An anti-CD22-seco-CBI-Dimer ADC for the treatment of non-Hodgkin lymphoma that provides a longer duration of response than auristatin ADCs in preclinical models

Abstract

We are interested in developing a second generation of antibody-drug conjugates (ADCs) for the treatment of non-Hodgkin's lymphoma (NHL) that could provide a longer duration of response and be more effective in indolent NHL than the microtubule inhibiting ADCs pinatuzumab vedotin (anti-CD22-vc-MMAE) and polatuzumab vedotin (anti-CD79b-vc-MMAE). Pinatuzumab vedotin (anti-CD22-vc-MMAE) and polatuzumab vedotin (anti-CD79b-vc-MMAE) are ADCs that contain the microtubule inhibitor monomethyl auristatin E (MMAE). Clinical trial data suggest that these ADCs have promising efficacy for the treatment of non-Hodgkin's lymphoma (NHL), however, some patients do not respond or become resistant to the ADCs. We tested an anti-CD22 ADC with a seco-CBI-dimer payload, thio Hu-anti-CD22-(LC:K149C)-SN36248, and compared it to pinatuzumab vedotin for its efficacy and duration of response in xenograft models and its ability to deplete normal B cells in cynomologus monkeys. We found that anti-CD22-(LC:K149C)-SN36248 was effective in xenograft models resistant to pinatuzumab vedotin, gave a longer duration of response, had a different mechanism of resistance and was able to deplete normal B cells better than pinatuzumab vedotin. These studies provide evidence that anti-CD22-(LC:K149C)-SN36248 has the potential for longer duration of response and more efficacy in indolent NHL than MMAE ADCs and may provide the opportunity to improve outcomes for NHL patients.