Date: February 20 - 22, 2017
Location: Maritim proArte Hotel Berlin
Over 300 of your ADC peers from 120 organisations will converge at Europe’s premier antibody drug conjugate summit. For 3 days they’ll submerge themselves in the latest ADC data, insight and lessons learned in the quest to widen the clinical therapeutic window.
Presenter: Jennifer Mitcham, Ph.D. - Director, Antibody Drug Conjugates, Catalent Biologics
Title: A site-specifically conjugated anti-CD22 antibody bearing an MDR1-resistant maytansine payload yields excellent efficacy and safety in preclinical models
Abstract: We describe a site-specifically-conjugated antibody-drug conjugate targeting CD22 and bearing a non-cleavable maytansine payload that is resistant to MDR1-mediated efflux. CD22 is a clinically-validated target for the treatment of Non-Hodgkin lymphoma (NHL) and ALL, but no anti-CD22 agents have yet been approved and an opportunity exists for a next-generation anti-CD22 ADC to address significant unmet medical needs in the relapsed/refractory NHL and ALL populations. NHL comprises a diverse group of cancers that collectively rank among the top 10 most commonly diagnosed cancers worldwide and there remains a significant unmet clinical need for treatments to help patients with relapsed or refractory disease, one cause of which is drug efflux through upregulation of xenobiotic pumps, such as MDR1. Our proprietary anti-CD22 antibody, based on the RFB4 sequence, was conjugated site-specifically using aldehyde tag technology (SMARTag) to a novel, non-cleavable 4AP linker-maytansine payload. The ADC was characterized functionally in vitro, and in vivo efficacy was determined in mice using two xenograft models. Tolerability studies were performed in both rat and cynomolgus monkeys. Pharmacodynamic studies were conducted in monkeys, and pharmaco- and toxicokinetic studies compared total ADC exposure in the efficacy and toxicity studies. The ADC, which had a DAR of 1.8, was very potent in vitro, even against cell lines that had been constructed to overexpress the efflux pump, MDR1. The ADC was efficacious at 10 mg/kg x 4 doses against NHL xenograft tumor models, and in a cynomolgus toxicity study the SMARTag CD22 ADC was dosed twice at 60 mg/kg with no observed adverse effects. Exposure to total ADC at these doses indicated that the exposure needed to achieve efficacy was below tolerable limits. Finally, an examination of the pharmacodynamic response in the treated monkeys demonstrated that the B-cell compartment was selectively depleted, indicating that the ADC eliminated targeted cells without notable off-target toxicity. The results suggest that this novel ADC has the potential to be used effectively in patients with CD22+ tumors that have developed MDR1-related resistance to prior therapies.