Abstract: Methods and compositions directed to improved universal antibody libraries that rationally exploit human diversity information contained within reference antibody libraries, such as universal antibody libraries, are disclosed. The disclosed processes involve use of a query CDR sequence to guide incorporation of human antibody diversity present within the reference library into cohort libraries of the invention. Methods for making and screening such cohort libraries for isolating therapeutics suitable for treating disease are also disclosed.

Abstract: Libraries of immunoglobulins of interest are described, the libraries containing mutated immunoglobulins of interest in which a single predetermined amino acid has been substituted in one or more positions in one or more complementarity-determining regions of the immunoglobulin of interest. The libraries comprise a series of subset libraries, in which the predetermined amino acid is “walked through” each of the six complementarity-determining regions (CDRs) of the immunoglobulin of interest not only individually but also for each of the possible combinatorial variations of the CDRs, resulting in subset libraries that include mutated immunoglobulins having the predetermined amino acid at one or more positions in each CDR, and collectively having the predetermined amino acid at each position in each CDR.

Abstract: A method for generating human IgG1 antibodies with enhanced Fc effector function is disclosed. In practicing the method, an IgG1 Fc look-through mutagenesis (LTM) coding library directed at four receptor-contact regions of the Fc CH2 portion of in human IgG1 Fc is expressed in a system in which the mutated Fc fragments are displayed on the surfaces of the expression cells. The fragments are then screened for altered binding affinity to a selected Fc receptor or other Fc-binding protein. The selected mutations may be used, in turn, to guide the selection of multiple substitutions in the construction of a walk-through mutation (WTM) library, for generating additional Fc fragment mutations with desired binding properties. The antibodies so produced have a variety of therapeutic and diagnostic applications.