Development of Antibody-TLR7/8 Agonist Conjugates

Small-molecule agonists at Toll-like receptor 7 (TLR7) and TLR8 have sparked a vivid interest in cancer research owing to their profound antitumoral activity. The predominant antitumoral mode of action of these small-molecule agonists is TLR7/8-mediated activation of the central transcription factor nuclear factor-jB, which leads to the induction of proinflammatory cytokines and other mediators. With state-of-art equipment, advanced techniques, and well-established synthesis platform, scientists from Creative Biolabs have explored several different agonists for the development of antibody- TLR7/8 agonist conjugates.

The Overview of TLR7/8 and TLR7/8 Agonist

TLR7 and TLR8 are phylogenetically and structurally closely related members of the TLR family; together with TLR9 they constitute one of the six major TLR clades. Except for a small proportion of TLR8 which is expressed at the cell surface, both TLR7 and TLR8 are localized intracellularly to endosomal membranes, similar to TLR3 and TLR9. These four intracellular receptors represent a group of so-called antiviral TLRs. Both TLR7 and TLR8 have been identified as natural receptors for single-stranded RNA, and they are thought to act as potent activators of innate immune responses upon viral infections. Sequence specificities of TLR7 and TLR8 have not been conclusively defined yet, but ssRNA sequences containing GU-rich or poly-U sequences can stimulate both receptors.

Imiquimod and resiquimod are imidazoquinolines, synthetic immune agonists that target TLR7 and TLR8. They have the advantage of activating innate and adaptive immune responses, while also activating NK cells. Imiquimod is the only approved TLR7 agonist for the treatment of genital warts, actinic keratoses, basal cell carcinoma, and lentigo maligna, where it has proven efficacy. It has also been used off-label to treat other HPV-associated lesions, as well as cutaneous melanoma. Resiquimod, related to imiquimod binds to both TLR7 and -8, is a considerably more potent analog, and is in testing stages for treatment of genital HSV. In animal models, when administered together with peptides, proteins, or bacterial vectors and DNA constructs encoding tumor antigens, these agents augment anti-tumor activity. DC activity against tumor antigens, including MAA, can also be substantially enhanced in vivo if the APC is first activated with TLR7/8 agonists.

Fig.1 TLR7/8 agonists and their immune effects. (Schön, 2018)

Antibody-TLR7/8 Agonist Conjugates Development Service

Immunotherapy with imiquimod is currently limited to topical formulation, as systemic TLR activation can be fatal. Recent efforts have therefore focused on reducing and eliminating this fatal shock caused by cytokine syndrome or cytokine storms. An ideal approach is to limit drug availability and localize inflammation by covalent conjugation to antibodies, which can effectively limit systemic cytokine levels but retain high levels of inflammation at the site of administration. Small molecule TLR agonists such as the purine analogs or imidazoquinolines that activate TLR7 and/or 8 are far better suited to ADC development as these small molecules lack any of the physicochemical features likely to compromise antibody specificity. Scientists at Creative Biolabs have identified three distinct therapeutic applications for TLR agonists conjugated to mAbs: to target therapeutic TLR activation to tumors; to promote mAb cytotoxicity; and to deliver TLR agonists to antigen-presenting cells (APC).

With our passionate team of scientists and experts, Creative Biolabs is committed to solving some of the most challenging issues in the development of novel antibody-drug conjugates. We can provide tailor-made antibody-TLR7/8 agonist conjugates development services according to your needs. If you are interested in our services, please contact us for more details.

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