Protein-Drug Conjugates

Conjugated non-antibody domain sized scaffolds: The next stage in clinical efficacy

Antibody drug conjugates (ADCs) are an increasingly important weapon in the fight against cancer. They form a rapidly growing area, with recent  approvals of the CD30 targeting brentuximab vedotin (Adcetris®) for the treatment of Hodgkin Lymphoma, and the Her2 targeting trastuzumab emtansine (Kadcycla®) for the treatment of Her2+ metastatic breast cancer adding to a growing number of authorised products. The number of current ADC clinical trials now exceeds 40 for both liquid and solid tumours. What is also beginning to hit the clinic are the domain sized conjugated approaches.


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Figure 1.

Almac Discovery are now developing the next generation ‘ADCs’ to treat solid tumours. We are combining proprietary site-specific protein conjugation chemistries, with smaller protein targeting vehicles, to engineer homogenous protein-drug conjugates with improved stability and tumour penetration.

Whilst antibodies have long circulating half-lives (in the region of three weeks) their large size of 150 kDa compromises their ability to penetrate into tumours. Additionally, the standard conjugation chemistries that have been used to attach the potent cytotoxic payloads to the antibody have often proved sub-optimal, yielding heterogeneous products with in vivo half-lives ranging from 1-7 days.

In collaboration with Elasmogen at the University of Aberdeen, we are exploiting the properties of shark VNAR domains to develop innovative therapeutics to treat cancer.

The serum of cartilaginous fish (sharks, skate, rays) contains Ig new antigen receptors (IgNARs), which are natural antibody-like proteins composed only of heavy chains. The antigen binding site is generated from a single domain termed a VNAR.

Domain architecture of the shark IgNAR proteins with the VNAR region highlighted

This unique VNAR domain is currently the smallest known naturally occurring antigen binding domain in the vertebrate kingdom (size of ~12 kDa), containing only two complementarity determining regions, CDR1 and CDR3, and is inherently soluble and stable.


Figure 2.

Utilising Elasmogens soloMERsTM (humanised VNARs) platform, high affinity shark VNARs are being developed to selected solid tumour targets. These smaller proteins can be expressed in prokaryotes, have tunable pharmacokinetic properties, and should provide superior solid tumour penetration.

Importantly, they are amenable to modification using novel improved site-specific conjugation technologies that we have developed, where full-target binding activity is maintained.

The co-development of VNAR-drug conjugates and engineered VNAR therapeutics with Elasmogen, has the potential to provide the next wave of targeted therapies to treat solid tumours.


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Related resources

Protein Drug Conjugate Resources

Peters C and Brown S. Antibody–drug conjugates as novel anti-cancer chemotherapeutics. Bioscience Reports, 2015, 35, e00225

Deonarain MP, Yahioglu G, Stamati I and Marklew J. Emerging formats for next-generation antibody drug conjugates. Expert Opin. Drug Discov., 2015, 10, 463-481.

Thom J, Anderson D, McGregor J and Cotton G. Recombinant protein hydrazides: application to site-specific protein PEGylation. Bioconjug Chem., 2011, 22, 1017-1020.

Koveleva M, Ferguson L, Steven J, Porter A and Barelle C. Shark variable new antigen receptor biologics – a novel technology platform for therapeutic drug development. Opin. Biol. Ther., 2014. 14. 1527-1539

Zielonka S, Empting M, Grzeschik J, Könning D, Barelle CJ and Kolmar H. Structural insights and biomedical potential of IgNAR scaffolds from sharks. 2015, 7, 15-25.

Vazquez-Lombardi R, Giang Phan T, Zimmermann C, Lowe D, Jermutus L, Christ D. Challenges and opportunities for non-antibody scaffold drugs. Drug Discovery Today. 2015, 20, 1271-1283

Perez H L, Cardarelli P M, Deshpande S, Gangwar S, Schroeder G M, Vite G D, Borzilleri R M. Antibody-drug conjugates: current status and future directions. Drug Discovery Today 2014. 7, 869 – 881

Kim, E G and Kim K M. Strategies and advancement in antibody-drug conjugate optimisation for targeted cancer therapeutics. Ther., 2015. 23 493-509