Next-IO™ Anti-TLR Therapeutic Monoclonal Antibody Program

About This Program

This program aims to develop anti-TLR therapeutic monoclonal antibody for immuno-oncology.

Toll-like receptors (TLRs) have recently been identified as key factors in the pathogenesis of tumors, innate and adaptive immune cells regulation, and tumor infiltration.

TLR-mediated metabolic reprogramming is important for the activation, maturation, and immunogenic function of macrophages and DCs. Studies from a variety of preclinical animal models and clinical trials show that TLR stimulation in tumor cells mediates tumor survival and growth. Recent studies also suggest that TLRs directly regulate tumor metabolism, affecting tumor behavior and function in melanoma, prostate cancer, head, neck, and breast cancer. In addition, increasing evidence supports that TLR signaling also affects the differentiation and function of T cell subsets. In summary, TLR-based immunotherapy may show a great promise in cancer research.

TLR

TLRs, a type I membrane protein, are the best-studied pattern recognition receptors (PRRs) that consist of 10 functional members. They exist in immune cells mostly as homodimers or heterodimers. The extracellular domain of TLR protrudes out of the membrane and binds to PAMP / DAMP, while the conserved toll / IL-1 receptor (TIR) exists in the intracellular domain to coordinate the downstream signaling pathway inside cell. The cellular localization of TLR family members reflects the location of its activated PAMP / DAMP ligand: TLR1, 2, 4, 5 and 6 are localized at the plasma membrane and primarily responsive to bacterial proteins; while TLRs 3, 7, 8 and 9 are located in the endosome and reacts to the intracellular compartments of the lysosome.

Fig.1 TLRs mediated the T cells response and programmed cell death process toward tumor environment.¹

TLRs present on the surface of macrophage cells and TME to regulate tumor growth and progression.
TLRs can destroy incoming pathogens, but also able to alert adaptive immune system infections.
Artificial activation of TLRs on immune cells, including monocytes, macrophages, and dendritic cells (DCs), triggers response of CD8+ T cells and natural killer (NK) cells, producing powerful anti-cancer effects.
Several TLR ligands, including imiquimod (TLR7) and CpG (TLR9), have shown significant promise for cancer therapy.

TLR in Cancer Studies

Here are some published data about TLR working as a potential target for cancer immunotherapy.

Anti-TLR ligands antibody (Pam3CSK4) enhances the antitumor efficacy by anti-CTLA-4 antibody.

Fig.2 Pam3CSK4 plus anti–CTLA-4 antibody enhances tumor rejection, increases survival, and produces immunological memory after B16/F10 tumor challenge.²

TLR agonists and systemic anti-PD-1 antibody exhibits therapeutic efficacy at both primary and distant sites of tumor cells.

Fig.3 Treatment with 1V270 or SD-101 suppresses tumor growth of HPV-positive HNSCC.³

Ongoing Clinical Trials

Currently, several anti- TLR antibodies are being evaluated in clinical trials after successful testing in animal models. An increasing number of therapeutic molecules are getting confirmed for its role in immune responses and early clinical trial data shows great promise. However, further studies are needed to optimize the efficacy, safety, and combination strategies to achieve greater clinical success.
In this case, TLR is still a compelling target for cancer immunotherapy. In an effort to optimally leverage TLR-mediated immune response, our next generation of TLR targeting treatment attempts to explore combination therapy trials by involving other immunomodulatory agents.

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.

Fig.4 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-TLR therapeutic monoclonal 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

Xiaohong, C.; et al. The Role of Toll-Like Receptor in Inflammation and Tumor Immunity. Frontiers in Pharmacology, 2018, 9:878.
Sharma, N.; et al. TLR1/2 ligand enhances antitumor efficacy of CTLA-4 blockade by increasing intratumoral Treg depletion.PNAS, 21, 2019, 116(21):10453-10462.
Fumi, S K.; et al. Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer. JCI Insight, 2017, 2(18):93397.

For Research Use Only | Not For Clinical Use