SBIR-STTR Award

Quantitative Characterization ff Submicron Aggregates for Antibody Therapeutics
Award last edited on: 7/29/13

Sponsored Program
SBIR
Awarding Agency
NIH : NCATS
Total Award Amount
$1,402,868
Award Phase
2
Solicitation Topic Code
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Principal Investigator
Bridget Carragher

Company Information

NanoImaging Services Inc

4940 Carroll Canyon Road Suite 115
San Diego, CA 92121
Location: Single
Congr. District: 52
County: San Diego

Phase I

Contract Number: 1R43RR028166-01
Start Date: 4/1/10    Completed: 3/31/11
Phase I year
2010
Phase I Amount
$193,829
Characterization of nanoparticles and biologics is a critical step in the development of important new pharmaceutical therapeutics as, in many cases, preclinical characterization is the rate-limiting phase of the commercialization process. Nanoparticle therapeutics poses unique challenges for characterization that require an interdisciplinary approach in which several orthogonal methods are required to provide a complete picture. Cryo-electron microscopy, with its unique capability for providing exact visual information of size, shape, morphology, and aggregation of a sample in its natural hydrated state, is a powerful additional tool in the armamentarium of characterization techniques applied to nanoparticles. NanoImaging Services, Inc. was established in 2007 in order to provide cryoEM imaging services specifically focused on the characterization of biologics and nanoparticles. Over the past 18 months it has become clear that there is a critical need for more quantitative analysis of multiple cryoEM images. The images must be processed, analyzed and evaluated with the goal of providing numerical data that can be used for assessing the characteristics of the samples and comparing these characteristics to the results obtained from other orthogonal methods. Quantitation is critical for assessing lot-to-lot comparisons, quality assurance and control, monitoring samples over time, and when providing data to the regulatory agencies. Here we request support to undertake a 6 month study to determine the feasibility of developing several quantitative characterization protocols that are designed to address specific needs in the research and development of new biologics and nanoparticles as therapeutics. Specifically we will develop quantitative tools to characterize particle morphology and aggregation state and test and validate the methods using a number of samples of high interest as pharmaceutical therapeutics.

Public Health Relevance:
Arguably two of the fastest growing sectors of the biopharmaceutical industry are the production of biologics as therapeutic agents and nanoparticles as drug delivery vehicles. There is considerable evidence that the physical properties of biologics and nanoparticles is tightly linked to their functional behavior and may thus be a determining factor in the biodistribution, safety, and efficacy of the pharmaceutical product. Cryo- electron microscopy, with its unique potential for providing quantitative information of size, shape, morphology, and aggregation of a sample in its natural hydrated state, is a powerful additional tool in the armamentarium of characterization techniques applied to nanoparticles.

Thesaurus Terms:
Address; Antibodies; Appearance; Behavior; Biodistribution; Biologic Products; Biological Agent; Biological Products; Cancers; Characteristics; Chemicals; Communicable Diseases; Complex; Cryo-Electron Microscopy; Cryoelectron Microscopy; Data; Development; Development And Research; Disease; Disorder; Drug Delivery; Drug Delivery Systems; Drug Targeting; Drug Targetings; Drugs; Electron Cryomicroscopy; Goals; Image; Industry; Infectious Disease Pathway; Infectious Diseases; Infectious Diseases And Manifestations; Infectious Disorder; Link; Lipids; Malignant Neoplasms; Malignant Tumor; Marketing; Measures; Medication; Methods; Methods And Techniques; Methods, Other; Metric; Moab, Clinical Treatment; Modeling; Monitor; Monoclonal Antibodies; Morphology; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Phase; Prevention; Process; Production; Protocol; Protocols Documentation; R & D; R&D; Safety; Sampling; Sampling Studies; Services; Shapes; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Viral Vaccines; Virus; Viruses, General; Visual; Biopharmaceutical; Biotherapeutic Agent; Commercialization; Cryoem; Design; Designing; Disease/Disorder; Drug/Agent; Imaging; Interdisciplinary Approach; Interest; Malignancy; Mathematical Algorithm; Nano Imaging; Nano Particle; Nanoimaging; Nanoparticle; Neoplasm/Cancer; Particle; Physical Property; Pre-Clinical; Preclinical; Public Health Relevance; Quality Assurance; Research And Development; Tool; Visual Information

Phase II

Contract Number: 9R44TR000182-02
Start Date: 00/00/00    Completed: 00/00/00
Phase II year
2012
(last award dollars: 2013)
Phase II Amount
$1,209,039

Aggregation in antibody therapeutics is a topic of increasing concern in the biopharmaceutical industry, as these aggregates are believed to play an undesirable role resulting in adverse health effects to patients by inducing immunogenicity, altering therapeutic pharmacokinetics, or decreasing efficacy of the drug product. While methods are available to count (and in some cases, image) visible, and to a lesser extent sub-visible, particles, there is currently no reliable way to count and identify aggregates with sizes smaller than 1 micron. Studies on the mechanism of antibody aggregation indicate a process of formation that begins with very small sub-micron sized seed aggregates, which suggests the value of sub-micron characterization as a predictive indicator of therapeutic stability. It is hypothesized that humanized antibody therapeutics break B-cell tolerance by presenting the self-antigen in a "foreign" array through ordered packing in aggregates; not unlike the mechanism by which viruses elicit a vigorous immune response. This poses the question-what are the cutting-edge technologies utilized by scientists to study the size, shape, and morphology of viruses, and are these technologies applicable to the problem of sub-micron aggregate characterization? Molecular microscopy is a non-invasive molecular imaging technology that uses advanced specimen preparation and imaging methods designed specifically to visualize complex biological samples, under conditions close to their native state. For well-ordered samples such as viruses, and virus-antibody complexes, the achievable resolution can be <0.4 nm. In order to address the problem of quantitative sub- micron aggregate characterization of monoclonal antibody therapeutics, our technology applies high- throughput molecular microscopy to directly visualize antibody monomers and aggregates at multiple scales of magnification to provide quantitative measures of antibody aggregate count, size, shape, and morphology as well as antibody monomer loss in a single experiment. This technology utilizes a complex and expensive TEM instrument and automated software that requires a significant level of expertise to achieve reliable and high- throughput results, and is thus not readily accessible as an in-house method. We propose to make this technology available by incorporating a robust "Antibody Therapeutic Submicron Aggregate Characterization" service into the armamentarium of fee-for-service TEM capabilities that we already offer to the biopharmaceutical industry. To this end, our Phase II proposal has the following milestones: 1) Defining technology specifications and limitations in quantitative terms that are meaningful to antibody therapeutic formulations and characterization scientists, in consultation with protein therapeutic characterization expert, Dr. Kogan Bao (Allergan Pharmaceuticals, CA); 2) Validating the technology through comparison to accepted methodologies, in partnership with protein aggregation expert, Dr. John Carpenter (UC Denver, CO); and 3) Developing and implementing software algorithms to enhance technology throughput in a cost-effective manner. This will prepare us for Phase III, when we will provide trial service offerings to a select number of our existing pharmaceutical and biotechnology clients.

Public Health Relevance:
Aggregation in antibody therapeutics is a topic of increasing concern in the biopharmaceutical industry, because these aggregates are believed to play an undesirable role resulting in adverse health effects to patients; as a result, there is increasing pressure from the U.S. Food and Drug Administration to develop quantitative characterization tools for submicron aggregate particles in biopharmaceutical drug products. Our technology applies high-throughput molecular microscopy to identify and quantify sub-micron protein aggregates in antibody therapeutics. These new analytical methods will contribute to the armamentarium of analytical techniques aimed at helping reduce costs and improve safety and efficacy of antibody therapeutics.

Public Health Relevance Statement:
Aggregation in antibody therapeutics is a topic of increasing concern in the biopharmaceutical industry, because these aggregates are believed to play an undesirable role resulting in adverse health effects to patients; as a result, there is increasing pressure from the U.S. Food and Drug Administration to develop quantitative characterization tools for submicron aggregate particles in biopharmaceutical drug products. Our technology applies high-throughput molecular microscopy to identify and quantify sub-micron protein aggregates in antibody therapeutics. These new analytical methods will contribute to the armamentarium of analytical techniques aimed at helping reduce costs and improve safety and efficacy of antibody therapeutics.

Project Terms:
Address; Algorithms; analytical method; Antibodies; Autoantigens; Automation; B-Lymphocytes; Biological; Biological Products; Biotechnology; Client; Collaborations; Colorado; Complex; Computer software; Consultations; cost; cost effective; Data; Data Analyses; Data Collection; Descriptor; design; Detection; Development; drug efficacy; Drug Formulations; Drug Kinetics; Ensure; Face; falls; Fee-for-Service Plans; financial incentive; Freezing; Generations; Health; Housing; humanized antibody; Image; imaging modality; Imaging technology; Immune response; immunogenicity; Immunoglobulin G; improved; Industry; innovation; instrument; Joints; Marketing; Measures; method development; Methodology; Methods; Microscopy; Molecular; molecular imaging; monomer; Morphology; particle; Particulate; Patients; Peer Review; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Play; Preparation; pressure; Process; protein aggregate; protein aggregation; Publications; Reporting; research study; Resolution; Role; Safety; Sampling; Scientist; Seeds; Services; Shapes; software development; Specimen; Stress; submicron; Techniques; Technology; Therapeutic; Therapeutic antibodies; Therapeutic Monoclonal Antibodies; therapeutic protein; tool; Translations; United States Food and Drug Administration; Universities; Validation; Virus; virus morphology; Work;