City of Hope

Thomas Jefferson University

Other

Xilio Development, Inc.

John C Williams

Ulrich Rodeck

David A Horne

Kendra Nicole Avery

Joshua Michael Donaldson

Cindy Zer

Jun Xie

Christine E Brown

Krzysztof Bzymek

Yuelong Ma

Heng Wei Chang

Csaba Kari

Don Jeffrey Diamond

Kurt Jenkins

Shubbir Ahmed

Margaret Karow

Stephen J Forman

Xiuli Wang

Bart Otto Roep

Miso Park

Jose Enrique Montero Casimiro

Jeremy King

The invention provides activatable masked anti-CTLA4 binding proteins (e.g., antibodies, bispecific antibodies, and chimeric receptors) and their use in treating and preventing cancer, as well as compositions and kits comprising the activatable masked anti-CTLA4 binding proteins.

Activatable masked anti-CTLA4 binding proteins

Provided herein are, inter alia, anti-CD6 antibody-growth factor complexes including an anti-CD6 antibody portion bound to a growth factor protein (e.g., EGF) through a linker, which may be cleavable by a protease (e.g., diabetic microenvironment specific protease). The compositions provided herein are, inter alia, useful for the treatment of autoimmune diseases (e.g., type I diabetes).

Anti-CD6 antibody-growth factor complex for treating autoimmune diseases

Provided herein are, inter alia, methods and compositions including T cells expressing (i) a recombinant CAR protein which includes a peptide binding site and is capable of specifically binding cancer-specific antigens and (ii) a T cell receptor specific for a viral antigen (e.g., a CMV pp65 protein). The engineered T cells provided herein may be used in combination with a viral vaccine (e.g. cytomegalovirus (CMV) Triplex Vaccine) to treat a variety of cancers. The methods described herein also permit in vivo expansion of CMV-specific CAR T cells, instead of or in addition to ex vivo expansion, avoiding excessive T cell exhaustion that results in some cases from ex vivo manufacturing.

Use of endogenous viral vaccine in chimeric antigen receptor T cell therapy

Provided herein are, inter alia, novel peptide compositions having multi-specific binding capabilities useful for therapeutic and diagnostic purposes. The peptide compositions provided herein are polypeptide conjugates including at least two ligand binding domains able to target (bind) two or more ligands (e.g., antigens) at the same time. The peptide compositions provided herein can be produced at very high yields and are therefore easy to manufacture.

Multi-specific ligand binders

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

Provided herein are functionalized monoclonal antibodies (mAbs) including antibody fragments, including those where a Fab-binding molecule (Fab binding moiety) linked to a steric hindering molecule (steric hindering chemical moiety) is mechanically interlocked (e.g., through noncovalent conjugation) with the antibody or antibody fragment. Also provided are compositions that form highly stable and versatile drug delivery and diagnostic compositions.

Mechanically interlocking complexes

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

Antibodies and meditopes that bind to the antibodies are provided, as well as complexes, compositions and combinations containing the meditopes and antibodies, and methods of producing, using, testing, and screening the same, including therapeutic and diagnostic methods and uses.

Meditopes and meditope-binding antibodies and uses thereof

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

Provided herein are, inter alia, methods and compositions including T cells expressing (i) a recombinant CAR protein which includes a peptide binding site and is capable of specifically binding cancer-specific antigens and (ii) a T cell receptor specific for a viral antigen (e.g., a CMV pp65 protein). The engineered T cells provided herein may be used in combination with a viral vaccine (e.g. cytomegalovirus (CMV) Triplex Vaccine) to treat a variety of cancers. The methods described herein also permit in viva expansion of CMV-specific CAR T cells, instead of or in addition to ex vivo expansion, avoiding excessive T cell exhaustion that results in some cases from ex vivo manufacturing.

Provided herein are compositions, which exhibit diagnostic capabilities and allow to rapidly add functionality to adoptive immunotherapy. The compositions include isolated nucleic acids encoding proteins including antibody regions capable of binding compounds including a peptidyl moiety (e.g., a meditope). The recombinant proteins provided herein are useful, inter alia, for a broad variety of therapeutic and diagnostic purposes. For example, the recombinant proteins provided herein including embodiments thereof may be used as non-invasive means to characterize chimeric antigen receptor (CAR) T cells before and/or during treatment of diseases (e.g., cancer).

Growing community of inventors

Monrovia, CA, United States of America

John C Williams