Engineered bacterial beta-lactamase (SEAKER enzyme) (SEAKER enzyme)

The Engineered bacterial beta-lactamase is the central enzymatic component of the Synthetic Enzyme-Armed Killer (SEAKER) platform, a technology designed to enhance the efficacy of CAR-T cell therapies against solid tumors (Gardner et al., 2022). In this system, T cells are engineered to not only target tumor antigens but also to produce and secrete a non-human enzyme, typically derived from Enterobacter cloacae, at the site of the malignancy (MSKCC, 2021). This enzyme serves as a localized catalyst that specifically recognizes and cleaves a systemically administered, non-toxic small-molecule prodrug. Upon cleavage of the prodrug's beta-lactam or cephalosporin linker, a highly potent cytotoxic agent, such as monomethyl auristatin E (MMAE), is released directly into the tumor microenvironment. This approach allows for high local concentrations of chemotherapy while minimizing systemic side effects, effectively bypassing the limitations of CAR-T cells in penetrating dense solid tumor masses. The localized release of the drug also facilitates a bystander effect, killing nearby tumor cells that may not express the CAR-T target antigen (Gardner et al., 2022). While highly effective in preclinical models, the use of a bacterial enzyme presents challenges such as potential immunogenicity and the development of anti-drug antibodies. Overall, the SEAKER enzyme represents a sophisticated fusion of cellular and chemical engineering to expand the therapeutic reach of immunotherapy.

Other names

Synthetic Enzyme-Armed Killer enzymeSEAKER-beta-lactamaseBacterial beta-lactamase (Enterobacter cloacae)β-lactamase (SEAKER platform)

The enzyme catalyzes the hydrolysis of the beta-lactam ring in a cephalosporin-based prodrug, triggering a self-immolative elimination that releases a potent cytotoxic payload (e.g., MMAE) specifically within the tumor microenvironment.