Next-IO™ IL-4R Therapeutic Fusion Protein Program

About This Program

This program aims to develop IL-4R therapeutic fusion protein for immuno-oncology.

The IL4/IL4R signaling axis is a strong promoter of the pro-metastatic phenotype in epithelial cancer cells, including enhanced migration, invasion, survival, and proliferation. Biopsy samples from adult and pediatric patients with central nervous system tumors showed recurrent GBM and overexpress IL4R, while only a little or no IL4R expression is found in normal brain tissues. In addition, IL4R is expressed in myeloid suppressor cells and tumor-associated macrophages, which are known to protect tumors from cancer-killing immune cells and key components in the immunosuppressive tumor microenvironment (TME). These data highlight the rationality of IL-4R as a promising target for immuno-oncology.

IL-4 / IL-4R

IL-4 is one of the Th2 cytokines produced primarily by activated T cells, mast cells, basophils, and eosinophils to regulate lymphocyte proliferation and survival. Two types of IL4R control the physiological function of IL4 and each receptor consists of two protein subunits that will heterodimerize when binding occurred. Type I IL4R is mainly expressed by hematopoietic cells and has IL4Rα and a common γC (γc) subunit. On the other hand, type II IL4R produced by non-hematopoietic cells consists of IL13Rα1 and IL4Rα subunits. In addition, the IL-4 / IL-4R complex initiates signal transduction via the JAK / STAT6 pathway and also flags the IRS / PI3K / AKT pathway.

  • Polarized macrophages are characterized by high levels of cathepsin protease activity leading to tumor growth, angiogenesis and invasion.
  • Paracrine and autocrine IL-4 activate the same intracellular pathway, producing pSTAT6, ERK and AKT, which led to tumor invasion, metastasis, resistance and survival of Cancer Stem Cells (CSCs).

IL-4 induces the polarization of macrophages recruited in the tumor microenvironment. (Setrerrahmane, et al., 2017)Fig.1 IL-4 induces the polarization of macrophages recruited in the tumor microenvironment.1

IL-4R in Cancer Studies

Here are some published data about IL-4R working as a potential target for cancer immunotherapy.

  • The level of IL4R closely relates to the progression of 4T1 tumors.
  • Tumor volume changes and quantification of total photon flux at tumor regions in WT and IL4Ra-/- mice. (Vadevoo, et al., 2017)

    Tumor volume changes and quantification of total photon flux at tumor regions in WT and IL4Ra-/- mice. (Vadevoo, et al., 2017)

    Fig.2 Tumor volume changes and quantification of total photon flux at tumor regions in WT and IL4Ra-/- mice.2

  • IL-4R fusion protein and anti-PD-1 produce robust anti-tumor efficacy.

Indications

Normal epithelial tissues do not express IL4R. But type II IL4R is detected at the high level on the surface of many solid tumors including, but not limited to, renal cell carcinoma, melanoma, breast cancer, ovarian cancer, and colon cancer. High level of IL-4 and its receptor (IL-4R) are expressed in many human tumors, including malignant glioma, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, and bladder cancer.

In fact, IL4R expressions on cancer cells are very robust and have been used as a targeting molecule to anti-cancer toxins and its fusion to IL4. Clinical trials of various cancers are currently undergoing, i.e recurrent metastatic breast cancer, kidney cancer, and Non-small cell lung cancer.

Ongoing Clinical Trials

  • Currently, most clinical trials on IL-4R-targeted therapy are focusing on the development of antibody inhibitors. Only one anti-IL4R fusion protein, designated MDNA55, is evaluated in phase II.
  • In this case, IL-4R is still a compelling target for cancer immunotherapy. In an effort to optimally leverage IL-4R-mediated immune response, our next generation of IL-4R targeting treatment attempts to explore combination therapy trials with other immunomodulatory agents.

Program Planning and Management

We have extensive knowledge of end-to-end program development. For each program, we are committed to delivering the final complete program to our clients within 1.5 years before entering the IND stage.

Project pipeline management of therapeutic monoclonal antibody. (Creative Biolabs Original)Fig.3 Project pipeline management of therapeutic monoclonal antibody.

Cooperation

Creative Biolabs is looking for potential partners (include but not limit to major pharma or biotech firms) to develop IL-4R therapeutic fusion protein program together. Our scientists are dedicated to bringing years of valuable experience to our partner and achieve a meaningful partnership. For any partners interest in our Next-IO™ programs, Creative Biolabs welcomes collaboration.

Here are two ways for your choice, and please contact us for more details.

1) Collaborate with us and co-develop the programs from the discovery phase to IND enabling. Costs will be shared.

2) Become a licensed candidate for our programs.

With our quality control protocol and knowledge of global regulatory requirements, we can help our partners advance their programs with more chance to succeed. Look forward to cooperating with you in the near future.

Reference

  • Setrerrahmane S., et al. Tumor-related interleukins: old validated targets for new anti-cancer drug development [J]. Molecular Cancer, 2017, 16(1): 153.
  • Vadevoo, S. M.; et al. IL4 Receptor–Targeted Proapoptotic Peptide Blocks Tumor Growth and Metastasis by Enhancing Antitumor Immunity. Molecular Cancer Therapeutics. 2017, 16(12): 2803-2816.

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