Harnessing the Dual-Action Hexameric CTLA4-FasL Fusion Protein for Lymphoma: Mechanism, Efficacy, and Safety Profile

The article discusses the effectiveness of a fusion protein, CTLA4-FasL (KAHR-102), which is composed of CTLA4 and FasL domains and forms stable homo-hexamers. This protein has the unique ability to target both B7 receptors on immune cells and functional Fas-receptors (CD95) to induce cell death, particularly in B cell lymphoma cells. The study demonstrates CTLA4-FasL's potency in inducing apoptosis in highly resistant DLBCL cell lines, with an EC50 range of 0.02-0.06 nM, as determined by the MTS assay and confirmed by the annexin-PI assay.

The research highlights that CTLA4-FasL activates pro-apoptotic pathways and inhibits anti-apoptotic signals in cells with both B7 and Fas receptors, and notably, it prevents the activation of the non-canonical NFkB pathway. This protein's combined effects are highly effective in inducing apoptosis and are not observed in B7-negative cells or with B7 blocking antibodies.

In preclinical studies, CTLA4-FasL significantly improved survival in mouse models of systemic lymphoma, administered through subcutaneous injections. It was found to be equally active on mouse and human cells. Toxicity evaluations in mice and cynomolgus monkeys revealed no significant adverse effects, except for transient leukopenia and increased AST, ALT, and CPK levels in monkeys.

Pharmacokinetic studies showed that the protein reached maximum plasma concentrations 4 hours post-injection in mice and 4-6 hours in monkeys, with a half-life of approximately 2 hours in mice and 10-20 hours in monkeys. CTLA4-FasL was detectable in monkeys after 48 hours but not in mice after 24 hours.

In conclusion, the fusion protein CTLA4-FasL has shown to be an effective treatment for B cell lymphoma in pre-clinical studies, with transient leukopenia being the only significant adverse effect observed in monkeys. A Phase I/IIa clinical trial for lymphoma patients with both B7 and FasL on tumor cells is planned for 2016. The disclosures section mentions affiliations and interests of the authors related to KAHR Medical LTD.