Increasingly next generation proteins are being used over traditional monoclonal antibodies. Here we explore the competitive advantages that these next gen protein therapeutics offer. This is an extract from a whitepaper on the different approaches, competitive advantages and challenges of next gen therapeutics over traditional mAbs. Download the full whitepaper for free here.
Next generation protein therapeutics each have their own unique attributes, however the limitations of mAbs provide an opportunity for next generation therapeutic competitive advantage. The limitations of monoclonal antibodies include:
- large size leading to steric hindrance and restricted tissue penetration of mAbs into solid tumors and lightly vascularized tissues
- an intrinsically restricted binding interface that is not ideal for binding certain conformations or catalytic sites1
- room for stability improvement
- mAbs do not function effectively intracellularly compared to small molecules2
- clinical efficacy requiring high doses
- large room for improvement in costs-of-goods and cost effective manufacturing
- although on the whole beneficial the Fc region can sometimes cause antibody-dependent-enhancement of infection by some viruses3
Many of the leading next generation therapeutics are of small size (1-20 kDa). This contrasts full length monoclonal antibodies which are typically 150 kDa. This has led to the hypothesis that they could penetrate dense tissues such as solid tumours or muscle more efficiently than full length monoclonal antibodies, although this theory requires clinical validation in many settings. Small size also potentially allows them to bind targets at locations that monoclonal antibodies cannot access due to steric hinderance from their large size. The stability (Tm) of next generation protein therapeutics is equivalent or better than most full length monoclonal antibodies4.
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New technologies such as the Feldan protein shuttle allow impermeable proteins to be delivered intracellularly for therapy5. This could potentially allow antibody-like molecules to target intracellular pathways therapeutically. However, mAbs are not ideally suited to this as their large size is not efficient for protein shuttle across the cell membrane and in addition mAbs have altered binding capacity intracellularly due to the different pH environment compared to the circulatory system6. Next generation therapeutics are a more optimal size for protein shuttle and can be engineered to actively target intracellular proteins opening up new therapeutic possibilities. The smaller size of next generation therapeutics makes them more akin to small molecules than monoclonal antibodies in terms of dosing, for example less total therapeutic weight is required to bind the same number of target molecules with next generation protein therapeutics than with monoclonal antibodies. This results in a lower cost of goods for next generation therapeutics.
Next generation protein therapeutics can be manufactured in E. coli and Pichia yeast optimised for human glycosylation at a fraction of the cost required to produce full length monoclonal antibodies in mammalian cell culture systems. Regulatory burden is reduced for next generation protein therapeutics. Mammalian cell cultures require extensive viral clearance studies to prove that the manufacturing process does not allow viruses to contaminate the final clinical product, even when conducted under sterile conditions. Such extensive studies are not required in non-mammalian systems.
The delivery of next generation protein therapeutics is more versatile as they can potentially be delivered orally by formulation into nanoparticles, inhaled, or delivered ocularly. Intravenously delivery similar to monoclonal antibodies is also viable.
Download the full whitepaper for free here.
References
1. Skerra A. Engineered protein scaffolds for molecular recognition. J Mol Recognit. 2000 13(4):167-87. Review. PubMed PMID: 10931555.
2. Tiede C, et al. Affimer proteins are versatile and renewable affinity reagents. Elife. 2017 27:6. pii: e24903. doi: 10.7554/eLife.24903. PubMed PMID: 28654419
3. Paul LM. et al. Dengue virus antibodies enhance Zika virus infection. Clin Transl Immunology. 2016 5(12):e117. doi: 10.1038/cti.2016.72. PubMed PMID: 28090318
4. McConnell AD, et al. A general approach to antibody thermostabilization. MAbs. 2014;6(5):1274-82. doi: 10.4161/mabs.29680. PubMed PMID: 25517312
5. Del’Guidice, et al. Feldan Shuttle - Advanced Protein Delivery Technology for Cell Therapy. Molecular Therapy. 2016. 24(sup 1):S239. https://doi.org/10.1016/ S1525-0016(16)33411-6
6. Biocca S, et al. Redox state of single chain Fv fragments targeted to the endoplasmic reticulum, cytosol and mitochondria. Biotechnology (N Y). 1995;13(10):1110-5. PubMed PMID: 9636285.