With the approvals of antibody-drug conjugates, such as Kadcyla®, Adcetris® and Besponsa®, and an increasing number of ADCs entering clinical trials, the targeted delivery of cytotoxic agents to cancer cells is proving to be a powerful approach for the treatment of both hematological malignances and solid tumors.
Whilst efforts to date have focused on the use of large full-length antibodies as the payload delivery vehicle, there is considerable scope for exploiting smaller protein domains as the targeting agents. These offer a number of potential benefits including increased tumor penetration, amenability to protein engineering and site-specific conjugation, and improved tolerability.
Recognizing the potential of small-protein drug conjugates, Almac Discovery is collaborating with Elasmogen to develop an oncology protein therapeutics platform based on shark Variable New Antigen Receptor (VNAR) proteins; the smallest antigen binding domain in the vertebrate kingdom with a binding mechanism distinct to antibodies.
Having established novel site-specific conjugation technologies and robust methods for the engineering of VNAR domains, the platform is being applied to a number of different targets overexpressed on solid tumors; including the onco-embryonic receptor tyrosine kinase ROR1.
The expression pattern of ROR1, coupled with its functional role in tumourigenesis and disease progression, make it an attractive protein drug conjugate target for a variety of different cancers. Using a combination of direct immunization and synthetic VNAR library screening, a series of selective, high affinity ROR1 binders have been generated.
Exploiting the modular nature of the VNAR domain, multiple formats with different characteristics have been flexibly engineered and screened (including ROR1 targeting multimers, bi-paratopic binders, bi-specifics, Fc fusions and half-life extended formats through fusion to the serum albumin binding domain NDure™). This has led to the development of potent, stable, homogenous VNAR drug conjugates using established cytotoxic payloads and novel linker-payloads developed by Almac Discovery. The in vivo efficacy of these ROR1 VNAR drug conjugates is currently being profiled in pre-clinical models of cancer.
This series of novel ROR1-targeting protein drug conjugates, utilizing the advantageous properties of small VNAR domains, offers great therapeutic potential for the treatment of a wide range of oncology indications.
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