About This Program

This program aims to develop ICOS × PD-1 therapeutic bispecific antibody for colorectal cancer immunotherapy.

Rationale for our program:

• Blocking of the PD-1 / L1 axis has shown durable responses and prolonged overall survival in a variety of cancer types. However, there is still a significant unmet need for relapsed patients.
• ICOS is a costimulatory molecule expressed on activated T cells (e.g., TEff and TReg cells) in the tumor microenvironment (TME). Studies indicate that ICOS agonism could improve TEff cell survival and IFNy release, thereby activating T cell-dependent tumor eradication.
• Current therapeutic antibody treatment interventions for multiple PD1/costimulatory combinations have shown compelling activity for cancer immunotherapy.

Here, we propose a novel combination: ICOS × PD-1 therapeutic bispecific antibody, which could synergistically improve the anti-tumor response of tumor-reactive TILs.

ICOS × PD-1

Binding of PD-L1 to PD-1 on activated T cells inhibits expansion and survival of CD8-positive T cells, suppresses the immune system and leads to immune evasion. Blocking PD-1 abolishes T cell inhibition, activates antigen-specific T lymphocytes and enhances cytotoxic T cell-mediated tumor cell lysis, which may result in reduced tumor growth.

Inducible co-stimulator (ICOS) is the third member of the CD28/CTLA-4 family. As is well known, CD28 and CTLA-4, as one of the T cell-specific cell-surface receptors, are important regulators of the immune system. ICOS is a homodimeric protein and has only low levels of resting, naïve T cells. It binds specifically to its ligand (ICOS-L), also known as B7-related protein-1 (B7RP-1), which is expressed constitutively on B cells. ICOS/ICOSL axis has a dual effect and might participate in anti-tumour T cell response as well as a pro-tumour response due to its connection with regulatory T-cells (Tregs) suppressive activity.

Supporting Data

The following data support the rationale for the development of ICOS × PD-1 BiAbs with an improved therapeutic index more than anti-PD1 or anti-ICOS antibodies.

• ICOS × PD-1 BiAb (XmAb23104) significantly enhances T cell activation in vitro.
• XmAb23104 enhances T cell activation (left) and exacerbates GVHD in huPBMC-NSG mice (right).

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

• Currently, only one biotechnology company (Xencor, Inc) presented preclinical data on the ICOS x PD-1 BiAb XmAb23104 they are developing on a public poster in April 2017. In May 2019, XmAb23104 entered a phase I clinical study to treat some patients with advanced solid tumors.
• We believe that this dual-targeting strategy will provide insights into the tumor immunotherapy, especially in the treatment of colorectal cancer. In an effort to optimally leverage ICOS × PD-1-mediated immune response, our Next-IO™ ICOS × PD-1 targeted antibody program attempts to explore the optimal combination strategy - that is, how to exert the best anti-tumor outcome while synergistically produce ICOS × PD-L1.

Program 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.

Fig.1 The timeline of Next-IOᵀᴹ programs.

Cooperation

Creative Biolabs is looking for potential partners (include but not limit to major pharma or biotech firms) to develop ICOS × PD-1 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.

For Research Use Only | Not For Clinical Use