About This Program

This program aims to develop PD-L1 × 4-1BB therapeutic bispecific DART for immuno-oncology.

Currently, clinical blockade of the PD-1/L1 axis as cancer immunotherapy has shown long-lasting efficacy on patients with cancers, such as prolonged overall survival rate. However, relapsed patients do not experience the positive effects and there is an increasing need to study its effects on this group.

Activation of the tumor necrosis factor receptor (TNFR) superfamily is the key in cancer immunotherapy. From what we already knew, 4-1BB-mediated co-stimulation can support cell activation, survival, and proliferation. For this reason, we think agonist treatment with 4-1BB will become a great promise.

In summary, we propose to develop a novel bispecific DART, PD-L1x 4-1BB. Hopefully, the end product can bind to the checkpoint of the inhibitory PD-1: PD-L1 signal axis, and conditionally stimulates T cells by activating the 4-1BB receptor to enhance the immune response and allow effective cancer cells elimination.

PD-L1 × 4-1BB

The programmed death-ligand 1 (PD-L1; or CD274, B7-H1) is a key anti-phagocytic signal, i.e "don't find me" signal, to the adaptive immune system.

4-1 BB (also known as CD1370 is a member of TNFR superfamily, expressing in both innate and adaptive immune cells. By regulating tumor microenvironment (TME), CD137 can enhance anti-tumor responses and, therefore, considered as an attractive target in cancer immunotherapy.

(Berezhnoy, 2018)

PD-L1 × 4-1BB in Cancer Studies

Following are the supporting data from the public poster announced by MacroGenics, which demonstrated that PD-L1×4-1BB DART molecule inhibits tumor growth in combination with redirected T-cell killing.

(Berezhnoy, 2018)

Ongoing Clinical Trials

• According to a recent report published in July 2019, BioNTech and Genmab announced the launch of their first-in-human phase I/IIa trial of PD-L1 x 4-1BB bispecific DART in solid tumors. To the best of our knowledge, this is the first and only PD-L1x4-1BB DART that has entered the clinical stage. Our program will be the pioneer and still have great potential when entering the market.
• In an effort to optimally leverage PD-L1 × 4-1BB-mediated immune response, our next-generation PD-L1 × 4-1BB targeted DART program attempts to explore the optimal combination strategy - that is, how to exert the best anti-tumor effect when PD-L1 × 4-1BB is synergistically expressed.

Program Planning and 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 focuses to discover and develop innovative monoclonal DART-based therapies. We are looking for potential partners (include but not limit to major pharma or biotech firms) to develop PD-L1 × 4-1BB bispecific DART 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 advance their programs with more chance to succeed. Look forward to cooperating with you in the near future.

References

• Liu, X.; et al. Dual targeting of innate and adaptive checkpoints on tumor cells limits immune evasion. Cell reports. 2018, 24(8): 2101-2111.
• Berezhnoy, A.; et al. Converting PD-L1-induced T-lymphocyte inhibition into CD137-mediated costimulation via PD-L1xCD137 bispecific DART (R) molecules. EUROPEAN JOURNAL OF CANCER. THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND: ELSEVIER SCI LTD. 2018, 103: E76-E76.

For Research Use Only | Not For Clinical Use