Erasmus University Medical Center

Erasmus University Medical Centre

Erasmus University Medical Center Rotterdam

Craig, Roger Kingdon

Richard Wilhelm Janssens

Franklin Gerardus Grosveld

Roger Kingdon Craig

Dubravka Drabek

Marinus Johannes Van Haperen

Ernie De Boer

Tao Chen

Magnus Johannes Van Haperen

A transgenic non-human mammal containing a heterologous lambda light chain gene locus, and/or a heterologous kappa light chain gene locus, and/or a heterologous heavy chain gene locus, each of which can re-arrange so that immunoglobulin heavy and light chain genes are formed and expressed in B-cells following antigen challenge.

Antibody production

A transgenic non-human mammal containing a heterologous heavy chain gene locus that is capable of producing soluble heavy chain only antibodies and antigen-binding fragments thereof following immunization.

Production of heavy chain only antibodies in transgenic mammals

The present invention relates to a method for the generation of Vheavy chain-only antibodies in a transgenic non-human mammal. In particular, the present invention relates to a method for the production of a Vheavy chain-only antibody in a transgenic non-human mammal comprising the step of expressing more than one heterologous Vheavy chain locus in that mammal.

Generation of heavy-chain only antibodies in transgenic animals

The present invention provides a high affinity, antigen-specific, soluble heavy chain-only antibody which: lacks hallmark camelid-related amino acid substitutions and has FR2 substitutions which are not found in antibodies which comprise heavy and light chain; shows increased net hydrophobicity within CDR1 and an increased number of charged amino acids present in CDR3; and comprises one or more amino acid substitutions within the framework &#x3b2;-pleated sheet leading to increased net hydrophobicity within FR1 and increased number of charged amino acids present in FR3. Also provided are VH domains having the same properties, gene segments for their production, methods for their production, transgenic animals and uses of the antibody of the VH domains in therapy.

Soluble heavy-chain only antibodies

The present invention relates to the manufacture of a diverse repertoire of functional heavy chain-only antibodies that undergo affinity maturation, and uses thereof. The invention also relates to the manufacture and use of a diverse repertoire of class-specific heavy chain-only antibodies and to the manufacture and use of multivalent polypeptide complexes with antibody heavy chain functionality, preferably antibody heavy chain binding functionality, constant region effector activity and, optionally, additional effector functions. The present invention also relates to a method of generation of fully functional heavy chain-only antibodies in transgenic mice in response to antigen challenge. In particular, the present invention relates to a method for the generation of human antigen-specific, high affinity, heavy chain-only antibodies of any class, or mixture of classes and the isolation and expression of fully functional VH antigen-binding domains.

Growing community of inventors

Rotterdam, Netherlands

Richard Wilhelm Janssens