Development of TNF-based Bispecific ADCs

Creative Biolabs is committed to providing high-quality bispecific antibody-drug conjugates (ADCs) services to support our clients’ projects. Through the method of covalent linkage, payloads can be efficiently attached to the antibody. Relying on the state-of-the-art facilities, our one-stop bispecific ADCs development will be meticulously monitored and controlled to ensure the high quality of final products.

The Overview of TNF

The tumor necrosis factor (TNF) superfamily (TNFSF) and the TNF receptor (TNFR) superfamily (TNFRSF) form the corresponding ligand and receptor systems that are widely distributed in different tissues and cell types. Collectively they play critical roles in numerous aspects of mammalian biology, including embryonic development, innate and adaptive immunity, and maintenance of cellular homeostasis. Agents that manipulate the signaling of these receptors are being used or showing promise towards the treatment and prevention of many human diseases.

TNFSF members are generally homotrimeric type II transmembrane proteins, many of which can be shed from the cell surface to act as soluble signaling molecules. The defining feature of this family of extracellular ligands is the trimeric TNF homology domain (THD), comprising of three jelly roll protomers. Each protomer is formed by two β-sheets composed of strands A’AHCF and B’BGDE. These domains are exclusively located in the C-terminal region of the protein. The family can be divided into three groups (the conventional, the EF-disulfide containing, and the divergent), based on sequence and structural features in the THD.

Fig.1 Structures of TNFSF and TNFRSF members and complexes. (Wu, 2010)

Antibodies-based Therapeutics Targeting TNF

There are several TNF antagonists are under development. All agents except are anti-TNF mAbs or fragments thereof, while etanercept is a genetically engineered fusion protein composed of a dimer of the extracellular portions of human TNFR2 fused to the Fc portion of human IgG1. Natural mAbs are derived from single B cells that clonally express copies of a unique heavy (H) chain and a unique light (L) chain that are covalently linked to form an antibody molecule of unique specificity. Being structurally identical to natural mAbs, engineered mAbs can are created by gene splicing and mutation procedures, mimicking natural gene rearrangement, and somatic mutation events in B cells.

Fig.2 Simplified diagrams of the molecular structures of 5 TNF antagonists. (Tracey, 2008)

What Can We Do for You?

Bispecific antibodies (bsAb) targeting TNF and IL-23 are in preclinical development for the treatment of inflammatory bowel disease (IBD) and other autoimmune/inflammatory diseases. In a CD40-induced colitis model, a murine bsAb targeting IL-23 and TNF showed synergistic efficacy when compared to antibodies against TNF and IL-23 alone. A TNF x IL-23 bsAb would represent one of the first examples of a bsAb targeting two validated pathways with validated efficacy in IBD.

Creative Biolabs has devoted to the field of ADC for over a decade and established a series of comprehensive platforms to discover novel ADCs. We have constructed different epitope combinations for TNF-based bispecific ADCs development, including TNF x NGF, TNF x IL-1, TNF x IL-6R, TNF x IL-17A, and TNF x IL-23. With the extensive experience, abundant industry knowledge, and advanced technical skills, our scientists are fully confident in accomplishing even the most challenging project. If you are interested in our services, please contact us for more details.

References

1. Wu, H. and Hymowitz, S.G. Structure and function of tumor necrosis factor (TNF) at the cell surface. In Handbook of cell signaling (pp. 265-275). 2010, Academic Press.
2. Tracey D.; et al. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther, 2008, 117(2): 244-279.

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