SBIR-STTR Award

Monoclonal antibodies (mAbs) have demonstrated considerable utility in cancer treatment. There are a number of unmodified mAbs currently available for patient treatment, including Rituxan (non-Hodgkin's lymphoma), Erbitux (colorectal carcinoma), Herceptin (metastatic breast cancer), and Avastin (colorectal cancer). In order to improve the therapeutic value of mAbs, considerable effort is now being focused on enhancing their activity by attaching cytotoxic drugs to the biomolecules. This combination of small molecule drugs and antigen specific biomolecules results in a targeted system for drug delivery, an antibody-drug conjugate (ADC). However, many ADCs in development have had issues with variable potency as well as toxicity, in particular, hepatotoxicity. A significant obstacle to the creation of a successful modified ADC therapeutic is the need to produce the conjugated product in a homogenous form with a defined and controlled toxic payload. However, the existing methods for chemical protein modification result in mixtures of product, with varying amounts of toxin conjugated to the peptide backbone. We have developed a technology platform that modifies proteins in a controlled, site-specific manner. This technology can generate a modified recombinant IgG that has homogenous attachment sites and is easy to chemically elaborate, resulting in a conjugated antibody coupled to a defined amount of drug. If successful, we believe this work will change the utility of ADC therapeutics and will result in a robust pipeline of best in class biotherapeutics.

Public Health Relevance:
The combination of small molecule drugs and antigen specific biomolecules results in a targeted system for drug delivery, an antibody-drug conjugate (ADC). Redwood Bioscience's aldehyde-tagged technology can generate a novel, modified recombinant ADC. We believe this work will change the utility of ADC therapeutics and will result in a robust pipeline of best in class biotherapeutics.

Thesaurus Terms:
Atgn;Aldehydes;Antibodies;Antigenic Determinants;Antigens;Avastin;Bl-Cam;Binding Determinants;Biologic Therapy;Biological Response Modifier Therapy;Biological Therapy;Biosynthetic Proteins;Cd19;Cd19 Gene;Cd22;Cd22 Gene;Cancer Treatment;Cancer Of Breast;Carcinoma Of The Large Bowel;Carcinoma Of The Large Intestine;Chemicals;Chemistry;Chimeric Toxins;Colorectal Cancer;Colorectal Carcinomas;Constant Region;Constant Region, Ig;Coupled;Cytotoxic Agent;Cytotoxic Drug;Development;Drug Delivery;Drug Delivery Systems;Drug Targeting;Drug Targetings;Drugs;Epitopes;Erbitux;Gamma Globulin, 7s;Genentech Brand Of Rituximab;Genentech Brand Of Trastuzumab;Hepatotoxic Effect;Hepatotoxicity;Herceptin;Hoffman-La Roche Brand Of Trastuzumab;Hoffmann-La Roche Brand Of Rituximab;Idec Brand Of Rituximab;Igg;Immunoglobulin Constant Region;Immunoglobulin G;Immunoglobulin V;Immunoglobulin Variable Region;Large Intestine Carcinoma;Light;Liver Toxicity;Lymphoma, Non-Hodgkin's;Lymphoma, Nonhodgkins;Mabthera;Malignant Neoplasm Therapy;Malignant Neoplasm Treatment;Malignant Tumor Of The Breast;Malignant Neoplasm Of Breast;Medication;Methods;Moab, Clinical Treatment;Monoclonal Antibodies;Non-Hodgkin's Lymphoma;Patients;Peptides;Pharmaceutic Preparations;Pharmaceutical Preparations;Photoradiation;Plasmids;Post-Translational Modifications;Post-Translational Protein Processing;Posttranslational Modifications;Production;Protein Modification;Protein Modification, Post-Translational;Protein Processing, Post-Translational;Protein Processing, Posttranslational;Protein/Amino Acid Biochemistry, Post-Translational Modification;Proteins;Reaction;Recombinant Antibody;Recombinant Proteins;Recombinants;Redwood;Rituxan;Roche Brand Of Rituximab;Roche Brand Of Trastuzumab;Siglec2;Science Of Chemistry;Site;Spinal Column;Spine;Technology;Testing;Therapeutic;Toxic Effect;Toxic Effect On Liver Cells;Toxicities;Toxin Carriers;Toxin Conjugates;Variable Region;Variable Region, Ig;Vertebral Column;Work;Antibody;Antibody Conjugate;Anticancer Therapy;Backbone;Biotherapeutics;Biotherapy;Cancer Therapy;Design;Designing;Drug /Agent;Drug/Agent;Gene Product;Hepatoxicity;Immunogen;Improved;Malignant Breast Neoplasm;Monoclonal Antibody;Non-Hodgkins Disease;Non-Hodgkins Lymphoma;Novel;Small Molecule

Monoclonal antibodies (mAbs) have demonstrated considerable utility in cancer treatment. There are a number of unmodified mAbs currently available for patient treatment. However, in order to improve the therapeutic value of mAbs considerable effort is being focused on enhancing their activity by attaching cytotoxic drugs to the biomolecules. This combination of small molecule drugs and antigen specific biomolecules results in a targeted system for drug delivery, an antibody-drug conjugate (ADC). However, many ADCs in development have had issues with variable potency as well as toxicity. A significant obstacle to the creation of a successful modified ADC therapeutic is the need to produce the conjugated product in a homogenous form with a defined and controlled toxic payload. However, the existing methods for chemical protein modification result in mixtures of product, with varying amounts of toxin conjugated to the antibody in numerous locations. We have developed a technology platform that enables the chemical modification of proteins in a controlled, site-specific manner. Using this technology we can generate a panel of modified recombinant IgGs that have homogenous attachment sites and are easy to chemically elaborate with a toxic payload. The resulting homogenous ADCs are loaded with a defined amount of drug placed at a defined position on the protein. If successful, we believe this work will change the utility of ADC therapeutics and will result in a robust pipeline of best in class drugs. Our first proposed ADC product is an anti-CD22 IgG site-specifically conjugated with maytansine to be used for the treatment of B-cell leukemia and lymphomas. We will generate a panel of anti-CD22 ADCs and select a lead candidate to be developed as a potential biotherapeutic for clinical studies.

Public Health Relevance Statement:


Public Health Relevance:
The combination of small molecule drugs and antigen specific biomolecules results in a targeted system for drug delivery, an antibody-drug conjugate (ADC). Redwood Bioscience's aldehyde-tagged technology can generate novel, best-in-class ADCs. The first ADC therapeutic will be for the treatment B-cell leukemia and lymphomas.

Project Terms:
Affect; Aldehydes; Antibodies; antibody conjugate; antigen binding; Antigens; Avastin; Biological Assay; Biological Response Modifier Therapy; cancer therapy; catalyst; CD22 gene; Cell Line; Characteristics; chemical stability; Chemicals; Chinese Hamster Ovary Cell; Chronic Lymphocytic Leukemia; Clinical; Clinical Research; Colorectal Cancer; Coupled; Cytotoxic agent; cytotoxicity; Data; Data Set; design; Development; Drug Delivery Systems; Enzymes; Erbitux; fluorophore; formylglycine; Immunoglobulin G; improved; In Vitro; in vivo; Kinetics; Large Intestine Carcinoma; Lead; leukemia/lymphoma; Light; Location; malignant breast neoplasm; Malignant Neoplasms; Methods; Monoclonal Antibodies; Non-Hodgkin's Lymphoma; novel; Patients; Peptides; Pharmaceutical Preparations; Positioning Attribute; Post-Translational Protein Processing; pre-clinical; Production; Proteins; Protocols documentation; public health relevance; Recombinants; Redwood; Relative (related person); Roche brand of rituximab; Roche brand of trastuzumab; Safety; scale up; Series; Site; small molecule; Solutions; Suspension substance; Suspensions; Technology; Therapeutic; tool; Toxic effect; Toxicology; Toxin; Toxin Conjugates; Vertebral column; Work