The United States of America, as Represented by the Secretary, Department of Health and Human Services

Biomed Valley Discoveries, Inc.

Johns Hopkins University

Novartis Ag

Scott & White Healthcare (Swh)

Brad St Croix

Saurabh Saha

Xiaoyan Michelle Zhang

Dimiter Stanchev Dimitrov

Zhongyu Zhu

Enrique Zudaire

Bert Vogelstein

Kenneth W Kinzler

Stephen H Leppla

Dean Welsch

Gary DeCrescenzo

Arthur E Frankel

Tony Fleming

Gary A Decrescenzo

Yunpeng Su

Steven Seaman

Mary Beth Hilton

Eleanor Carson-Walter

Amit Chaudhary

Rou-fun Kwong

Dimiter Dimitrov

Gary Decrescenzo

The present invention provides, inter alia, methods for treating or ameliorating the effects of a disease, such as cancer, in a subject. The methods include: administering to a subject in need thereof (a) a therapeutically effective amount of an agent selected from the group consisting of an anti-angiogenic agent, a vascular disrupting agent (VDA), and combinations thereof; and (b) a therapeutically effective amount of a monoclonal antibody or antigen binding fragment thereof, wherein the monoclonal antibody contains: (i) a heavy chain variable region (VH), which includes an amino acid sequence selected from SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, and SEQ ID NO:7; and (ii) a light chain variable region (VL), which includes an amino acid sequence selected from SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, and SEQ ID NO:8. Compositions, including pharmaceutical compositions, and kits for treating diseases, such as cancer, are also provided.

Combination therapies targeting tumor-associated stroma or tumor cells

The present invention provides, inter alia, methods for treating or ameliorating the effects of a disease, such as cancer, in a subject. The methods include: administering to a subject in need thereof (a) a therapeutically effective amount of a microtubule inhibitor; and (b) a therapeutically effective amount of a monoclonal antibody or antigen binding fragment thereof, wherein the monoclonal antibody contains: (i) a heavy chain variable region (VH), which includes an amino acid sequence selected from SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, and SEQ ID NO:7; and (ii) a light chain variable region (VL), which includes an amino acid sequence selected from SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, and SEQ ID NO:8. Compositions, including pharmaceutical compositions, and kits for treating diseases, such as cancer, are also provided herein.

Combination therapies targeting tumor-associated stroma or tumor cells and microtubules

The present invention provides, inter alia, methods for treating or ameliorating the effects of a disease, such as cancer, in a subject. The methods include: administering to a subject in need thereof (a) a therapeutically effective amount of a monoclonal antibody or antigen binding fragment of the present invention, and (b) a therapeutically effective amount of a combination therapy including bevacizumab and at least one additional therapeutic agent; or a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of a COX-2 inhibitor (COXIB), a non-steroidal anti-inflammatory drug (NSAID), a prostaglandin E2 (PGE2) synthase inhibitor, and combinations thereof. Compositions, including pharmaceutical compositions, and kits for treating diseases, such as cancer, are also provided herein.

Combination therapies using agents that target tumor-associated stroma or tumor cells and tumor vasculature

The present invention provides, inter alia, methods for treating or ameliorating the effects of a disease, such as cancer, in a subject. The methods include: administering to a subject in need thereof (a) a therapeutically effective amount of an alkylating agent; and (b) a therapeutically effective amount of a monoclonal antibody or antigen binding fragment thereof, wherein the monoclonal antibody contains: (i) a heavy chain variable region (VH), which includes an amino acid sequence selected from SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, and SEQ ID NO:7; and (ii) a light chain variable region (VL), which includes an amino acid sequence selected from SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, and SEQ ID NO:8. Compositions, including pharmaceutical compositions, and kits for treating diseases, such as cancer, are also provided herein.

Combination therapies using agents that target tumor-associated stroma or tumor cells and alkylating agents

The present invention provides, inter alia, methods for treating or ameliorating the effects of a disease, such as cancer, in a subject. The methods include: administering to a subject in need thereof (a) a therapeutically effective amount of a topoisomerase inhibitor; and (b) a therapeutically effective amount of a monoclonal antibody or antigen binding fragment thereof, wherein the monoclonal antibody contains: (i) a heavy chain variable region (VH), which includes an amino acid sequence selected from SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, and SEQ ID NO:7; and (ii) a light chain variable region (VL), which includes an amino acid sequence selected from SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, and SEQ ID NO:8. Compositions, including pharmaceutical compositions, and kits for treating diseases, such as cancer, are also provided herein.

Combination therapies targeting tumor-associated stroma or tumor cells and topoisomerase

The present invention provides, inter alia, methods for treating or ameliorating the effects of a disease, such as cancer in a subject. The methods include: administering to a subject in need thereof (a) a therapeutically effective amount of a molecularly targeted agent; and (b) a therapeutically effective amount of a monoclonal antibody or antigen binding fragment thereof, wherein the monoclonal antibody contains: (i) a heavy chain variable region (VH), which includes an amino acid sequence selected from SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, and SEQ ID NO:7; and (ii) a light chain variable region (VL), which includes an amino acid sequence selected from SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, and SEQ ID NO:8. Compositions, including pharmaceutical compositions, and kits for treating diseases, such as cancer, are also provided herein.

Combination therapies using agents that target tumor-associated stroma or tumor cells and other pathways

The present invention provides, inter alia, methods for treating or ameliorating the effects of a disease, such as cancer, in a subject. The methods include: administering to a subject in need thereof (a) a therapeutically effective amount of an agent selected from an anti-metabolite agent or analog thereof and combinations thereof; and (b) a therapeutically effective amount of a monoclonal antibody or antigen binding fragment thereof, wherein the monoclonal antibody contains: (i) a heavy chain variable region (VH), which includes an amino acid sequence selected from SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, and SEQ ID NO:7; and (ii) a light chain variable region (VL), which includes an amino acid sequence selected from SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, and SEQ ID NO:8. Compositions, including pharmaceutical compositions, and kits for treating diseases, such as cancer, are also provided herein.

Combination therapies using anti-metabolites and agents that target tumor-associated stroma or tumor cells

Methods, pharmaceutical compositions, and kits for treating a disease, such as cancer, in a subject. The methods include: administering to a subject in need thereof (a) a therapeutically effective amount of a platinum agent; and (b) a therapeutically effective amount of a monoclonal antibody or antigen binding fragment thereof.

Combination therapies using platinum agents and agents that target tumor-associated stroma or tumor cells

The present invention is directed to particular antibodies and fragments thereof that find use in the detection, prevention and treatment of diseases and disorders associated with abnormal angiogenesis. In particular, these antibodies detect tumor endothelial marker 8 (TEM8) in its native and cell-surface expressed form. Also disclosed are improved methods for producing monoclonal antibodies, as well as pharmaceutical compositions and kits.

Antibodies to tumor endothelial marker 8

Antibodies that specifically bind TEM8 protein, conjugates thereof, and their use, are disclosed herein. In some examples the conjugates and antibodies are useful for methods of detecting and treating pathogenic angiogenesis. In other examples the conjugates and antibodies are useful for methods of detecting and treating cancer. In additional examples, the conjugates and antibodies are useful for methods of decreasing binding of Anthrax protective antigen to a cell.

TEM8 antibodies and their use in treatment and detection of tumors

Antibodies that specifically bind TEM8 protein, and conjugates thereof, are disclosed herein. In some examples the conjugates and antibodies are useful for methods of detecting and treating pathogenic angiogenesis. In other examples the conjugates and antibodies are useful for methods of detecting and treating cancer. In additional examples, the conjugates and antibodies are useful for methods of decreasing binding of Anthrax protective antigen to a cell.

TEM8 antibodies, conjugates thereof, and their use

Methods of inhibiting pathological angiogenesis in a subject are disclosed. In particular examples, the method includes administering a therapeutically effective amount of a composition to a subject wherein the composition includes a specific binding agent that preferentially binds to one or more pathological angiogenesis marker proteins including Vscp, CD276, ETSvg4 (Pea3), CD137(4-1BB), MiRP2, Ubiquitin D (Fat10), Doppel (prion-PLP), Apelin, Plgf, Ptprn (IA-2), CD109, Ankylosis, and collagen VIII&#x3b1;1. In additional examples, methods to deliver a therapeutic agent to a brain or liver endothelial cell are also disclosed.

Differential gene expression in physiological and pathological angiogenesis

To gain a better understanding of tumor angiogenesis, new techniques for isolating endothelial cells (ECs) and evaluating gene expression patterns were developed. When transcripts from ECs derived from normal and malignant colorectal tissues were compared with transcripts from non-endothelial cells, over 170 genes predominantly expressed in the endothelium were identified. Comparison between normal- and tumor-derived endothelium revealed 79 differentially expressed genes, including 46 that were specifically elevated in tumor-associated endothelium. Experiments with representative genes from this group demonstrated that most were similarly expressed in the endothelium of primary lung, breast, brain, and pancreatic cancers as well as in metastatic lesions of the liver. These results demonstrate that neoplastic and normal endothelium in humans are distinct at the molecular level, and have significant implications for the development of anti-angiogenic therapies in the future.

Growing community of inventors

Frederick, MD, United States of America

Brad St Croix