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.We have generated a novel therapeutic with super efficacy for treatment of lymphoma that
invades the skin (CTCL). In addition to targeting and killing cancerous CTCL cells, our candidate
drug also targets a specific type of normal blood cell known to suppress immune responses to
many types of cancer. This promising therapeutic is being developed for treatment of CTCL and
also has potential to improve tumor immunotherapy for a broad spectrum of cancers.