RESUMEN

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.

Asunto(s)

Anticuerpos/farmacología , Antineoplásicos Inmunológicos/farmacología , Complejo CD3/metabolismo , Inmunoterapia/métodos , Linfocitos T/inmunología , Animales , Anticuerpos/genética , Antineoplásicos Inmunológicos/inmunología , Sitios de Unión , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Efecto Espectador , Línea Celular Tumoral , Femenino , Antígeno HLA-A2/genética , Antígeno HLA-A2/inmunología , Humanos , Activación de Linfocitos , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Medicina de Precisión/métodos , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/farmacología , Anticuerpos de Dominio Único/genética , Anticuerpos de Dominio Único/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto