Cambridge Antibody Technology Limited

Other

Medical Research Council

Medimmune Limited

Iontas Limited

Cancer Research Technology Limited

John Gerald McCafferty

James David Marks

Gregory Paul Winter

Andrew David Griffiths

Kevin Stuart Johnson

David John Chiswell

Ronald Henry Jackson

Anthony Richard Pope

Timothy Peter Bonnert

Timothy Piers Clackson

Kaspar Philipp Holliger

Geoffrey Walter Grigg

Hendricus Renerus Jacobus Mattheus Hoogenboom

Henricus Renerus Jacobus Mattheus Hoogenboom

Tristan J Vaughan

Elaine Joy Derbyshire

Michael Richard Dyson

Jane Katharine Osbourn

Kothai Parthiban

Alison Jane Wilton

Philip Ronald Tempest

Louise Conroy

Julia Elizabeth Thompson

Simon Nicholas Lennard

Peta Sally Helena Braddock

Sarah Leila Du Fou

John H Kenten

Mark T Martin

Rodger G Smith

Deborah J Allen

Richard C Titmas

Michael J Darsley

Gerard John Graham

Richard O Williams

Hendricus Renerus Hoogenboom

Rajika Perera

Frances Rosemary Balkwill

Johanna Liinamaria Syrjanen

Gillian Murphy

Kasper Philipp Holliger

Henricus Renerus Hoogenboom

Jane Katharine Osbourne

Aneesh Karatt Vellatt

Christopher Tape

Hendricus Reneus Jacobus Mattheus Hoogenboom

Kevin Fitzgerald

Peter Slavny

The invention relates to methods of producing eukaryotic cell libraries encoding a repertoire of binding molecules ('binders'), wherein the methods use a site-specific nuclease for targeted cleavage of cellular DNA to enhance site-specific integration of binder genes through endogenous cellular repair mechanisms. Populations of eukaryotic cells are produced in which a repertoire of genes encoding binders are integrated into a desired locus in cellular DNA (e.g., a genomic locus) allowing expression of the encoded binding molecule, thereby creating a population of cells expressing different binders.

Preparation of libraries of protein variants expressed in eukaryotic cells and use for selecting binding molecules

Use of the surface presentation level of binders (e.g., antibodies, receptors) on cultured higher eukaryotic cells in vitro as a predictive indicator of developability characteristics, e.g., solubility, of the binders. Display libraries of higher eukaryotic cells, e.g., mammalian cells, adapted for use in screening surface-displayed binders for developability and affinity of target binding. High-throughput screening of display libraries with in-built selection for developability including binder solubility, capability to be formulated at high concentrations, low propensity for non-specific binding, and half-life. Enrichment of populations of binders for developability characteristics and/or other qualities such as target binding and affinity, by controlling cell surface presentation of binders from an inducible promoter operably linked to binder-encoding DNA.

Selecting for developability of polypeptide drugs in eukaryotic cell display systems

Anti-CXCL12 antibody molecules and their uses are disclosed, and in particular anti-CXCL12 antibody molecules that are capable of inhibiting a biological activity of CXCL12 in vitro and in vivo and their use for treating CXCL12-mediated disease.

Anti-CXCL12 antibody molecules and their uses

Anti-TACE (ADAM17) antibodies are disclosed that for the first time in the art are capable of binding to TACE, of acting as antagonists of one or more its biological activities, in particular by binding to TACE in a cross domain binding mode in which residues in both the catalytic domain and in the cysteine rich/disintegrin domains (Dis-Cys) are involved in antibody binding to TACE, helping to improve the specificity of the antibody binding and/or helping to improve inhibition of TACE biological activity. The therapeutic uses of the antibodies, in particular for the treatment of cancer are disclosed.

Anti-tace antibody molecules and their uses

A member of a specific binding pair (sbp) is identified by expressing DNA encoding a genetically diverse population of such sbp members in recombinant host cells in which the sbp members are displayed in functional form at the surface of a filamentous bacteriophage particle containing DNA encoding the sbp member, wherein the sbp member has a binding domain that consists of a dAb fragment. The displayed sbps may be selected by affinity with a complementary sbp member, and the DNA recovered from selected filamentous bacteriophage particles for expression of the selected sbp members.

Methods for producing members of specific binding pairs

A member of a specific binding pair (sbp) is identified by expressing DNA encoding a genetically diverse population of such sbp members in recombinant host cells in which the sbp members are displayed in functional form at the surface of a secreted recombinant genetic display package (rgdp) containing DNA encoding the sbp member or a polypeptide component thereof, by virtue of the sbp member or a polypeptide component thereof being expressed as a fusion with a capsid component of the rgdp. The displayed sbps may be selected by affinity with a complementary sbp member, and the DNA recovered from selected rgdps for expression of the selected sbp members. Antibody sbp members may be thus obtained, with the different chains thereof expressed, one fused to the capsid component and the other in free form for association with the fusion partner polypeptide. A phagemid may be used as an expression vector, with said capsid fusion helping to package the phagemid DNA. Using this method libraries of DNA encoding respective chains of such multimeric sbp members may be combined, thereby obtaining a much greater genetic diversity in the sbp members than could easily be obtained by conventional methods.

A member of a specific binding pair (sbp) is identified by expressing DNA encoding a genetically diverse population of such sbp members in recombinant host cells in which the sbp members are displayed in functional form at the surface of a secreted recombinant genetic display package (rgdp) containing DNA encoding the sbp member or a polypeptide component thereof, by virtue of the sbp member or a polypeptide component thereof being expressed as a fusion with a capsid component of the rgdp. The displayed sbps may be selected by affinity with a complementary sbp member, and the DNA recovered from selected rgdps for expression of the selected sbp members. A phagemid may be used as an expression vector, with said capsid fusion helping to package the phagemid DNA.

Methods are disclosed for the production of anti-self antibodies and antibody fragments, being antibodies or fragments of a particular species of mammal which bind self antigens of that species. Methods comprise providing a library of replicable genetic display packages (rgdps), such as filamentous phage, each rgdp displaying at its surface member of a specific binding pair which is an antibody or antibody fragment, and each rgdp containing nucleic acid sequence derived from a species of mammal. The nucleic acid sequence in each rgdp encodes a polypeptide chain which is a component part of the sbp member displayed at the surface of that rgdp. Anti-self antibody fragments are selected by binding with a self antigen from the said species of mammal. The displayed antibody fragments may be scFv, Fd, Fab or any other fragment which has the capability of binding antigen. Nucleic acid libraries used may be derived from a rearranged V-gene sequences of unimmunised mammal. Synthetic or artificial libraries are described and shown to be useful.

Production of anti-self antibodies from antibody segment repertoires and displayed on phage

The invention provides specific binding members, for example in the form of antibody variable domains, based on the CDR3 sequences of the antibody VH regions of SL15 (SEQ ID NO:4) and JT182 (SEQ ID NO:10). The antibodies have strong neutralising activity for TGF&#x3b2;and are useful in treating conditions associated with excess TGF&#x3b2;activity, such as fibrosis, immune responses and tumor progression.

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Cambridgeshire, United Kingdom

John Gerald McCafferty