Next-IO™ VEGF × DLL4 Therapeutic Bispecific Antibody Program

About This Program

This program aims to develop VEGF × DLL4 therapeutic bispecific antibody for immuno-oncology.

Rationale when developing the program:

  • DLL4 plays a central role in both embryonic development, including the formation of the vascular system, and adult cell regulation, including stalk cell homeostasis, gastrointestinal differentiation, and neovascularization.
  • Destruction of DLL4 signaling results in increased VEGF activity in the vasculature and VEGF-mediated hyperproliferation, consequently, leading to impaired angiogenesis.
  • Preclinical data demonstrate that DLL4 blockade shown potent anti-tumor effects in solid tumors such as colon, pancreatic, breast, and lung cancer.
  • VEGF inhibition is a highly developed anti-tumor therapy. A variety of inhibitors are already approved for its roles in solid tumors.

VEGF × DLL4

DLL4 is a protein-coding gene that acts as a ligand for Notch receptors family. It plays a vital role in normal development and tissue homeostasis in the immune system, gastrointestinal tract and vascular system. Also, because Notch signaling is a very important mechanism in the maintenance and proliferation of cancer stem cells (CSCs), thus, DLL4 also plays an important role in stem cell biology.

VEGF, on the other hand, is a key mediator for angiogenesis in cancer and considered to have potent anti-cancer effects.

MOA of VEGF and DLL4:

  • VEGF release in the hypoxic region triggers the tip cells to display more Dll4 protein on surface of tumor cells.
  • Dll4 binds to the Notch receptor, making stalk cells.
  • As blood vessels germinate, VEGF level increases, and a high levels of VEGF, which associate with elevated levels of D114, leads to dysplasia, reduced branching and vasodilation.

VEGF and Dll4 regulate blood vessel branching and expansion. (Bridges, et al., 2016)Fig.1 VEGF and Dll4 regulate blood vessel branching and expansion.2

VEGF × DLL4 in Cancer Studies

Here are some published data about VEGF × DLL4 work as a potential target for cancer immunotherapy.

  • The bispecific antibody HB-32 (anti-VEGF × DLL4) shows potent anti-tumor activity in breast cancer xenograft models.

MDA-MB-231 tumor growth curves and tumor inhibition rates for nude mice of different dosage groups. (Zhou, et al., 2019)Fig.2 MDA-MB-231 tumor growth curves and tumor inhibition rates for nude mice of different dosage groups.1

Ongoing Clinical Trials

  • Currently, as far as we know, only one bispecific anti-DLL4/anti-VEGF antibody named navicixizumab (or OMP-305B83) is being evaluated in the first human phase 1 study.
  • In this case, VEGF × DLL4 is still a compelling combination for cancer immunotherapy. In an effort to optimally leverage VEGF × DLL4-mediated immune response, our next-generation VEGF x DLL4 targeted therapy attempts to explore the optimal combination strategy - that is, how to exert the best anti-tumor effect when VEGF x DLL4 is synergistically expressed.

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 VEGF × DLL4 bispecific antibody program together. Our scientists are dedicated to bringing years of valuable experience to our partner and achieve a meaningful partnership. 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

  • Zhou R., et al. The bispecific antibody HB-32, blockade of both VEGF and DLL4 shows potent anti-angiogenic activity in vitro and anti-tumor activity in breast cancer xenograft models. Experimental Cell Research. 2019,380(2):141-148.
  • Bridges, E. M., et al. Angiogenesis: to branch or to expand?. Elife. 2016, 5.17079.

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