University of California

Ixsys, Incorporated

Judith A Varner

William D Huse

Michael A Palladino

Bruce Andrew Lee

Rommie E Amaro

Robert Malmstrom

Michael C Schmid

Megan Kaneda

Victoria Feher

Barbara Garmy-Susini

The present invention is based on the finding that CD11b signaling inhibits immune suppression, modulates neovascularization and promotes anti-tumor immune responses in models of murine and human cancer. As such, provided herein are methods of treating cancer using an antibody, protein or small molecule that modulates CD11b activity or expression. Also provided are methods of identifying cancer that is amenable to such treatment and/or increasing susceptibility of cancer cells to treatment with a chemotherapeutic agent.

Methods of enhancing immunity

The present disclosure relates to PI3K&#x3b3; inhibitors and methods of their use.

PI3KGAMMA inhibitors

The present invention satisfies the need in the art by providing methods for altering hematopoietic progenitor cell adhesion and/or migration to a target tissue, and for altering hematopoietic progenitor cell differentiation into a second cell type. The invention also provides methods for screening test compounds for altering the level of hematopoietic progenitor cell adhesion and/or migration to a target tissue, and for altering hematopoietic progenitor cell differentiation into a second cell type. The invention further provides methods for isolating hematopoietic progenitor cells.

Method for altering hematopoietic progenitor cell adhesion, differentiation, and migration

The present invention is directed to compositions and methods for inhibiting the development of new lymphatic vessels, and for inhibiting tumor cell dissemination through the lymphatics. In preferred embodiments, the present invention utilizes agents that inhibit the specific binding of integrin alpha4beta1 (&#x3b1;4&#x3b2;1, VLA-4) to one or more of its ligands. The invention further relates to methods for screening test compounds for their ability to inhibit undesirable lymphangiogenesis and/or tumor metastasis.

Methods for inhibition of lymphangiogenesis and tumor metastasis

The present invention provides methods for reducing or inhibiting angiogenesis in a tissue, by contacting &#x3b1;5&#x3b2;1 integrin in the tissue with an agent that interferes with specific binding of the &#x3b1;5&#x3b2;1 integrin to a ligand expressed in the tissue. The invention further provides methods of reducing or inhibiting angiogenesis in a tissue in an individual, by administering to the individual an agent that interferes with the specific binding of &#x3b1;5&#x3b2;1 integrin to a ligand expressed in the tissue; and methods of reducing the severity of a pathological condition associated with angiogenesis in an individual, by administering to the individual an agent that interferes with specific binding of &#x3b1;5&#x3b2;1 integrin to a ligand in a tissue associated with the pathological condition.

Methods for detecting and inhibiting angiogenesis

The invention provides methods for detecting and inhibiting angiogenesis, endothelial cell adhesion, and endothelial cell migration using agents which inhibit the specific binding of integrin &#x3b1;4&#x3b2;1 to one or more of its ligands. The invention further provides methods for screening test compounds for their ability to inhibit angiogenesis, endothelial cell adhesion, or endothelial cell migration by employing agents which inhibit the specific binding of integrin &#x3b1;4&#x3b2;1 to one or more of its ligands. The invention additionally relates to methods for isolating endothelial progenitor cells which express integrin &#x3b1;4&#x3b2;1. The methods of the invention are useful in, for example, diagnosing and inhibiting pathological conditions that are associated with angiogenesis, endothelial cell adhesion, and/or endothelial cell migration. The invention's methods are also useful in isolating endothelial progenitor cells, and in determining the mechanisms that underlie angiogenesis, development, wound healing, and the function of the female reproductive system.

Methods for inhibiting angiogenesis

The present invention provides methods for reducing or inhibiting angiogenesis in a tissue, by contacting &#x3b1;5&#x3b2;1 integrin in the tissue with an agent that interferes with the specific binding of &#x3b1;5&#x3b2;1 integrin to a ligand expressed in the tissue; and methods of identifying angiogenesis in a tissue, by contacting the tissue with an agent that specifically binds &#x3b1;5&#x3b2;1 integrin, and detecting specific binding of the agent to &#x3b1;5&#x3b2;1 integrin associated with a blood vessel in the tissue. Also provided are methods of diagnosing a pathological condition characterized by angiogenesis in a tissue in an individual; methods of reducing or inhibiting angio genesis in a tissue in an individual; and methods of reducing the severity of a pathological condition associated with angiogenesis in an individual, by administering to the individual an agent that interferes with specific binding of &#x3b1;5&#x3b2;1 integrin to a ligand in a tissue associated with the pathological condition.

The present invention provides methods for reducing or inhibiting angiogenesis in a tissue, by contacting &#x3b1;5&#x3b2;1 integrin in the tissue with an agent that interferes with specific binding of the &#x3b1;5&#x3b2;1 integrin to a ligand expressed in the tissue; and methods of identifying angiogenesis in a tissue, by contacting the tissue with an agent that specifically binds &#x3b1;5&#x3b2;1 integrin, and detecting specific binding of the agent to &#x3b1;5&#x3b2;1 integrin associated with a blood vessel in the tissue. Also provided are methods of diagnosing a pathological condition characterized by angiogenesis in a tissue in an individual. The invention further provides methods of reducing or inhibiting angiogenesis in a tissue in an individual, by administering to the individual an agent that interferes with the specific binding of &#x3b1;5&#x3b2;1 integrin to a ligand expressed in the tissue; and methods of reducing the severity of a pathological condition associated with angiogenesis in an individual, by administering to the individual an agent that interferes with specific binding of &#x3b1;5&#x3b2;1 integrin to a ligand in a tissue associated with the pathological condition. The invention also provides methods of identifying an agent that reduces or inhibits angiogenesis associated with &#x3b1;5&#x3b2;1 integrin expression in a tissue by contacting a tissue exhibiting angiogenesis associated with &#x3b1;5&#x3b2;1 integrin expression with an agent, and detecting a reduction or inhibition of angiogenesis in the tissue.

The present invention includes non-RGD cyclic peptides that inhibit the function of the integrin receptor, .alpha..sub.v .beta..sub.3. The inventive peptides are between five to about thirty amino acids in length and include the sequence (SEQ ID NO:8), Arg-Cys-Asp-Gly-X.sub.i where X.sub.i is any amino acid, and a five-membered cyclic portion. These non-RGD peptides display surprisingly potent antagonist activity despite the lack of the consensus binding sequence Arg-Gly-Asp, and present opportunities for selective targeting to the .alpha..sub.v .beta..sub.3 receptor. Pharmaceutical compositions and methods of use are also disclosed. The therapeutic uses for the inventive peptides include treating diseases involving .alpha..sub.v .beta..sub.3 receptors such as cancer, osteoporosis, restenosis, and angiogenic-based diseases.

Fivemer cyclic peptide inhibitors of diseases involving .alpha..sub.v

The present invention includes non-RGD, nine amino acid cyclic peptides that inhibit the function of the integrin receptor, .alpha..sub.v .beta..sub.3. These peptides display surprisingly potent antagonist activity despite the lack of the consensus binding sequence Arg-Gly-Asp, and present opportunities for selective targeting to the .alpha..sub.v .beta..sub.3 receptor. Pharmaceutical compositions and methods of use are also disclosed. The therapeutic uses for the inventive peptides include treating diseases involving .alpha..sub.v .beta..sub.3 receptors such as osteoporosis, restenosis, and angiogenic-based diseases, including cancer, arthritis, and diabetic retinopathy.

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Encinitas, CA, United States of America

Judith A Varner