Dana-Farber-Cancer Institute Inc.

Center for Blood Research, Inc.

Children's Medical Center Corporation

The Cbr Institute for Biomedical Research, Inc.

California Institute of Technology

Dyax Corporation

Biogen, Incorporated

Immune Disease Institute, Inc.

Timothy a. Springer

Donald E. Staunton

Michael L. Dustin

Timothy Alan Springer

Michael L Dustin

Chafen Lu

Motomu Shimaoka

Donald E Staunton

Robert Rothlein

Steven D Marlin

Angel A Corbi

Isaac J Rondon

Edward Hirsch Cohen

Thomas M Roberts

Xianchi Dong

Michael S Diamond

Antonin R deFougerolles

Takashi K Kishimoto

Barbara P Wallner

Catherine A Hession

Stephen L Mayo

Moonsoo Jin

Robert H Vonderheide

Gaojie Song

Julia Shifman

Aiping Jiang

Adem Koksal

Richard Tizard

Bing Hao Luo

Robert Mattaliano

Michael Lawrence

Michelle W Carr

Yan Qin

Stephen J Roth

Disclosed are compositions and methods for modulating the activity of TGF-&#x3b2;. More particularly, compositions and methods for modulating the release of active TGF-&#x3b2; from an LRRC33-TGF-&#x3b2; prodomain-TGF-&#x3b2; ternary complex are provided, as are and methods of treatment based upon such modulation.

Methods and compositions for modulaton of transforming growth factor beta-regulated functions

Described herein are modified integrin &#x3b1; and/or &#x3b2; headpiece polypeptides, and crystallizable integrin polypeptide dimers comprising a modified integrin &#x3b1; and/or &#x3b2; headpiece polypeptide and a disulfide bond linking the two integrin headpiece polypeptide subunits. Methods for using the modified integrin &#x3b1; and/or &#x3b2; headpiece polypeptides and the integrin polypeptide dimers are also provided herein. For example, methods for characterizing integrin-ligand interaction and identifying integrin ligands are also provided herein. In some embodiments, the identified integrin ligands can be used as inhibitors of integrins.

Modified integrin polypeptides, modified integrin polypeptide dimers, and uses thereof

This invention relates to compositions and methods for eliciting an immune response against a parasite of the genusin a mammal.

Conformation-stabilized TRAP antigens

The methods and compositions described herein are based, in part, on the discovery that the introduction of a disulfide bond into an integrin polypeptide by the substitution of at least one cysteine residue in the polypeptide permits stabilization of the integrin in a 'closed/inactive' state. This stabilizing disulfide bond permits integrins to be screened for a candidate molecule that can bind to the closed state. In particular, this approach can be used to screen for agents that bind to the closed state of an integrin polypeptide, and are useful as therapeutic treatments to prevent integrin activation.

Stabilized low affinity conformation of integrins for drug discovery

The disclosure provides, inter alia, binding proteins (e.g., antibodies) that bind to an integrin in an activated conformation, e.g., activated LFA-1 ('aLFA-1 '), e.g., relative to a non-activated conformation of LFA-1. In one embodiment, the binding proteins inhibit at least one function of an aLFA-1, e.g., inhibit a binding interaction between aLFA-1 and a cognate ligand of aLFA-1, e.g., an ICAM protein. The binding proteins can be used to treat or prevent an inflammatory disorder or other disorder.

Conformation specific antibodies

The present invention provides a method for stabilizing a protein in a desired conformation by introducing at least one disulfide bond into the polypeptide. Computational design is used to identify positions where crysteine residues can be introduced to form a disulfide bond in only one protein conformation, and therefore lock the protein in a given conformation. Accordingly, antibody and small molecule therapeutics are selected that are specific for the desired protein conformation. The invention also provides modified integrin I-domain polypeptides that are stabilized in a desired conformation. The invention further provides screening assays and therapeutic methods utilizing the modified integrin I-domains of the invention.

Modified polypeptides stabilized in a desired conformation and methods for producing same

The present invention provides an isolated polypeptide capable of binding toCAM-1, comprising the integrin (XL I domain or biologically active portion thereof, wherein one or more residues is substituted, wherein the substituted polypeptide binds ICAM-I at a higher affinity than wild type integrin CCL protein. The invention provides a method for inhibiting ICAM-I and a pharmaceutical composition comprising an integrin (XL I domain polypeptide or biologically active portion of the polypeptides. The invention also provides a method of treating or preventing an LFA-I mediated ICAM-1 associated disease such as inflammation, artherosclerosis, allograft rejection, diabetes, T-cell mediated sensitization reaction, psoriasis, HIV infection, or rheumatoid arthritis.

Integrin alpha L I domain mutants with increased binding affinity

The present invention provides a method for stabilizing a protein in a desired conformation by introducing at least one disulfide bond into the polypeptide. Computational design is used to identify positions where cysteine residues can be introduced to form a disulfide bond in only one protein conformation, and therefore lock the protein in a given conformation. Accordingly, antibody and small molecule therapeutics are selected that are specific for the desired protein conformation. The invention also provides modified integrin I-domain polypeptides that are stabilized in a desired conformation. The invention further provides screening assays and therapeutic methods utilizing the modified integrin I-domains of the invention.

The disclosure provides, inter alia, binding proteins (e.g., antibodies) that bind to an integrin in an activated conformation, e.g., activated LFA-1 ('aLFA-1'), e.g., relative to a non-activated conformation of LFA-1. In one embodiment, the binding proteins inhibit at least one function of an aLFA-1, e.g., inhibit a binding interaction between aLFA-1 and a cognate ligand of aLFA-1, e.g., an ICAM protein. The binding proteins can be used to treat or prevent an inflammatory disorder or other disorder.

The present invention provides a method for stabilizing a protein in a desired conformation by introducing at least one disulfide bond into the polypeptide. Computational design is used to identify positions where cysteine residues can be introduced to form a disulfide bond in only one protein conformation, and therefore lock the protein in a given conformation. Accordingly, antibody and small molecule therapeutics are selected that are specific for the desired conformation. The invention also provides modified integrin I-domain polypeptides that are stabilized in a desired conformation. The invention further provides screening assays and therapeutic methods utilizing the modified integrin I-domains of the invention.

The present invention provides a method for stabilizing a protein in a desired conformation by introducing at least one disulfide bond into the polypeptide. Computational design is used to identify positions where cysteine residues can be introduced to form a disulfide bond in only one protein conformation, and therefore lock the protein in a given conformation. Accordingly, antibody and small molecule therapeutics are selected that are specific for the desired protein conformation. Modified integrin I-domain polypeptides stabilized in a desired conformation are also provided, as well as screening assays and therapeutic methods utilizing the modified integrin I-domain polypeptides.

The present invention relates to intercellular adhesion molecules (ICAM-1) which are involved in the process through which lymphocytes recognize and migrate to sites of inflammation as well as attach to cellular substrates during inflammation. The invention is directed toward such molecules, screening assays for identifying such molecules and antibodies capable of binding such molecules. The invention also includes uses for adhesion molecules and for the antibodies that are capable of binding them.

Functional derivatives of ICAM-1 with altered ability to bind LFA-1 or HRV

The present invention provides a method for stabilizing a protein in a desired conformation by introducing at least one disulfide bond into the polypeptide. Computational design is used to identify positions where cysteine residues can be introduced to form a disulfide bond in only one protein conformation, and therefore lock the protein in a given conformation. Accordingly, antibody and small molecule therapeutics are selected that are specific for the desired protein conformation. Modified integrin I-domain polypeptides that are stabilized in a desired conformation are also provided. Finally, screening assays and therapeutic methods utilizing the modified integrin I-domains of the invention are also provided.

Growing community of inventors

Newton, MA, United States of America

Timothy Alan Springer