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Bispecific Antibody Mimetics Development

Bispecific antibodies (BsAb) have been widely researched as diagnostic and therapeutic agents and the modular architecture of antibodies have been used to generate over 100 BsAb formats. Based on the platforms of BsAb and scaffold protein engineering, Creative Biolabs also provides bispecific antibody mimetics development services using alternative scaffold proteins with high affinity and selectivity.

Alternative Scaffolds as Antibody Mimetics

Antibody mimetics are a type of artificial peptides or proteins that can specifically bind to antigens similar to antibodies, and yet they are not derived from the immune system and have no structural relation to antibodies. They’re mostly irrelevant protein scaffolds composed by α-helices, β-sheets, or random coils that could bind to specific targets and be designed to incorporate novel binding sites via common protein engineering strategies. Antibodies are the first and now still the most popularly used biomolecular scaffold for generation of affinity reagents.

 X-Ray crystal structures of antibody mimetics.

Fig.1 X-Ray crystal structures of antibody mimetics. (Yu, 2017)

The scaffold commonly defines as a stable protein framework, harboring flexible loops or solvent accessible residues. Alternative scaffold proteins are a class of antibody mimetics sharing several essential properties with antibodies, the most important being the ability to recognize molecule architectures with high affinity and selectivity. Furthermore, alternative scaffolds often have improved qualities in terms of stability, reduced size, efficient recombinant features, few or no cysteines, etc. Due to small size and ease of recombinant manipulation, they are well suited for the production of bispecific proteins.

Bispecific Antibody Mimetics

In general, alternative scaffolds consist of a short and single peptide chain and thus are readily adapted into bispecific or multispecific formats. The possibility of facile construction of bispecific alternative scaffolds may potentially become a differentiating factor compared to conventional antibodies in the future. Applications of bispecific alternative scaffold proteins involve enhanced binding selectivity, increased receptor blocking capacity, provision of one biomolecule inhibiting two different receptors, and progress toward recruitment of effector functions. Another application for bispecific affinity molecules is to have one binding partner for extending serum half-life of molecules, while the other partner is to have a biological activity for specific purpose.

 Structures of alternative scaffolds that have been reported as bispecific constructs with enhanced biological function.

Fig.2 Structures of alternative scaffolds that have been reported as bispecific constructs with enhanced biological function. (Löfblom, 2011)

Bispecific Antibody Mimetics Services at Creative Biolabs

The promise of bispecific binding has initially been explored through the bivalent antibody but is expanded by adding new protein formats, both from immunoglobulin (Ig) derivatives and completely unrelated scaffolds. Here, Creative Biolabs has set up non-IgG-based protein scaffolds for engineering of bispecific recognition and is promoting alternative protein scaffolds as therapeutic antibody mimetics entering clinical validation.

Directed evolution cycle for isolating novel antibody mimetics.

Fig.3 Directed evolution cycle for isolating novel antibody mimetics. (Yu, 2017)

  • BsAb Mimetics with Enhanced Biological Function

We can design BsAb mimetics and improve their biological functions in many different strategies.

  • To increase the selectivity of a targeting moiety by simultaneously directing two receptors using fine-tuned affinities.
  • To block two receptors in the same signaling pathway. The simultaneous binding is not necessary, given that both receptors are blocked by either part of the bispecific scaffold.
  • To use bispecific molecules to increase the functional affinity and capability to block one single receptor.
  • To use one moiety of bispecific scaffold proteins to attract an effector function.

Besides, a number of alternative scaffolds stem from natural precursors that are formatted as repeated domains, meaning function in a multimeric format. And we can produce unique BsAb mimetics in distinct formats, like:

  • Adnectins
  • Affibody Molecules
  • Anticalins
  • Designed ankyrin repeat proteins
  • Single-Domain Bispecific Protein Scaffolds
    • BsAb Mimetics with Enhanced Half-Life

    Though some biologicals have been modified with polyethylene glycol (PEG) or fused to an Fc-portion of IgG or to serum albumin for increased half-life, alternative scaffolds proteins can, in addition, be raised against proteins such as Fc or albumin to take advantage of long circulation half-life of those serum proteins. By fusing such a binder to another binder owing therapeutic effects, a biomedical agent with extended half-life is created. At Creative Biolabs, we’re able to provide one-stop solutions to offer bispecific antibody mimetics as below.

  • Avimers
  • Bispecific Single-Domain ABD Molecules
  • Albumin-Binding Domain
    • BsAb Mimetics in Multiple Formats

    Non-antibody scaffolds can be divided into classes in varying ways, for example, based on origin, size, secondary structure composition, and so on. One commonly used classification system is determined by the site of diversification. Now, we can manufacture a stable framework with one or more randomized loops (the IgG fold belongs to this class) and scaffolds. The antibody fold, with diversified loops on a rigid framework, has been successfully employed in the molecular recognition both in nature and in vitro. If you have other special demands in formats, please contact us.

    Bispecific alternative scaffold can be a great option for half-life extensions, more efficient blocking of a receptor, better specificity for tumor cell targeting, as well as blocking two distinct receptors via only one biomolecule. With extensive research and years of experience in the field of scaffold proteins, Creative Biolabs is pleased to assist our clients to design and develop varieties of bispecific antibody mimetics with guaranteed properties and shorter timelines. Our seasoned scientists will sincerely serve you with considerate services.

    References

    1. Yu, X. ; et al. Beyond antibodies as binding partners: The role of antibody mimetics in bioanalysis. Annu Rev Anal Chem (Palo Alto Calif). 2017, 10(1): 293-320.
    2. Löfblom, Y.; et al. Alternative scaffolds as bispecific antibody mimetics. Bispecific Antibodies. 2011, 115-113.

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