Enhanced Anti-CD30 Therapy: The Potency of XmAb2513 in Targeting CD30-Positive Lymphomas

CD30, a member of the tumor necrosis factor receptor family, is typically found in low quantities on activated lymphocytes and plays a role in cell death and T-cell growth. It is notably present in Hodgkin’s disease and Anaplastic Large Cell Lymphoma. Various approaches targeting CD30, such as unmodified antibodies, bispecific antibodies, and conjugates with toxins or radioactive substances, have been explored in both preclinical and clinical settings. However, the effectiveness of unmodified antibodies has been limited, possibly due to insufficient interaction with immune cells. Bispecific antibodies have shown clinical benefits but are challenging to produce. Conjugates also involve complex manufacturing and handling processes.

Advancements in antibody engineering have resulted in "naked" antibodies with enhanced effector functions, achieved through mutations at the Fc-receptor binding site. A humanized antibody targeting CD30 has been developed with improved potency and efficacy, while maintaining the production and handling simplicity of a standard IgG antibody. The chimeric antibody cAC10 was optimized for human string content to create the humanized version hAC10, which demonstrates a fourfold higher affinity for the antigen than its chimeric counterpart.

By integrating the humanized variable domain with an altered Fc region, the resulting therapeutic candidate XmAb2513 showed a roughly 20-fold increase in affinity for the FcγRIIIA receptor. In preliminary development, production from a stable cell line was nearly 1 gram per liter. The cytotoxicity of XmAb2513 was assessed using Antibody Dependent Cell-mediated Cytotoxicity (ADCC) assays, which involved peripheral blood mononuclear cells as effectors and the CD30-expressing human Hodgkin’s cell line L540 as the target. Cytotoxicity was measured through the release of lactate dehydrogenase or preloaded TDA.

XmAb2513's performance was compared with cAC10-IgG1, which lacks Fc-receptor binding enhancement, and the antibody 5F11. The new antibody exhibited significant improvements in both potency and efficacy, with a potency approximately three times higher than cAC10-IgG1 and ten times higher than 5F11, and a fourfold increase in efficacy compared to cAC10-IgG1. XmAb2513 possesses favorable characteristics for treating CD30-positive lymphomas, such as high cytotoxicity and ease of production and handling. The encouraging outcomes merit further exploration.