Massachusetts Institute of Technology

University of Illinois

Adimab, LLC

Commonwealth Scientific and Industrial Research Organisation

Ludwig Institute for Cancer Research Limited

Other

The Rockefeller University

Cancer Research Technology Limited

K Dane Wittrup

David M Kranz

Maximiliano Vasquez

Eric T Boder

Tillman U Gerngross

Michael Feldhaus

Michele C Kieke

Lloyd J Old

Christilyn Graff

Antony Wilks Burgess

Douglas A Lauffenburger

Andrew Ewart Scott

Timothy Edward Adams

Terrance Grant Johns

Kerry Chester

Balaji M Rao

Ginger Chao

Peter Anthony Hoyne

Richard J H Begent

Phillip D Holler

Jack Raymond Wands

Jennifer R Cochran

Jeffrey V Ravetch

Andrew Mark Scott

Juergen Hermann Nett

Stephen Lael Sazinsky

Shanshan Wu Howland

Yik Andy Yeung

Michele Keike

David V Liu

Eric Shusta

Kelly J Davis

The present invention overcomes the inadequacies inherent in the known methods for generating libraries of antibody-encoding polynucleotides by specifically designing the libraries with directed sequence and length diversity. The libraries are designed to reflect the preimmune repertoire naturally created by the human immune system and are based on rational design informed by examination of publicly available databases of human antibody sequences.

Rationally designed, synthetic antibody libraries and uses therefor

The present invention overcomes the inadequacies inherent in the known methods for generating libraries of antibody-encoding polynucleotides by specifically designing the libraries with directed sequence and length diversity. The libraries are designed to reflect the preimmune repertoire naturally created by the human immune system, with or without DH segments derived from other species, and are based on rational design informed by examination of publicly available databases of antibody sequences.

Methods for purifying multispecific antibodies on interest (MAIs) that co-engage at least two different antigens or epitopes (also referred to targets, used interchangeably throughout), from compositions comprising the MAI and parental homodimeric antibody species are provided, as well as reagents which may be used to practice such methods.

Methods for purifying heterodimeric multispecific antibodies from parental homodimeric antibody species

The present invention provides a genetic method of tethering polypeptides to the yeast cell wall in a form accessible for binding to macromolecules. Combining this method with fluorescence-activated cell sorting provides a means of selecting proteins with increased or decreased affinity for another molecule, altered specificity, or conditional binding. As one embodiment, attaching an scFv antibody fragment to the Aga2p agglutinin effectively mimics the cell surface display of antibodies by B cells in the immune system for affinity maturation in vivo. As another embodiment, T cell receptor mutants can be isolated by this method that are efficiently displayed on the yeast cell surface, providing a means of altering T cell receptor binding affinity and specificity by library screening.

Yeast cell surface display of proteins and uses thereof

The present invention relates to mutant IL-2 polypeptides that act as receptor antagonists. The mutant IL-2 polypeptides bind CD 25 but do not activate the IL-2 receptor. Also provided are methods of using the mutant IL-2 polypeptides, for example, to treat a patient who has cancer or a viral infection. The mutant polypeptides can also be used in various delivery systems.

Mutant interleukin-2 (IL-2) polypeptides

The present invention is based, in part, on our discovery of immunoglobulins (e.g., immunoglobulin G (IgG)) polypeptides (e.g., murine or human IgG, such as human IgG1) that are aglycosylated yet retain the ability to bind to an Fc receptor, such as an activating Fc receptor (e.g., Fc&#x3b3;RIIA and/or Fc&#x3b3;RIIIA).

Aglycosylated immunoglobulin mutants

The present invention relates generally to growth factor receptor epitope peptides, particularly EGF family receptor epitope peptides. The invention also relates to the use of the receptor peptides in generating antibodies which have anti-tumor or anti-cancer activity or in stimulating an immunological response. The invention further relates to antibodies specifically directed against the receptor peptides. Methods for generating an immune response and for treatment of tumors and cancer are also provided.

Antibodies to EGF receptor epitope peptides and uses thereof

The present invention features engineered proteins that include a first polypeptide that specifically binds a first target (e.g., a cellular target, such as a cell-surface antigen) and a second polypeptide that selectively binds an activating FcR.

Directed engagement of activating Fc receptors

The present invention provides a genetic method for tethering polypeptides to the yeast cell wall in a form accessible for binding to macromolecules. Combining this method with fluorescence-activated cell sorting provides a means of selecting proteins with increased or decreased affinity for another molecule, altered specificity, or conditional binding. Also provided is a method for genetic fusion of the N terminus of a polypeptide of interest to the C-terminus of the yeast Aga2p cell wall protein. The outer wall of each yeast cell can display approximately 10protein agglutinins. The native agglutinins serve as specific adhesion contacts to fuse yeast cells of opposite mating type during mating. In effect, yeast has evolved a platform for protein-protein binding without steric hindrance from cell wall components. As one embodiment, attaching an scFv antibody fragment to the Aga2p agglutinin effectively mimics the cell surface display of antibodies by B cells in the immune system for affinity maturation in vivo. As another embodiment, T cell receptor mutants can be isolated by this method that are efficiently displayed on the yeast cell surface, providing a means of altering T cell receptor binding affinity and specificity by library screening.

The present invention is based, in part, on our discovery that EGF can be engineered to generate mutants that bind to the EGF receptor (EGFR) of a cell and that have a desirable effect on the activity of the cell. For example, the mutants can agonize the receptor (i.e., increase a biological activity of the receptor), or antagonize the receptor (i.e., decrease or inhibit a biological activity of the receptor). In turn, the rate at which the cell proliferates, for example, can be changed. Moreover, some of these mutants bind EGFR with a higher affinity than wild-type EGF exhibits. The affinity may increase by about, for example, 2-, 5-, 10-, 15-, 20-, 25-, 30-, 50-, or 100-fold relative to wild-type EGF.

Mutant epidermal growth factor polypeptides, nucleic acids, and uses therefor

The present invention relates to IL-2 mutants with increased affinity for the IL-2 alpha-receptor subunit (IL-2R&#x3b1;). The invention thus includes IL-2 mutants with improved biological potency. The invention also includes methods for directed evolution of IL-2&#x3b1; using yeast surface display to generate mutants with increased affinity for IL-2R&#x3b1;.

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Chestnut Hill, MA, United States of America

K Dane Wittrup