Abstract
Adoptive T cell therapies directed to the B cell malignancy antigen CD19 (CAR19 T cells) have transformed the care of otherwise refractory, last-line leukemia and lymphoma patients. The overall response rates achieved are very high, routinely above 60%, and a substantial number of responding patients have durable responses that can last many years. However, 50% of responders relapse within 6 months, and outcomes for these relapsed patients are poor. Relapses occur most often in patients whose initial CAR19 T cell expansion is suboptimal, and whose tumor cells reduce or lose expression of the target antigen, CD19.
We have created a CAR T Engager protein that is designed to improve responses to anti-CD19 CAR T treatment and is further designed to prevent relapses. This modular protein contains an anti-CD20 llama VHH linked to an optimized CD19 protein and further linked to an anti-albumin llama VHH. Thus, this CAR T Engager, called Aleta-001, binds to CD20 on B cell tumor cells, displays CD19 on the tumor cell surface thereby activating anti-CD19 CAR T cells, and binds to albumin, providing for a long half-life upon injection. Aleta-001 increases CD19 antigen density and/or replaces lost CD19 expression by coating cell surface CD20 with CD19.
Here we present studies that establish the efficacious dose to support the upcoming Phase 1/2 clinical trial to be run in collaboration with Cancer Research UK. Extensive in vitro modeling established that the Aleta-001 CAR T Engager specifically bound to CD20-positive/CD19 negative lymphoma cells, JeKo-1-CD19KO, that represent the phenotype of a lymphoma relapsing after losing CD19 expression. In the presence of CAR19 T cells, the Engager protein mediated cytotoxicity against the JeKo-1-CD19KO cells at sub-nM concentrations. The JeKo-1-CD19KO cells induced a rapid and lethal lymphoma when implanted into NSG mice. Administration of the Aleta-001 CAR T Engager and CAR19 T cells eliminated the JeKo-1-CD19KO lymphoma at administered protein concentrations as low as 0.5mg/kg.
These results support the clinical development of the Aleta-001 Engager protein. The protein is designed to be administered to patients who have received CAR19 T cell therapy and who fail to achieve a complete response at the time of their first clinical evaluation, or who relapse from a complete response thereafter. Patients who are enrolled will be dosed with the Aleta-001 Engager protein every two weeks. Aleta-001 has entered GMP production and IND enabling studies and will then enter Phase 1 dose escalation clinical studies in the UK.
Rennert: Aleta Biotherapeutics Inc.: Current Employment, Current holder of stock options in a privately-held company. Su: Aleta Biotherapeutics Inc.: Current Employment, Current holder of stock options in a privately-held company. Wu: Aleta Biotherapeutics Inc.: Current Employment, Current holder of stock options in a privately-held company. Lobb: Aleta Biotherapeutics Inc.: Consultancy, Current holder of stock options in a privately-held company. Ambrose: Aleta Biotherapeutics Inc.: Current Employment, Current holder of stock options in a privately-held company.
