The impact of CD3 affinity-attenuation on T cell engaging bispecific antibodies: is it really that simple?

INTRODUCTION: The first generation of approved T cell engagers (TCEs) showing promising efficacy in hematological and solid tumors relies on high binding affinity to CD3. Treatment of tumors with TCEs has been clinically associated with toxicities related to cytokine release syndrome (CRS). In addition to clinical strategies to mitigate CRS, antibody engineering efforts have been undertaken to generate TCEs with optimized therapeutic index. Strategies pursued in this context include affinity attenuation of CD3 binding arm, to achieve potent tumor cell killing with minimal cytokine secretion. AREAS COVERED: A literature search was conducted to identify peer-reviewed articles related to CD3 affinity and T cell engagers. Here, we provide an overview of the current state and recent developments in CD3 affinity-attenuation, both preclinically and clinically, with a focus on the challenges of developing TCEs with attenuated affinity to CD3 as well as identifying possible areas of improvement. EXPERT OPINION: CD3 affinity reduction can effectively lower cytokine levels preclinically; however, it is crucial to consider all factors influencing the mode of action of TCEs. Prioritizing the use of the most translatable preclinical models is essential to identify the right candidates for further development.