City of Hope

Thomas Jefferson University

The Wistar Institute

Ulrich Rodeck

John C Williams

Joshua Michael Donaldson

Csaba Kari

Meenhard Herlyn

Kurt Jenkins

Kendra Nicole Avery

Cindy Zer

Frank J Rauscher, Iii

Jennifer Morris

Miso Park

John Williams

Provided herein are recombinant CTLA-4 binding proteins, which are, inter alia, useful for the treatment of cancer. The recombinant proteins provided herein are, inter alia, capable of binding CTLA-4 proteins on a tumor cell. In a first aspect, there is provided a recombinant CTLA-4 binding protein including (i) a CTLA-4 binding domain; (ii) a CTLA-4 binding domain masking peptide; and (iii) a cleavable peptide linker connecting the CTLA-4 binding domain masking peptide to the CTLA-4 binding domain. In another aspect, there is provided a dimerizing domain covalently attached to the CTLA-4 binding domain, wherein the binding protein domains are bound together.

CTLA4-binding protein peptide-linker masks

In one embodiment, a masked monoclonal antibody (mAb) is provided, the mAb, encoded by a nucleic acid sequence or an amino acid sequence molecule comprising a signal sequence, a masking epitope sequence, a linker sequence that is cleavable by a protease specific to a target tissue; and an antibody or a functional fragment thereof. In another embodiment, a masked monoclonal antibody (mAb) is provided, which includes a therapeutic mAb and a mask, the mask comprising protein A and protein L attached by a protease cleavable linker.

Development of masked therapeutic antibodies to limit off-target effects

Provided herein are recombinant masking proteins and recombinant ligand proteins useful in treating cancer, neurodegenerative disease, and cardiovascular disease. The recombinant masking proteins provided herein may, inter alia, be used as non-covalent masks of antagonists of, for example, cellular growth factors (e.g., TNF) or cell surface proteins (e.g., CTLA-4).

Tumor-selective CTLA-4 antagonists

In one embodiment, a masked monoclonal antibody (mAb) is provided, the mAb, encoded by a nucleic acid sequence or an amino acid sequence molecule comprising a signal sequence, a masking epitope sequence, a linker sequence that is cleavable by a protease specific to a target tissue; and an antibody or a functional fragment thereof. In another embodiment, a cross-masked mAb heterodimer complex is provided, comprising a first masked mAb, comprising a first signal sequence, a first masking epitope sequence, a first linker that is cleavable by a protease specific to a target tissue, and a first antibody or fragment thereof; and a second masked mAb, comprising a second signal sequence, a second masking epitope sequence, a second linker that is cleavable by a protease specific to a target tissue, and a second antibody or fragment thereof.

Development of masked therapeutic antibodies to limit off-target effects: application to anti-EGFR antibodies

Development of masked therapeutic antibodies to limit off-target effects; application to anti-EGFR antibodies

The present invention provides three unique monoclonal antibodies directed against a portion of the Wilms' tumor antigen, and methods of use therefor in detecting, monitoring and diagnosing malignancies characterized by over-expression or inappropriate expression of the WT 1 protein.

WT1 monoclonal antibodies and methods of use therefor

Three unique monoclonal antibodies, each having an epitope located in amino acids 1-181 of the WT1 tumor protein, and the hybridomas which secrete them have been constructed. These monoclonal antibodies are useful in the detection, monitoring, and diagnosis of malignancies characterized by inappropriate expression of the WT1 protein.

WT1 monoclonal antibodies

Monoclonal antibody 425 having properties particularly beneficial for anti-tumor therapy has been raised. MAb 425 antibody binds to EGF-receptors and inhibits their bioactivities. The amount of binding of the antibody to cancer cells can be increased by treatment of the cells with lymphokine preparations. Radiolabeled MAb 425 is used for treatment of EGF receptor-expressing gliomas.

Growing community of inventors

Philadelphia, PA, United States of America

Ulrich Rodeck