Next-IO™ Anti-FASL Therapeutic scFv Antibody Program

About This Program

This program aims to develop anti-FASL therapeutic scFv antibodies in the immuno-oncology.

FasR (CD95, Apo-1) has apoptotic activity, meaning it mediates apoptosis of virus-infected cells, unwanted/autoreactive T cells or other cancer cells when engaging with CD8+ cytotoxic T lymphocytes. Studies have shown that altering the expression of Fas ligand (FasL) / Fas has a direct impact on the cancer prognosis and its damage may lead to apoptosis resistance. Therefore, the development of effective therapies for the FasL / Fas system is vital to combat cancers.

FASL

Fas ligand (FasL) FasL, also known as CD178, CD95 ligand, and TNFSF6, is a 40 kDa type II transmembrane glycoprotein and a member of the TNF superfamily. FasL is expressed on activated T cells, the spleen, testis, and eye tissues.

Its functions are as highlighted below:

• By binding to its receptor CD95 (Fas), FasL can destroy apoptotic cell to death and in turn, maintain peripheral tolerance.
• FasL overexpression in some tumors induces apoptosis of infiltrated lymphocytes, allowing tumors to escape immune responses.
• FAS/FASL interactions are thought to play a role in proliferation, neutrophil extravasation, chemotaxis and survival of CD8⁺ cells.

Fig.1 FasL and TRAIL pro- and anti-tumoral activities within the tumor nest.¹

FASL in Cancer Studies

Targeting the FasL / Fas system in therapeutic strategies is particularly complex, for the reason that interaction of intricate signal interaction with other molecules can be complicated. Here are some published data about FASL working as a potential target for cancer immunotherapy.

• A low FasL/Fas ratio is related to tumorigenesis and suggests a poorer prognosis in patients with Oral Squamous Cell Carcinoma (OSCC).

Fig.2 Clinical relevance of the Fas ligand (FasL)/Fas ratio in OSCC.²

• A low Fas ligand (FasL)/Fas ratio promotes tumor growth in patients with OSCC.
• scFv-FasL treatment can prolong survival rate in patients with cancer.

Clinical Trials under Progress

• Previously, research to activate Fas antibody injections in mice had induced hepatocyte apoptosis, liver failure, and death. For this reason, researchers disregard the idea to use the FasL system as a potential therapeutic target. However, it is now proved that this toxicity is attributed to the Fc portion of the antibody. Therefore, by reconstituting, scientists are now focusing on designing recombinant FasL or Fas molecules.

Fig.3 A low Fas ligand (FasL)/Fas ratio promotes tumor growth of OSCC in vitro and in vivo, qPCR Analysis of FAS.²

• Currently, only APO010 and APG101, two Fas hexamer agonists that synthesized by fusion of two trimer FasL, are being evaluated in clinical trials after the successful test in animal models.

Fig.4 Tumor growth rates of the OSCC lines in vivo.²

• FASL is still a compelling target for cancer immunotherapy. In an effort to optimally leverage FASL-mediated immune response, our next generation FASL targeted therapies seeks to explore various types of antibody, such as scFv, bispecific or Fab antibodies.

Program Planning and Management

We have extensive knowledge in 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.

Fig.5 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 anti-FASL therapeutic scFv antibody 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.

References

• Rossin A.,et al. TRAIL and FasL Functions in Cancer and Autoimmune Diseases: Towards an Increasing Complexity. Cancers. 2019, 11(5), 639.
• Chien MH., et al. A Fas Ligand (FasL)-Fused Humanized Antibody Against Tumor-Associated Glycoprotein 72 Selectively Exhibits the Cytotoxic Effect Against Oral Cancer Cells with a Low FasL/Fas Ratio. Molecular Cancer Therapeutics. 2017, 16(6):1102–1113.

For Research Use Only | Not For Clinical Use