Abstract
T cell-engaging immunotherapies are changing the landscape of current cancer care. However, suitable target antigens are scarce, restricting these strategies to very few tumor types. Here, we report on a T cell-engaging antibody derivative that comes in two complementary halves and addresses antigen combinations instead of single molecules. Each half, now coined hemibody, contains an antigen-specific single-chain variable fragment (scFv) fused to either the variable light (VL) or variable heavy (VH) chain domain of an anti-CD3 antibody. When the two hemibodies simultaneously bind their respective antigens on a single cell, they align and reconstitute the original CD3-binding site to engage T cells. Employing preclinical models for aggressive leukemia and breast cancer, we show that by the combinatorial nature of this approach, T lymphocytes exclusively eliminate dual antigen-positive cells while sparing single positive bystanders. This allows for precision targeting of cancers not amenable to current immunotherapies.
Highlights
T cell-engaging immunotherapies are changing the landscape of current cancer care
Hemibodies even when mixed prior to sizeexclusion chromatography (SEC) did not hetero-dimerize or multimerize (Fig. 2a, bottom, blue curve), an observation that is important in light of exposed hydrophobic patches at the αCD3 variable heavy (VH) and variable light (VL) interface that in some experimental models leads to aggregation[13,14,15,16,18,19,20]
This might not be the case for combinations of target antigens that are restricted to different membrane areas or where the involved epitopes are positioned too closely or too distantly from each other
Summary
T cell-engaging immunotherapies are changing the landscape of current cancer care. suitable target antigens are scarce, restricting these strategies to very few tumor types. Employing preclinical models for aggressive leukemia and breast cancer, we show that by the combinatorial nature of this approach, T lymphocytes exclusively eliminate dual antigen-positive cells while sparing single positive bystanders This allows for precision targeting of cancers not amenable to current immunotherapies. In light of the clinical efficacy of T cell-engaging therapies, we strive to redirect T lymphocytes for the lysis of tumor cells in a dual antigen-restricted fashion[11,12] To this end, we designed a tri-specific antibody split into two parts. When a complementary pair of hemibodies binds to the respective antigens on the surface of a single target cell, the VH and VL domains align, re-associate, and reconstitute the original CD3binding site This way, CD3-positive T lymphocytes become activated and retargeted for tumor cell lysis
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