Advancing NHL Treatment: The Emergence of a Novel Tri-Specific Antibody

Anti-CD20 monoclonal antibodies are a key treatment for B-cell malignancies, but some patients lack CD20 expression and others experience down-regulation after treatment, leading to poor outcomes. A new "1:2" bispecific antibody format has been developed to enhance tumor targeting and killing. CMG1A46 is a novel tri-specific antibody that targets CD3 on T cells and CD20 and CD19 on tumor cells, offering a high affinity for tumor cells and the potential to treat a range of B-cell lymphomas, including those with low CD20 expression.

In laboratory tests, CMG1A46 demonstrated effective tumor cell lysis with a low effective concentration and superior efficacy and safety compared to conventional bispecific antibodies. It induced significant tumor lysis in cells expressing both CD19 and CD20, as well as in cells with single marker expression. In mouse models with human PBMCs, CMG1A46 showed potent anti-tumor activity, rapidly reducing large tumors and allowing for higher doses without increased toxicity.

Pharmacokinetic studies in monkeys indicated that CMG1A46 has a long half-life in serum, supporting weekly dosing, and high doses did not result in significant adverse effects. The treatment rapidly depleted B cells in the blood and was followed by a transient decrease in T-cell counts and cytokine release, with quick recovery to normal levels. CD3 receptor occupancy was also transiently increased and then maintained at a low level.

The promising anti-tumor activity, potency, and safety of CMG1A46, as shown in both in vitro and in vivo studies, along with its favorable pharmacokinetic profile and manageable toxicity, support its advancement to clinical trials for CD20+ cancer patients, with a Phase 1 trial planned for April 2021.