Abstract
Despite advances in the treatment of B-cell non-Hodgkin lymphomas (B-NHL) and B-cell acute lymphoblastic leukemia (B-ALL), disease resistance, relapse, and treatment-related toxicities remain significant challenges. Antibody-drug conjugates (ADCs) have transformed the treatment of many cancers by enabling the selective delivery of cytotoxic payloads to malignant cells, potentially reducing systemic toxicities and improving patient outcomes. Here we describe AZD4512, a novel, first-in-class ADC targeting CD22, a surface antigen with expression restricted to the B-cell lineage and B-cell malignancies. The consistent expression of CD22 across different B-NHL and B-ALL subtypes and its rapid internalization upon antibody binding make it an ideal target for ADC therapies. AZD4512 consists of an anti-CD22 human monoclonal antibody conjugated to a topoisomerase 1 inhibitor payload via a novel cleavable linker. The primary mechanism of action for AZD4512 involves the intracellular delivery of the topoisomerase 1 inhibitor payload to CD22- expressing tumor cells via target-mediated internalization, leading to drug-release, DNA damage and apoptotic cell death. In vitro, AZD4512 exhibited potent and specific cytotoxicity against CD22-expressing tumor cells, with IC50 values in the picomolar to sub-nanomolar range. Importantly, AZD4512 did not exhibit cross-resistance in B-NHL cell lines resistant to an ADC containing the microtubule inhibitor MMAE, a payload deployed in multiple ADCs used for the treatment of B-NHL. Notably, AZD4512 demonstrated a substantially greater selectivity in primary cell settings by specifically targeting and killing CD22-positive B cells while not killing CD22-negative T cells, in contrast to a benchmark CD22-calicheamicin ADC, which showed a much narrower selective window. In vivo, AZD4512 exhibited robust antitumor activity and provided significant survival benefits across diverse models of B-NHL and B-ALL. In a study of 11 human B-NHL patient-derived xenografts (PDXs) encompassing diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL), a single intravenous dose of 1.6 mg/kg achieved a 100% overall response rate, defined as at least a 30% reduction in tumor volume from baseline, with a 36% response rate observed at 0.8 mg/kg. In a study of four B-ALL PDX models, including both Ph-positive, Ph-negative, and KMT2A-rearranged subtypes, treatment with AZD4512 at both 1.0 mg/kg and 2.4 mg/kg resulted in a significant reduction of disease burden in peripheral blood in three of the four models across most assessed time points over a five-week post-treatment period. Subsequently, AZD4512 provided a substantial survival benefit in these responsive models: median survival ranged from 35 to 41 days at 1.0 mg/kg and from 45 to 73 days at 2.4 mg/kg, compared to median survival of 27 to 32 days in untreated groups. Toxicology studies showed that AZD4512 was well-tolerated, with no unexpected side effects. Collectively, these findings highlight AZD4512 as a promising therapeutic candidate for the treatment of patients with B-ALL and B-NHL.
