About This Program

This program aims to develop LAG-3 x CTLA-4 therapeutic bispecific antibody for colorectal cancer immunotherapy.

Rationale

• CTLA-4 is a checkpoint receptor that is highly expressed on tumor-infiltrating T cells, especially T regulatory cells (Tregs).
• LAG-3 is a member of the immunoglobulin superfamily (IgSF), which is overexpressed by Treg in the TME, where they downregulate T-cell activation and proliferation.
• Bispecific antibody (BsAb) is a novel antibody that mediates specific killing by targeting two different antigens and selectively redirecting effector cells to target cells. This enhanced synergistic anti-tumor effect highlights a promising approach to immunotherapy.

Our program is designed to target both CTLA-4 and LAG-3 simultaneously, hopefully enhance T cell activation and proliferation through the dual checkpoint blockade mechanism, thus providing a promise for anti-tumor T cell immunity.

LAG-3 x CTLA-4

LAG-3 is a type I transmembrane protein of the IgSF. It is usually expressed in activated T cells, natural killer cells or B cells, and functionally negatively regulate the homeostasis of these cells. LAG-3 has been identified as a next generation of immunological checkpoint proteins that play a variety of roles in cancer immunity, including:

• Inhibition of Th1 cell proliferation, reduction the production of interleukin (IL), interferon-gamma and tumor necrosis factor in T cells.
• The interaction of LAG-3 with MHC-II prevents the binding of the same MHC molecule to TCR and CD4, thereby inhibiting the TCR signal.
• Crosslinking of LAG-3 and CD3/TCR complexes can impair T cell proliferation, cytokine secretion, and calcium flux.
• LAG-3 together with other immune checkpoints inhibits T cell activation, especially PD-1.

Fig.1 Model for LAG-3 modulation of antitumor immunity. (Long, 2018)

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4, CD152), an immune checkpoint, is a membrane glycoprotein involving in the suppression of T cell immune functions like proliferation and cytokine production. CTLA-4 is a negative regulator of anti-tumor T cells upon recognition of their ligands. Currently, therapeutic antibodies targeting CTLA-4, ipilimumab, and tremelimumab, are approved to be efficient in a wide range of hematological malignancies and solid tumors.

Colorectal Cancer

• CRC is one of the most common malignancies in humans. It is estimated that nearly 881,000 new deaths occurred in 2018, ranking second in cancer mortality.
• The global CRC drug market size estimate for 2018 is $994 million, and the compound annual growth rate is expected to be close to 3% between 2019 and 2023.
• The global immunotherapy market size for CRC in 2018 is estimated at 5 billion.

Ongoing Clinical Trials

• Up to now, only one anti-LAG-3 x CTLA-4 BsAb XmAb22841 developed by Xencor, Inc. is being studied in a clinical phase 1 trial. Our program still holds broad market prospects.

NCT ID	Status	Sponsor	Project	Phase	Update Time
NCT03849469	Recruiting	Xencor, Inc.	A Study of XmAb®22841 Monotherapy & in Combination w/ Pembrolizumab in Subjects w/ Selected Advanced Solid Tumors (DUET-4)	Phase 1	October 4, 2019

• In an effort to optimally leverage LAG-3 x CTLA-4-mediated immune response, our next-IO™ LAG-3 x CTLA-4 targeted antibody program attempts to explore the optimal combination strategy by involving other immunomodulatory agents.

Program Management

Creative Biolabs has 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.

Cooperation

Creative Biolabs is looking for potential partners (include but not limit to major pharma or biotech firms) to develop LAG-3 x CTLA-4 therapeutic bispecific antibody program together. Our scientists are dedicated to bringing years of valuable experience to our partner and achieve a meaningful partnership together. For any partners interested 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 further their programs with more chances to succeed. Look forward to cooperating with you in the near future.

References

• Long, L.; et al.The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy. Genes & cancer. 2018, 9(5-6): 176.
• Yu, X.; et al. Characterization of a novel anti-human lymphocyte activation gene 3 (LAG-3) antibody for cancer immunotherapy. MAbs. 2019, 11(6): 1139-1148.

For Research Use Only | Not For Clinical Use