Exquisite target binding specificity has made antibodies very successful therapeutics and in many cases, safe drugs. Having said that, a subset of these agents exhibits serious, mechanism-based toxicities that limit the use of the drugs and therefore may prevent patients from achieving maximal benefit. At CytomX Therapeutics, our approach is to combine our core competencies of bacterial cell surface display technology and protease substrate engineering to design and build therapeutics, Probodies, that have sufficient efficacy and minimal toxicities for a range of indications. Probodies exploit molecular logic by requiring the presence of a disease-regulated enzyme to become maximally active. Our ongoing research has identified some of the main technical considerations that need to be addressed to optimize these constructs but the preliminary data are quite encouraging. In this research, we plan to design and construct a family of Probodies to the epidermal growth factor receptor (EGFR) using our proprietary peptide discovery technologies. Approved EGFR antagonists are known to produce skin toxicities in the vast majority of patients as well as in non-clinical studies of non-human primates. For these reasons, EGFR was chosen for CytomX's first pre-clinical Probody program. Recognizing that any new protein therapeutic faces many challenges, we have designed this Phase I effort to move the molecules from discovery through cell-based assays to early, outsourced animal testing in an oncology model. In this way, at the close of the project, we will have gained valuable information about the stability and activity of the molecules in vivo as well as a deeper understanding of the discovery process. If successful, we will be poised to embark on a more complete study of the activity and safety of the lead candidate(s) in Phase II and compare these directly to one or more approved agents.
Public Health Relevance: Much can be learned about normal and disease biology from recently approved drugs, their benefits across various pathologies and their side effects. Several targeted therapies exist that show both activity and toxicity due to the distribution of their target in the body. Our R&D efforts plan to take advantage of this knowledge and improve on the targeting of drugs in a wide range of indications, from oncology to rheumatoid arthritis to respiratory and bowel diseases, to improve patient outcomes.
Public Health Relevance Statement: Much can be learned about normal and disease biology from recently approved drugs, their benefits across various pathologies and their side effects. Several targeted therapies exist that show both activity and toxicity due to the distribution of their target in the body. Our R&D efforts plan to take advantage of this knowledge and improve on the targeting of drugs in a wide range of indications, from oncology to rheumatoid arthritis to respiratory and bowel diseases, to improve patient outcomes.
NIH Spending Category: Arthritis; Biotechnology; Cancer; Immunization; Lung; Lung Cancer
Project Terms: ABX-EGF; ABX-EGF MAb; Abbott brand of adalimumab; Address; Adverse effects; Affinity; Animal Model; Animal Models and Related Studies; Animal Testing; Anti-EGFR Monoclonal Antibody; Anti-Epidermal Growth Factor Receptor Monoclonal Antibody; Antibodies; Antibody Binding Sites; Antibody Therapy; Apoplexy; Assay; Asthma; Astrocytoma, Grade IV; Athymic Nude Mouse; Atrophic Arthritis; Avastin; Bacteriophage M13; Binding; Binding (Molecular Function); Binding Sites, Antibody; Bioassay; Biodistribution; Biologic Assays; Biological; Biological Assay; Biology; Blood Serum; Bronchial Asthma; Cancer Patient; Cancer cell line; Cancer of Breast; Cancer of Lung; Cancer, Oncology; Cancers; Cardiac Failure Congestive; Cardiac infarction; Cell Culture Techniques; Cell surface; Cells; Centocor Brand of Infliximab; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Cerebrovascular accident; Cetuximab; Clinical; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; Coliphage M13; Collaborations; Colon Cancer; Colon Carcinoma; Colonic Carcinoma; Computer Simulation; Computerized Models; Congestive Heart Failure; Consensus Sequence; ConsensusSequence; Contracting Opportunities; Contracts; Crab-Eating Macaque; Data; Dermatologic; Development; Development and Research; Disease; Disease by Site; Disorder; Disorder by Site; Drug Delivery; Drug Delivery Systems; Drug Industry; Drug Targeting; Drug Targetings; Drug usage; Drugs; EGFR; ELISA; ERBB Protein; ERBB1; Engineering; Engineerings; Enterobacteria phage M13; Enzyme-Linked Immunosorbent Assay; Enzymes; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Equilibrium; Erbitux; Esteroproteases; Evaluation; Event; Exhibits; Face; Family; GI perforation; Genentech brand of trastuzumab; Glioblastoma; Goals; Government; Grade IV Astrocytic Neoplasm; Grade IV Astrocytic Tumor; HER1; HIV Infections; HTLV-III Infections; HTLV-III-LAV Infections; Head and Neck Cancer; Heart Decompensation; Heart Failure, Congestive; Herceptin; Hoffman-La Roche brand of trastuzumab; Human; Human, General; Humira; IgG1; Individual; Industry; Industry, Pharmaceutic; Inflammatory Arthritis; Intestinal; Intestines; Kinetic; Kinetics; Knowledge; Laboratories; Lead; Learning; Left; Legal patent; Length; Libraries; Life Cycle; Life Cycle Stages; Logic; M13 Phage; MAb Therapeutics; MAb cA2; Macaca fascicularis; Magic; Malignant Head and Neck Neoplasm; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Breast; Malignant Tumor of the Head and Neck; Malignant Tumor of the Lung; Malignant neoplasm of breast; Malignant neoplasm of lung; Mammalian Cell; Mammals, Mice; Man (Taxonomy); Man, Modern; Marketing; Masks; Massachusetts; Mathematical Model Simulation; Mathematical Models and Simulations; Measures; Medication; Mice; Mice, Athymic; Mice, Nude; MoAb ABX-EGF; Moab, Clinical Treatment; Modeling; Models, Computer; Modification; Molecular; Molecular Interaction; Monkey, Crab-Eating; Monkey, Cynomolgus; Monoclonal Antibodies; Monoclonal Antibody ABX-EGF; Murine; Mus; Myocardial Infarct; Myocardial Infarction; Nude Mice; Opportunistic Infections; Outcome; Outsourcing; Paratopes; Patents; Pathology; Patients; Pb element; Peptidases; Peptide Hydrolases; Peptides; Persons; Phage Display; Pharmaceutic Preparations; Pharmaceutical Industry; Pharmaceutical Preparations; Phase; Process; Programs (PT); Programs [Publication Type]; Proteases; Proteinases; Proteolytic Enzymes; Pulmonary Cancer; Pulmonary Fibrosis; Pulmonary malignant Neoplasm; R & D; R&D; Receptor Inhibition; Receptor Signaling; Receptor, EGF; Receptor, TGF-alpha; Receptor, Urogastrone; Receptors, Epidermal Growth Factor-Urogastrone; Remicade; Research; Rheumatoid Arthritis; Risk; Rivers; Roche brand of trastuzumab; SAE; Safety; Sales; Sepsis; Serious Adverse Event; Serum; Simulation, Computer based; Site; Skin; Specificity; Stroke; Surface Plasmon Resonance; T-Lymphotropic Virus Type III Infections, Human; Technology; Therapeutic; Therapeutic Index; Therapeutic Monoclonal Antibodies; Therapeutic antibodies; Toxic effect; Toxicities; Transforming Growth Factor alpha Receptor; Treatment Side Effects; Tuberculosis; Ulcerated Colitis; Ulcerative Colitis; VEGFs; Vascular Accident, Brain; Vascular Endothelial Growth Factors; Vectibix; Vegf; Vendor; Ventricular; antibody combining site; antigen binding; balance; balance function; base; bloodstream infection; bowel; brain attack; c-erbB-1; c-erbB-1 Protein; cardiac infarct; cerebral vascular accident; clinical investigation; combinatorial; comparative efficacy; computational modeling; computational models; computational simulation; computer based models; computerized modeling; computerized simulation; coronary attack; coronary infarct; coronary infarction; design; design and construction; designing; disease/disorder; disseminated TB; disseminated tuberculosis; drug development; drug use; drug/agent; erbB-1; erbB-1 Proto-Oncogene Protein; erbBl; facial; gastrointestinal perforation; glioblastoma multiforme; head & neck cancer; head & neck tumor; heart attack; heart infarct; heart infarction; heavy metal Pb; heavy metal lead; immunogenicity; improved; in silico; in vivo; infliximab; interest; life course; lung Carcinoma; lung cancer; malignancy; malignant breast neoplasm; model organism; monoclonal antibody cA2; neoplasm/cancer; non-human primate; nonhuman primate; novel; oncology; panitumumab; pre-clinical; preclinical; preclinical evaluation; prevent; preventing; product development; programs; proto-oncogene protein c-erbB-1; public health relevance; receptor binding; research and development; respiratory; side effect; small molecule; spongioblastoma multiforme; stroke; therapeutic development; therapeutic protein; therapy adverse effect; tool; treatment adverse effect; tuberculous spondyloarthropathy; tumor; virtual simulation
