SBIR-STTR Award

Specific Aim of this Innovative Molecular Analysis Technologies (IMAT) SBIR Phase I grant proposal is to show the feasibility of a high-throughput molecular technology for discovery of monoclonal antibody (mAb) drugs for oncology from human B cell repertoires. Drug companies spend up to $5 billion to produce a single FDA-approved monoclonal antibody, or mAb (DiMasi & Grabowski, 2007; Nelson et al., 2010). High mAb development cost is at least partly due to the high failure rate of candidates. A technology that improves mAb selection by just 10% before entering clinical development could save the drug industry ~$400 million per FDA- approved mAb. Immune systems are 'test tubes' that constantly select for antibodies with strong potential as drugs. GigaLink' will be a research service for drug discovery programs that leverages these antibody selection test tubes. In mouse systems, our technology could eventually replace B cell immortalization. In human systems, our technology could eventually replace phage display. Antibody fragments identified in our DNA libraries will be easily modified into mAbs, because they are fully human, are already known to express on the surface of B cells, and have already shown positive selection in vivo. In Phase I we will integrate our current molecular and bioinformatic methods with mammalian expression and affinity screening. The project will focus on antibody fragments against epidermal growth factor receptor (EGFR), because many anti-EGFR biologics are available to help us test our system. Though we focus on EGFR, the primary outcome of this project is platform development - ideal for the IMAT program at the National Cancer Institute (NCI). We will accomplish the Specific Aim by performing the following tasks: (i) Optimize mammalian expression and affinity screening using known anti-EGFR antibody fragments; (ii) Implement computational methods for quantitatively integrating genomic and affinity data; and (iii) Screen pancreatic cancer patient B cells for anti-EGFR antibody fragments. To be successful, we must achieve the following metrics: (i) Recover >80% of known anti-EGFR antibody fragments by mammalian expression and affinity screening (power=0.8, ¿=0.05); and (ii) Use germline divergence rates and affinity screening to discover no less than ten anti-EGFR antibody fragments with affinity constant (Kaff)<10-7 and significant sequence evolution rates (power=0.8,¿=0.05). In Phase II, we will focus on laboratory and computational methods for affinity maturation of fully human monoclonal antibodies from GigaLink' antibody fragments. Once Phase II is complete, GigaGen will compete directly with mAb discovery services such as Morphosys and Adimab. Future grant applications will focus on oncology targets for discovery and development of GigaGen-proprietary drugs for pancreatic cancer targets (Dodson et al., 2011), but this will only be possible once the current IMAT project has been completed.

Thesaurus Terms:
Affinity;Antibodies;Applications Grants;B Cell Repertoire;B Lymphocyte Immortalization;B-Lymphocytes;Bioinformatics;Biological Products;Biological Research;Blood;Cancer Patient;Capital;Cell Immortalization;Cells;Clinical;Clinical Efficacy;Computing Methodologies;Contracts;Cost;Cost Savings;Cytokine;Data;Detection;Development;Diagnostic;Disease;Dna Library;Dna Sequence;Drug Discovery;Drug Industry;Elderly;Epidermal Growth Factor Receptor;Evolution;Failure (Biologic Function);Fertilization In Vitro;Future;Generations;Genomics;Human;Human Monoclonal Antibodies;Immune;Immune System;Immunogenicity;Immunoglobulin Fragments;Improved;In Vivo;Innovation;Institutes;Laboratories;Lead;Licensing;Life;Light;Malignant Neoplasm Of Pancreas;Malignant Neoplasms;Mammalian Cell;Marketing;Medical Specialties;Methods;Metric;Microfluidics;Molecular;Molecular Analysis;Monoclonal Antibodies;Mus;National Cancer Institute;New Technology;Novel Therapeutics;Oncology;Oncology Service;Phage Display;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Phase I Clinical Trials;Primary Outcome;Productivity;Programs;Public Health Relevance;Research;Research And Development;Screening;Services;Small Business Innovation Research Grant;Staging;Surface;Surveys;System;Technology;Testing;Therapeutic;Therapeutic Agents;Therapeutic Antibodies;Tube;United States Food And Drug Administration;United States National Institutes Of Health;Work;

Despite an enormous investment in novel therapies, cancer still accounts for 25% of US deaths, killing >1500 people every day. For example, only 25% of pancreatic cancer patients and 17% of lung cancer patients survive one year after diagnosis. Additionally, oncology treatments cost $127 billion per year in the US, and are expected to grow at 27% per year through 2020. Monoclonal antibodies (mAbs) are now the biological agents of choice for cancer therapy. Three of the top six grossing therapeutics worldwide (bevacizumab, rituximab, and trastuzumab) are oncology mAbs. Today, most mAb discovery programs use either some flavor of single chain variable fragment (scFv) display or mouse immunization followed by hybridoma isolation. Display technologies like phage display have tremendous ease of use, which enables R&D programs to screen through billions of antibodies in parallel. Unlike conventional phage display technologies, mouse immunizations produce fully natural antibodies, which are often easier to develop than antibodies discovered through display. Though display and mouse immunizations have produced breakthrough therapeutic antibodies, R&D programs are always looking for faster, deeper, and more efficient antibody technologies. The Specific Aim of this IMAT Phase II SBIR project is to develop GigaLink™, a next-generation high-throughput molecular technology for discovery and development of oncology drugs from mammalian B cell repertoires. GigaLink™ is the only technology that uses primary B cells to make millions- to billions-diverse DNA libraries of antibodies, and then expresses the DNA libraries as protein for affinity screening and antigen discovery. As a DNA-based technology, GigaLink™ uniquely enables massively parallel antibody screening, engineering, and development. A successful IMAT Phase II SBIR project will show that the GigaLink™ antibody R&D platform can help our customers understand basic tumor immunology and discover and develop therapeutic antibody candidates. We will use the profits from GigaLink™ service revenues plus venture capital to build our own internal programs for oncology therapeutic antibody discovery.

Public Health Relevance Statement:
PROJECT NARRATIVE Project Title: Next-Generation Antibody Discovery and Development Technology Organization: GigaGen Inc. PI: David S. Johnson, Ph.D. Better methods for discovery of antibodies could eventually lead to drugs for treatment of a variety of diseases and conditions, including cancer. We are building a novel technology that uses microfluidics and DNA sequencing to capture and characterize new therapeutic antibodies from immune cells in human and mouse blood.

NIH Spending Category:
Bioengineering; Biotechnology; Cancer; Immunization; Prevention; Vaccine Related

Project Terms:
Accounting; Address; Affinity; Antibodies; antibody libraries; Antigens; B cell repertoire; B-Lymphocytes; base; bevacizumab; Biological Products; Biotechnology; Blood; Cancer Patient; cancer therapy; Capital; Cells; Cessation of life; CLIA certified; commercialization; Development; Diagnosis; Diagnostic; Diagnostic tests; Directed Molecular Evolution; Disease; DNA; DNA Library; DNA Sequence; Doctor of Philosophy; Engineering; Flavoring; Flow Cytometry; Genomics; Human; Hybridomas; Immune; Immunization; In Vitro; inhibitor/antagonist; Innovation Corps; interest; Interview; Investments; Killings; Lead; Libraries; Link; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant Neoplasms; Methods; Microfluidics; Molecular; Monoclonal Antibodies; Mus; new technology; next generation; novel; novel therapeutics; oncology; oncology program; Phage Display; Pharmaceutical Preparations; Pharmacotherapy; Phase; product development; programs; Proteins; research and development; rituximab; Scientist; screening; Screening for cancer; Sensitivity and Specificity; Sequoia; Services; Small Business Innovation Research Grant; Specialist; Technology; technology development; Therapeutic; Therapeutic antibodies; Time; Trastuzumab; Treatment Cost; tumor immunology; United States National Institutes of Health