Protein Drug Conjugates
With the increasing number of antibody-drug conjugate approvals, including for use in the adjuvant setting (Kadcyla®), and with a growing 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 haematological malignancies and solid tumours.
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 tumour penetration, amenability to protein engineering and site-specific conjugation, and improved tolerability.
Recognising the potential of small-protein drug conjugates, Almac Discovery has developed an oncology protein therapeutics platform based on single domain protein binders. This enabling format is being combined with established and novel linker-payloads, to deliver next generation protein drug conjugates for the treatment of solid tumour indications with high unmet need
Variable New Antigen Receptor (VNAR) proteins are the smallest antigen binding domain in the vertebrate kingdom with a binding mechanism distinct to antibodies. Through our collaboration with Elasmogen, VNAR binders are being developed to specific targets overexpressed on solid tumours. These building blocks are then readily engineered into selected therapeutic formats to deliver potent targeted therapeutics. This approach is being applied to a number of tumour associated antigens including the onco-embryonic receptor tyrosine kinase ROR1, which is Discovery’s lead PDC programme.
The expression pattern of ROR1, coupled with its functional role in tumourigenesis, disease progression and drug resistance , make it an attractive protein drug conjugate target for a variety of different cancers including triple negative breast cancer (TNBC). Using a combination of direct immunisation and synthetic VNAR library screening, a series of selective, high affinity ROR1 binders have been generated.
Exploiting the modular nature of the VNAR domain, selected formats with different characteristics have been flexibly engineered and screened (Fc fusions, bi-paratopic binders, bi-specifics). This has led to the development of potent, stable, homogenous VNAR drug conjugates incorporating novel linker-payloads developed by Almac Discovery. The lead ROR1 VNAR drug conjugates are well tolerated and show excellent in vivo efficacy in pre-clinical models of cancer, including complete and durable regressions in TNBC patient derived xenograft models, with candidate nomination on track for later this year.
This series of novel ROR1-targeting protein drug conjugates, utilising 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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