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Transgenic Mouse Generates Human Single Domain Antibody VH Fragments

Wed, 01/16/2013 - 2:39pm

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Crescendo Biologics announces the Crescendo Mouse using antibody fragment technology that allows the efficient generation of high-quality fully human single domain antibody VH fragmentsfrom a transgenic mouse. VH fragments are next-generation antibody-based therapeutic proteins that have applications beyond the scope of full length antibodies. They are the smallest antibody fragments that retain the ability to bind antigens specifically and with high affinity and, when generated in the Crescendo Mouse, human VH have biophysical properties that make them highly attractive drug products. VH fragments can be formulated for topical delivery, are highly amenable to modular engineering of bispecific and multivalent products, have superior tissue penetration characteristics, and are simple to manufacture in microbial systems.

Key to generation of VH fragments in the mouse is Crescendo’s proprietary triple knock out (TKO) background, which is completely devoid of all endogenous immunoglobulin chains, and therefore enables in vivo maturation of human VH single domains uncontaminated by association with any light chains. B cell development within the Crescendo Mouse is driven from a construct introduced into the TKO background that combines human V- D- and J- genes, together with murine constant and regulatory regions, to generate heavy chain only antibodies.  The power of the mouse immune system is consequently fully harnessed to drive B cell development and maturation, leading to a diverse repertoire of fully-human VH domains with superior stability and solubility.

The Crescendo Mouse responds robustly to immunisation with target proteins and in vivo B cell maturation yields diverse human VH domains, from all VH families, which have also undergone somatic hypermutation. Because the antibody response following immunisation is entirely encompassed within the VH domain, Crescendo has been able to develop a fully integrated discovery process utilising in vitro display to comprehensively mine and rapidly identify VH drug candidates directly from immunised mice.  Purified VH fragments have been shown to bind immunogen with high affinity, exhibit very high thermostability and have excellent expression levels. These data indicate that B cell maturation in the Crescendo Mouse is driving selection and optimization of matured human VH domains, with all of the properties that make them highly potent, drug quality antibody-based therapeutics.

Crescendo Biologics, +44 (0) 1223 497140, www.crescendobiologics.com

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