XmAb™2513, an Fc Engineered Humanized Anti-CD30 Monoclonal Antibody, Has Potent In Vitro and In Vivo Activities, and Has the Potential for Treating Hematologic Malignancies.

XmAb2513 is a novel humanized monoclonal antibody (mAb) that binds to the human cell surface antigen CD30 and demonstrates anti-proliferative activity against CD30-positive (CD30+) cell lines. XmAb2513 also has an engineered Fc region to enhance cell killing activity via recruitment of effector cells through increased binding affinity to Fcγ receptors (FcγRs). Consequently, XmAb2513 exhibits superior antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP), when compared to a native IgG1 (unengineered) version of the antibody. To evaluate the potential clinical activity of XmAb2513 in CD30+ diseases such as Hodgkin Lymphoma (HL) and Anaplastic Large Cell Lymphoma (ALCL), XmAb2513 was tested in murine subcutaneous xenograft models of HL using the CD30+ L540 cell line. In the ICR-SCID mouse strain, intraperitoneal (ip) administration of XmAb2513 at 3 mg/kg every 4 days for 10 doses (q4d ×10), gave a statistically significant reduction in tumor growth and enhanced survival relative to the control. At doses of 10 and 30 mg/kg XmAb2513 (ip, q4d ×10) tumor growth was not only slowed, but elimination of established tumors was observed in 3/9 and 5/9 animals respectively. The treatment was well-tolerated. Preclinical studies were conducted to evaluate the safety and pharmacokinetics of XmAb2513 in large animals. In vitro studies demonstrated that the cynomolgus monkey was the appropriate species for study. Binding affinities of XmAb2513 to both human and cynomolgus monkey CD30 and FcγRs were evaluated by Biacore methods and were found to be similar. Additionally, fluorescein-XmAb2513 gave similar staining patterns in immunohistochemistry cross-reactivity studies with normal human and cynomolgus monkey tissue panels. As evidenced by in-life observations single (0, 1 and 100 mg/kg XmAb2513, intravenous [iv] infusion) and repeat dose (0, 10, 30 and 100 mg/kg XmAb2513, q5d ×6, iv infusion) treatment with XmAb2513 was well-tolerated. Serum cytokines showed no trend that was indicative of an XmAb2513-related effect following single dose administration. The pharmacokinetics of XmAb2513 was also determined after either single or repeat dose administration. In the repeat dose study (0, 3, 10 and 30 mg/kg XmAb2513, q5d ×6, iv infusion) exposure increased in a dose proportional manner, and terminal half-life (t_1/2) ranged from 12–17 days. In the single dose study (0, 1 and 100 mg/kg XmAb2513, iv infusion) exposure was also proportional to dose. The exposure and t_1/2 data support an every other week dosing interval in the clinic. These preclinical data provide a rationale for the clinical testing of XmAb2513 in patients with hematologic malignancies that express CD30, specifically HL and ALCL, and support the safety of repeat administration of XmAb2513 in humans.