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Multimeric antibodies with increased valency surpassing functional affinity and potency thresholds using novel formats

DOI: 10.1080/19420862.2020.1752529 DOI Help

Authors: Ami Miller (University of Oxford) , Stephen Carr (Research Complex at Harwell) , Terry Rabbitts (University of Oxford) , Hanif Ali (Quadrucept Bio Limited)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Mabs , VOL 12

State: Published (Approved)
Published: January 2020
Diamond Proposal Number(s): 12346

Open Access Open Access

Abstract: The success of therapeutic antibodies is largely attributed for their exquisite specificity, homogeneity, and functionality. There is, however, a need to engineer antibodies to extend and enhance their potency. One parameter is functional affinity augmentation, since antibodies matured in vivo have a natural affinity threshold. Generation of multivalent antibodies is one option capable of surpassing this affinity threshold through increased avidity. In this study, we present a novel platform consisting of an array of multivalent antibody formats, termed Quads, generated using the self-assembling tetramerization domain from p53. We demonstrate the versatility of this tetramerization domain by engineering anti-tumor necrosis factor (TNF) Quads that exhibit major increases in binding potency and in neutralizing TNF-mediated cytotoxicity compared to parental anti-TNF molecules. Further, Quads are amenable to fusion with different binding domains, allowing generation of novel multivalent monospecific and bispecific formats. Quads are thus a novel group of molecules that can be engineered to yield potential therapeutics with novel modalities and potencies.

Journal Keywords: Multivalent; antibody; tetravalent; octavalent; avidity; bispecific

Subject Areas: Biology and Bio-materials, Medicine


Instruments: B21-High Throughput SAXS

Added On: 30/04/2020 09:22

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1.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Structural biology

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)