Sloan-kettering Institute for Cancer Research

Rutgers, The State University of New Jersey

Georgetown University

Memorial Sloan Kettering Cancer Center

Dana-farber-cancer Institute Inc.

Pharma Mar, S.a.

Pharma Mar, S.a.u.

Joseph R Bertino

Chen-Yong Lin

Debabrata Banerjee

Siang-Yo Lin

Samuel J Danishefsky

Ting-Chao Chou

Michel Sadelain

Scott D Kuduk

Peter Bertinato

Dai-Shi Su

Kenneth Allen Savin

Erik J Sorensen

Aaron Balog

Ted Kamenecka

Christina Harris

Xiu-Guo Zhang

Glynn Thomas Faircloth

Tamara Minko

Stefano Rivella

Olga B Garbuzenko

DongFang Meng

Chad May

John E Kerrigan

Daniel S Martin

Emine E Abali

Jason Koutcher

Kathleen W Scotto

Emine A Ercikan-Abali

Shin Mineishi

Xiaoqi Xie

Kenneth Carl Anderson

Dongfang Meng

Mehdi Javanmard

Constantine S Mitsiades

Barry D Kahan

Nicholas Mitsiades

Michael D Johnson

Zoltan Szekely

Daniel J Medina

Youzhi Tong

Xinyue Liu-Chen

Jianye Sui

Karan Ahuja

Debabrata Barnejee

Saydam Guray

José Jimeno

Daniel Medina

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

This disclosure provides methods and systems for classifying biological particles, e.g., blood cells, microbes, circulating tumor cells (CTCs). Using impedance flow cytometry, such as multi-frequency impedance cytometry, in conjunction with supervised machine learning, the disclosed methods and systems demonstrated improved accuracy in classifying biological particles.

Use of multi-frequency impedance cytometry in conjunction with machine learning for classification of biological particles

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 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 instant invention provides amino acid sequences competing with E2F for DNA binding. Methods of using said amino acid sequences for treatment of hormone-refractory prostate cancer are also provided.

E2F as a target of hormone refractory prostate cancer

Recombinant lentiviral vectors having a region encoding a functional &#x3b2;-globin gene; and large portions of the &#x3b2;-globin locus control regions which include DNase I hypersensitive sites HS2, HS3 and HS4 provides expression of &#x3b2;-globin when introduced into a mammal, for example a human, in vivo. Optionally, the vector further includes a region encoding a dihydrofolate reductase. The vector may be used in treatment of hemoglobinopathies, including &#x3b2;-thalessemia and sickle-cell disease. For example, hematopoietic progenitor or stem cells may be transformed ex vivo and then restored to the patient. Selection processes may be used to increase the percentage of transformed cells in the returned population. For example, a selection marker which makes transformed cells more drug resistant than untransformed cells allows selection by treatment of the cells with the corresponding drug.

Vector encoding human globin gene and use thereof in treatment of hemoglobinopathies

Aplidine and aplidine analogues are of use for the treatment of cancer, in particular in the treatment of leukemias and lymphomas, especially in combination therapies.

Antitumoral treatments

Recombinant lentiviral vectors having a region encoding a functional &#x3b2;-globin gene; and large portions of the &#x3b2;-globin locus control regions which include DNase I hypersensitive sites HS2, HS3 and HS4 provides expression of &#x3b2;-globin when introduced into a mammal, for example a human, in vivo. Optionally, the vector further includes a region encoding a dihydrofolate reductase. The vector may be used in treatment of hemoglobinopathies, including &#x3b2;-thalessemia and sickle-cell disease. For example, hematopoietic progenitor or stem cells may be transformed ex vivo and then restored to the patient. Selection processes may be used to increase the percentage of transformed cells in the returned population. For example, a selection marker which makes transformed cells more drug resistant than un-transformed cells allows selection by treatment of the cells with the corresponding drug.

This invention also provides a method for treating a cancer subject comprising administering to the subject a combination of ATP-depleting agents at concentrations which deplete the ATP level to, or close to, at least 15% of normal in cancer cells wherein at least one of the ATP-depleting agents is a mitochondrial ATP-inhibitor, a methylthioadenosine phosphorylase inhibitor or an inhibitor of De Novo purine synthesis other than 6-Methylmercaptopurine riboside, wherein said composition produces a substantially better effect than a composition without at least one of the ATP-depleting agents: a mitochondrial ATP-inhibitor, a glycolytic inhibitor, a methylthioadenosine phosphorylase inhibitor and an inhibitor of De Novo purine synthesis other than 6-Methylmercaptopurine riboside.

In-vivo energy depleting strategies for killing drug-resistant cancer cells

Aplidine and aplidine analogues are used in the manufacture of a medicament for treating multiple myeloma.

Aplidine for multiple myeloma treatment

This invention provides a method for treating a cancer subject comprising administering to the subject a combination of ATP-depleting agents at concentrations which deplete the ATP level to at least 15% of normal in cancer cells, a pyrimidine antagonist, and an anticancer agent to which the treated cancer is sensitive. This invention also provides a composition comprising a combination of ATP-depleting agents at concentrations which deplete the ATP level to at least 15% of normal in cancer cells, a pyrimidine antagonist, and an anticancer agent to which the treated cancer is sensitive. Finally this invention provides a pharmaceutical composition comprising the above composition or a combination thereof and a pharmaceutically acceptable carrier.

Treatment of cancer by reduction of intracellular energy and pyrimidines

The present invention provides convergent processes for preparing epothilone A and B, desoxyepothilones A and B, and analogues thereof, useful in the treatment of cancer and cancer which has developed a multidrug-resistant phenotype. Also provided are intermediates useful for preparing said epothilones.

Synthesis of epothilones, intermediates thereto and analogues thereof

Growing community of inventors

Branford, CT, United States of America

Joseph R Bertino