Molecular Templates, Inc.

Jack Higgins

Erin Willert

Eric Poma

Jason Kim

Jensing Liu

Rodney Flores-Lefranc

Sangeetha Rajagopalan

Provided herein are multivalent CD20-binding molecules, and compositions thereof, for use in selective killing of specific cell types and/or as therapeutics for the treatment of a variety of diseases, including cancer, tumors, and immune disorders. Certain multivalent CD20-binding molecules can be used to deliver agents into CD20-expressing cells, collecting diagnostic information, and/or monitoring the treatment of diseases, such as cancers, tumors, and immune disorders.

Multivalent CD20-binding molecule comprising Shiga toxin A subunit effector polypeptides and enriched compositions thereof

Provided herein are HER2-targeting molecules comprising Shiga toxin A Subunit derived polypeptides having 1) de-immunization and 2) reduced, protease-cleavage sensitivity while retaining Shiga toxin function(s), such as, e.g., potent cytotoxicity via ribosome inhibition. Certain HER2-targeting molecules of the present invention exhibit reduced immunogenic potential in mammals and are well-tolerated by mammals while retaining aforementioned features. The HER2-targeting molecules of the present invention have uses for selectively killing specific cells (e.g., HER positive tumor cells); for selectively delivering cargos to specific cells (e.g., HER positive tumor cells), and as therapeutic and/or diagnostic molecules for treating and diagnosing a variety of conditions, including cancers and tumors involving the expression or over-expression of cell-surface HER2.

HER2-targeting molecules comprising de-immunized, Shiga toxin A subunit scaffolds

The present invention provides CD20-binding proteins that bind to and rapidly internalize in a CD20-mediated fashion from a cell surface location to the interior of the cell. CD20-binding proteins of the invention comprise a CD20 binding region and a Shiga toxin effector region. Certain of the disclosed CD20-binding proteins kill cells that express CD20 on their surface. Further, the presently disclosed CD20-binding proteins can comprise additional exogenous materials, such as, e.g., antigens, and are capable of targeted delivery of these additional exogenous materials into the interior of CD20 expressing cells. These CD20-binding proteins have uses in methods such as, e.g., methods involving the efficient cellular internalization of CD20, targeted killing of CD20 expressing cells, delivering exogenous materials inside CD20 expressing cells, detecting CD20 expressing cells, and treating a variety of conditions involving CD20 expressing cells including cancers, tumors, growth abnormalities, and immune disorders.

CD20-binding proteins comprising Shiga toxin A subunit effector regions for inducing cellular internalization and methods using same

The present invention provides multivalent CD20-binding molecules and compositions thereof, such as enriched compositions comprising large proportions of multivalent CD20-binding molecules relative to monovalent CD20-binding molecules. Certain multivalent CD20-binding molecules of the present invention comprise (i) two or more CD20-binding regions and (ii) one or more Shiga toxin effector polypeptide regions derived from an A Subunit of a member of the Shiga toxin family. Certain multivalent CD20-binding molecules of the present invention, and compositions thereof, have uses for selective killing of specific cell types and as therapeutics for the treatment of a variety of diseases, including cancers, tumors, and immune disorders. Certain multivalent CD20-binding molecules of the present invention, and compositions thereof, have uses for delivering agents into CD20-expressing cells, collecting diagnostic information, and monitoring the treatment of a variety of diseases, such as cancers, tumors, and immune disorders which involve CD20-expressing cells.

Multivalent CD20-binding molecules comprising Shiga toxin a subunit effector regions and enriched compositions thereof

The present invention provides protease-cleavage resistant molecules comprising Shiga toxin effector polypeptides capable of exhibiting potent, Shiga toxin functions (e.g. subcellular routing and cytotoxicity). The present invention also provides protease-cleavage resistant, cell-targeting molecules for targeting specific cell types, e.g., infected or malignant cells. Certain molecules of the present invention are cytotoxic, and certain cell-targeting molecules of the present invention may be used for the targeted killing of specific cell types and the treatment of a variety of diseases, disorders, and conditions, including cancers, tumors, growth abnormalities, immune disorders, and microbial infections. Certain cell-targeting molecules of the invention exhibit improved, in vivo tolerability as compared to related cell-targeted molecules comprising protease-cleavage sensitive, wild-type, Shiga toxin effector polypeptides. The cell-targeting molecules of the invention can deliver additional materials, such as, e.g., antigens, cytotoxic agents, and detection-promoting agents, into the interiors of target cells.

Cell-targeting molecules comprising protease-cleavage resistant, Shiga toxin A subunit effector polypeptides and carboxy-terminal moieties

The present invention provides CD20-binding proteins that bind to and rapidly internalize CD20 antigens from a cell surface location to the interior of a cell. CD20-binding proteins of the invention comprise a CD20 binding region and a Shiga toxin effector region. Certain of the disclosed CD20-binding proteins kill cells that express CD20 on their surface. Further, the presently disclosed CD20-binding proteins can comprise additional exogenous materials and are capable of targeted delivery of these additional exogenous materials into the interior of CD20 expressing cells. Such additional materials may include peptides, antigens, enzymes, and polynucleotides. These CD20-binding proteins have uses in methods of internalizing themselves, targeted killing of CD20 expressing cells, delivering exogenous materials into CD20 expressing cells, and treating a variety of diseases involving CD20 expressing cells, such as cancers and immune disorders.

CD20-binding immunotoxins for inducing cellular internalization and methods using same

The present invention relates to methods of screening libraries of chimeric molecules comprising ribotoxic polypeptides, where screening is based on the interim reduction or elimination of ribotoxicity and the methods can identify cytotoxic molecules, each comprising a binding region and a ribotoxic region which jointly possess a desired assay-selectable characteristic, such as, e.g., binding to a target biomolecule, binding to a target cell, and/or cellular internalization.

Methods of screening, selecting, and identifying cytotoxic recombinant polypeptides based on an interim diminution of ribotoxicity

The present invention provides multivalent CD20-binding molecules, and compositions thereof, such as enriched compositions comprising large proportions of multivalent CD20-binding molecule relative to monovalent CD20-binding molecule. Certain multivalent CD20-binding molecules of the present invention comprise 1) two or more CD20 binding regions and 2) one or more Shiga toxin effector polypeptide regions derived from an A Subunit of a member of the Shiga toxin family. Certain multivalent CD20-binding molecules of the present invention, and compositions thereof, have uses for selective killing specific cell types and as therapeutics for the treatment of a variety of diseases, including cancers, tumors, and immune disorders. Certain multivalent CD20-binding molecules of the present invention, and compositions thereof, have uses for delivering agents into CD20-expressing cells, including for the intracellular labeling of CD20-expressing cells, collecting diagnostic information, and monitoring the treatment of variety diseases, such as cancers, tumors, and immune disorders which involve CD20-expressing cells.

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Georgetown, TX, United States of America

Jack Higgins