REVIEW: Non-Immunoglobulin Synthetic Binding Proteins for Oncology

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Temitope I. David^1,2, Nikolay B. Pestov^1,3,4,a*, Tatyana V. Korneenko⁴, and Nikolai A. Barlev^1,3,5,6

¹Institute of Biomedical Chemistry, 119121 Moscow, Russia

²Laboratory of Molecular Oncology, Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Moscow Region, Russia

³Laboratory of Tick-Borne Encephalitis and Other Viral Encephalitides, Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products, Russian Academy of Sciences, 108819 Moscow, Russia

⁴Group of Cross-Linking Enzymes, Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia

⁵Institute of Cytology Russian Academy of Sciences, 194064 St.-Petersburg, Russia

⁶School of Medicine, Nazarbayev University, 010000 Astana, Kazakhstan

^* To whom correspondence should be addressed.

Received June 6, 2023; Revised August 1, 2023; Accepted August 1, 2023

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Extensive application of technologies like phage display in screening peptide and protein combinatorial libraries has not only facilitated creation of new recombinant antibodies but has also significantly enriched repertoire of the protein binders that have polypeptide scaffolds without homology to immunoglobulins. These innovative synthetic binding protein (SBP) platforms have grown in number and now encompass monobodies/adnectins, DARPins, lipocalins/anticalins, and a variety of miniproteins such as affibodies and knottins, among others. They serve as versatile modules for developing complex affinity tools that hold promise in both diagnostic and therapeutic settings. An optimal scaffold typically has low molecular weight, minimal immunogenicity, and demonstrates resistance against various challenging conditions, including proteolysis – making it potentially suitable for peroral administration. Retaining functionality under reducing intracellular milieu is also advantageous. However, paramount to its functionality is the scaffold’s ability to tolerate mutations across numerous positions, allowing for the formation of a sufficiently large target binding region. This is achieved through the library construction, screening, and subsequent expression in an appropriate system. Scaffolds that exhibit high thermodynamic stability are especially coveted by the developers of new SBPs. These are steadily making their way into clinical settings, notably as antagonists of oncoproteins in signaling pathways. This review surveys the diverse landscape of SBPs, placing particular emphasis on the inhibitors targeting the oncoprotein KRAS, and highlights groundbreaking opportunities for SBPs in oncology.

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KEY WORDS: monobodies, adnectins, lipocalins, affibodies, DARPins

DOI: 10.1134/S0006297923090043

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