Millennium Pharmaceuticals Limited

Molecular Templates, Inc.

Nibedita Chattopadhyay

Erin Willert

Eric Poma

George J Mulligan

Matthew C Schu

Allison Berger

Erik M Koenig

Hughes Bernard

The instant invention provides binding proteins ('CD38-binding proteins') which each comprise (1) a CD38-binding region for cell-targeting and (2) a Shiga toxin A Subunit effector polypeptide (“Shiga toxin effector polypeptide”). The Shiga toxin effector polypeptide components of the CD38-binding proteins may comprise a combination of mutations relative to a wild-type Shiga toxin sequence providing (1) de-immunization and/or (2) a reduction in protease sensitivity; wherein each Shiga toxin effector polypeptide retains one or more Shiga toxin function, such as, e.g., stimulating cellular internalization, directing intracellular routing, catalytic activity, and/or potent cytotoxicity. The CD38-binding proteins may have one or multiple uses, e.g., the selective killing of a specific CD38-expressing cell-type; and more generally, for the diagnosis and treatment of cancers and disorders involving CD38-expressing cells, e.g., in CD38-positive hematopoietic cancers such as multiple myeloma.

CD38-binding proteins comprising de-immunized Shiga toxin A subunit effectors

The instant invention provides binding proteins ('CD38-binding proteins') which each comprise (1) a CD38-binding region for cell-targeting and (2) a Shiga toxin A Subunit effector polypeptide ('Shiga toxin effector polypeptide'). The Shiga toxin effector polypeptide components of the CD38-binding proteins may comprise a combination of mutations relative to a wild-type Shiga toxin sequence providing (1) de-immunization and/or (2) a reduction in protease sensitivity; wherein each Shiga toxin effector polypeptide retains one or more Shiga toxin function, such as, e.g., stimulating cellular internalization, directing intracellular routing, catalytic activity, and/or potent cytotoxicity. The CD38-binding proteins may have one or multiple uses, e.g., the selective killing of a specific CD38-expressing cell-type; and more generally, for the diagnosis and treatment of cancers and disorders involving CD38-expressing cells, e.g., in CD38-positive hematopoietic cancers such as multiple myeloma.

Disclosed are markers associated with sensitivity to treatment with proteasome inhibitors. Sensitivity is observed when RAS gene is wild type in tumor cells. Compositions and methods are further provided to assess markers of marker genes to predict outcome of treatment using proteasome inhibitors to patients having a solid tumor, such as a lung tumor or a colon tumor.

Biomarkers of response to proteasome inhibitors

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Wellesley, MA, United States of America

Nibedita Chattopadhyay