Georgetown University

Rutgers, The State University of New Jersey

Chen-Yong Lin

Joseph R Bertino

Siang-Yo Lin

Robert B Dickson

Michael D Johnson

Shaomeng Wang

Istvan J Enyedy

Zoltan Szekely

Feng-Pai Chou

Sheau-Ling Lee

Joseph Bertino

The present invention relates to anti-matriptase antibodies and immunoconjugates of anti-matriptase antibodies with cytotoxic agents and the use thereof for killing or inhibiting the growth of matriptase-expressing cancer cells, such as those of multiple myeloma and breast cancers. In particular, immunoconjugates comprising an anti-matriptase monoclonal antibody and anticancer agents such as auristatin, including monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) are introduced, which have potent antitumor activity in vivo. Moreover, importantly; there was no weight loss or other evidence of toxicity in the animals, indicating that no significant free drug was released into the circulation from the conjugate. The present invention also provides compositions comprising these new immunoconjugates and use of them for treatment of malignancies comprising cells that express matriptase. In addition, administration of an anti-matriptase antibody or immunoconjugates of an anti-matriptase antibody and a cytotoxic agent in combination with administration of an immunomodulatory agent, such as thalidomide or an analog thereof, provides a more effective treatment of these cancers.

Targeting tumor cells with chemotherapeutic agents conjugated to anti-matriptase antibodies by in vivo cleavable linking moieties

The present invention relates to matriptase antibodies and immunoconjugates of matriptase antibodies with cytotoxic agents and the use thereof for killing or inhibiting the growth of matriptase-expressing cancer cells, such as those of multiple myeloma and breast cancers. In particular, immunoconjugates comprising a matriptase monoclonal antibody and anticancer agents such as auristatin, including monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) are introduced, which have potent antitumor activity in vivo. Moreover, importantly; there was no weight loss or other evidence of toxicity in the animals, indicating that no significant free drug was released into the circulation from the conjugate. The present invention also provides compositions comprising these new immunoconjugates and use of them for treatment of malignancies comprising cells that express matriptase. In addition, administration of a matriptase antibody or immunoconjugates of a matriptase antibody and a cytotoxic agent in combination with administration of an immunomodulatory agent, such as thalidomide or an analog thereof, provides a more effective treatment of these cancers.

Targeting tumor cells with chemotherapeutic agents conjugated to matriptase antibodies

The present invention relates to methods of determining the presence or absence of abnormal lymphoid cells or abnormal myeloid cells in a cell sample, with the methods comprising subjecting the cell sample to conditions that will activate any inactive matriptase present in the cell sample and measuring the levels of activated matriptase in the cell sample. Once measured, these levels can then be compared to control levels of active matriptase to determine if the cell sample has elevated levels of activated matriptase over control levels of active matriptase. An elevation in the levels of activated matriptase in the cell sample is indicative that the cell sample contains abnormal lymphoid cells or abnormal myeloid cells.

Markers for abnormal cells

The present invention relates to matriptase antibodies and immunoconjugates of matriptase antibodies with cytotoxic agents and the use thereof for killing or inhibiting the growth of matriptase-expressing cancer cells, such as those of multiple myeloma and breast cancers. In particular, immunoconjugates comprising a matriptase monoclonal antibody and anticancer agents such as auristatin, including monomethyl auristatin E(MMAE) and monomethyl auristatin F(MMAF) are introduced, which have potent antitumor activity in vivo. Moreover, importantly; there was no weight loss or other evidence of toxicity in the animals, indicating that no significant free drug was released into the circulation from the conjugate. The present invention also provides compositions comprising these new immunoconjugates and use of them for treatment of malignancies comprising cells that express matriptase. In addition, administration of a matriptase antibody or immunoconjugates of a matriptase antibody and a cytotoxic agent in combination with administration of an immunomodulatory agent, such as thalidomide or an analog thereof, provides a more effective treatment of these cancers.

The present invention relates to matriptase antibodies and immunoconjugates of matriptase antibodies with cytotoxic agents and the use thereof for killing or inhibiting the growth of matriptase-expressing cancer cells, such as those of multiple myeloma and breast cancers. In particular, immunoconjugates comprising a matriptase monoclonal antibody and anticancer agents such as doxorubicin (DOX) are introduced, which are equipotent to anticancer agents used in free form but exhibit significantly reduced cardiotoxicity and almost no adverse effects on normal bone marrow-derived mesenchymal stromal cells that do not express matriptase. The present invention also provides compositions comprising these new immunoconjugates and use of them for treatment of malignancies comprising cells that express matriptase. In addition, administration of a matriptase antibody or immunoconjugates of a matriptase antibody and a cytotoxic agent in combination with administration of an immunomodulatory agent, such as thalidomide or an analog thereof, provides a more effective treatment of these cancers.

Targeting matriptase expressing tumor cells with chemotherapeutic agents conjugated to matriptase antibodies

Disclosed are antibody drug conjugates (ADC) that include highly potent toxic agents with specific antibodies to target tumors. Also disclosed are related antibodies, polypeptides, nucleic acids, host cells, compositions, and uses.

Specific delivery of toxins conjugated with antibodies to activate matripase

The invention is directed to a method of detecting a malignancy or a pre-malignant lesion in breast or other tissue, or a pathologic condition, by detecting the presence of single-chain or two-chain forms of matriptase in the tissue. The invention is further directed to a method of treating malignancies, which have the phenotype of matriptase production by administering a tumor formation inhibiting effective amount of concentrate of Bowman-Birk inhibitor (BBIC), or other matriptase inhibitor. The invention also is directed to nucleic acids encoding a matriptase protein or fragments thereof, and their use for structure elucidation and modeling to identify other inhibitors of matriptase, as well as to methods of identifying matriptase modulating agents, including activators and inhibitors.

Matriptase, a serine protease and its applications

The present invention relates to a method of inhibiting carcinoma progression wherein matriptase plays a role in a subject in need of such inhibition including administering to a subject an effective amount of a compound comprising two positively charged groups, which are the same or different. The groups are linked by a chemical group having a length of between 5 and 30 A, and preferably between 15 and 24 A. Diagnostic methods based on matriptase action and therapeutic methods involving inhibition of matriptase activity are provided.

Structure based discovery of inhibitors of matriptase for the treatment of cancer and other conditions

Compositions of the instant invention comprise a monoclonal antibody designated as 21-9 which binds selectively with an 80 kDa matrix-degrading proteinase having an average molecular weight of about 80 kDa, which is active in the presence of Ca.sup.2, Mg.sup.2+ and Mn.sup.2+.

Growing community of inventors

Falls Church, VA, United States of America

Chen-Yong Lin