CCR4-IL2 Bispecific Immunotoxin for Targeted Therapy of Cutaneous T-Cell Lymphoma

Abstract Cutaneous T-cell lymphoma (CTCL) is a type of extra-nodal non-Hodgkin’s lymphoma characterized by skin lesions resulting from infiltration of malignant T lymphocytes. Mycosis fungoides and Sezary syndrome are the two most common types of CTCL. Although treatments exist, they are mainly palliative with low response and durability of response without any cure. The objective response rate remains approximately 30% with the current treatment strategies for refractory or recurrent CTCL. Despite CTCL being an indolent, chronic disease in most cases, some patients experience severe debilitating itchiness, while others have progressive disease with extensive skin and organ involvement. There is an unmet medical need for more effective treatments with improved response for refractory or recurrent CTCL patients. The majority of clinically diagnosed CTCL highly express the surface markers CC chemokine receptor 4 (CCR4) and/or CD25. We have generated a promising diphtheria toxin based CCR4-IL2 bispecific immunotoxin therapeutic candidate for targeted immunotherapy of CTCL. Our candidate drug is genetically engineered to contain both anti-human CCR4 scFv and human IL2 fused to a truncated diphtheria toxin. Our candidate drug has demonstrated promising preclinical efficacy in a mouse tumor model showing 106% improvement in survival (69 vs. 33.5 days) compared to an Ontak® -like human IL-2 fusion toxin. Our candidate drug is expressed using a novel, advanced diphtheria toxin-resistant yeast (Pichia pastoris) expression system. Our yeast expression system overcomes expression and purification problems encountered with E. coli-based expressions systems to deliver high production levels and excellent purification quality of our immunotoxin. Importantly, the surface receptors CCR4 and CD25 are also expressed on tumor-infiltrating effector T regulatory cells (Tregs) known to play a role in suppressing anti-tumor immune responses. Therefore, a potential follow-on indication for our candidate drug is depletion of tumor infiltrating CCR4+ or/and CD25+ Tregs to boost tumor immunotherapy for a broad spectrum of cancers. In phase I of this application, we will perform pilot non-GLP toxicology, pharmacokinetics, and immunogenicity studies in both rats and minipigs. In phase II, we will 1) develop a scalable standard operating procedure (SOP) for large-scale good manufacturing practice (GMP) production and produce enough GMP grade CCR4-IL2 bispecific immunotoxin for phase I and II clinical trials, and 2) perform GLP toxicology, pharmacokinetics, and immunogenicity studies in both rats and minipigs. Our goal is to prepare an IND-ready preclinical data package and then move this product into clinical trials.