trimer formation and activity in the tumor microenvironment. The core mechanism of action is implemented using mass-action binding, in line with other recently published models.^{5 6}

Results With a mathematical analysis, we show that the (CD3 or tumor antigen) receptor occupancy (RO) required for maximal efficacy of T cell redirectors is molecule-specific and can vary from less than 10% to more than 90%. We further show that trimer formation has an intrinsic upper bound, influenced primarily by the density of the high affinity antigen and the K_D of the low affinity binder. Finally, we show that the combination of attenuated CD3 binding and low target expression is potentially more likely to lead to bell-shaped dose-response curves.

Conclusions Attenuation of CD3 binding in T cell redirectors has the potential to improve therapeutic index but may also cause a reduction in trimer formation that cannot be overcome by increasing dose. The competing effects of antigen densities and binding affinities should be quantitatively characterized using mechanistic models to help guide target selection and lead design and to assess the therapeutic potential of various compounds on a case-by-case basis.

Acknowledgements Acknowledgements to J&J Oncology, Clinical Pharmacology & Pharmacometrics, Translational Research, & Compound Development Teams.

References

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