Document text
Principal Investigator: Milen Kirilov
Organization: INGENIOUS TARGETING LABORATORY, INC.
Fiscal Year: 2022
Award: $998,985
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Genetically-modified mouse models have proven to be essential for the production of antibody-related
biological drugs (biologics). To date, the majority of biologics originate from mouse models, and small animal
models are used not only to generate the antibodies, but also as a platform for further optimization and testing
of the biologics. Camelid-based antibodies, which have superior antigen binding and physicochemical
properties (stability, hydrophilicity, etc.) have not realized their full potential, to the same extent that
conventional antibodies have. This is founded in the logistic and financial hurdles immunization of camelids
pose for monoclonal heavy-chain antibody (HCAb) production and the fact that in vitro technologies cannot
fully recapitulate the exceptional natural selection towards extremely diversified, high-affinity binders that
occurs in animals. In this SBIR project we propose to develop genetic platforms in a murine host for the
discovery and development of partially humanized hybrid HCAbs (and their products). Since their discovery in
the early 1990s, HCAbs have generated progressive interest in the biotech, diagnostic and therapeutic fields
due to their intrinsic properties and adaptability. Apart from a small size paired with robustness and superior
access to difficult epitopes, HCAbs can be easily processed into, and utilized as, single domain binding units
(VHH) while preserving their affinity towards antigens (in contrast to conventional antibodies). The proposed
targeted mouse models carrying an engineered immunoglobulin locus will potentiate the production of high
affinity HCAbs by serving as an alternative, hybrid Ab host. It will allow natural, in vivo affinity-maturation of
antigen-specific HCAbs in a small animal platform, one amenable to further genetic manipulation. It will enable
larger cohort sizes than the natural camelid hosts, and streamline HCAb generation, thus providing further
potential for the development of HCAb and VHH domains for downstream applications. In our Aim 1, we focus
on honing and characterizing our hybrid camelid immunoglobulin locus by adding more camelid VHHs and
introducing modified human VHs into the locus while also evaluating B-cell development and antibody affininty
and diversity. In Aim 2, our focus is to benchmark the the repertoire and efficiency of the Ab response with
competing technologies by using disease-relevant, difficult antigens and progress promising hits to hybridoma
development and larger scale antibody production. In accomplishing these milestone based Aims, we will be
able to develop our business and begin licensing of the platforms to individual labs and established
pharmaceutical companies to support discovery of novel antibodies for high-value targets.
Terms: <2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><AIDS Virus><Ab response><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affinity><Alpaca><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Affinity><Antibody Formation><Antibody Production><Antibody Response><Antigen Binding Fragment><Antigenic Determinants><Antigens><Autoantigens><Autologous Antigens><B-Cell Development><Bacteria><Basic Research><Basic Science><Benchmarking><Best Practice Analysis><Binding><Binding Determinants><Biologic Products><Biological><Biological Agent><Biological Products><Biotech><Biotechnology><Breeding><Businesses><COVID-19 S protein><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID19 S protein><COVID19 spike glycoprotein><COVID19 spike protein><Camels><Cancers><Cell Body><Cells><Characteristics><Client><Clinical><Complex><Coupled><Custom><Development><Development and Research><Diagnostic><Diagnostics Research><Disease><Disorder><Drugs><E cloacae><E. cloacae><ES cell><Engineering><Enterobacter cloacae><Epitopes><Fab Fragments><Fab Immunoglobulins><Future><GEM model><GEMM model><Gene Bank><Gene Proteins><Gene Targeting><Generations><Genes><Genetic><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetically Engineered Mouse><Goals><HIV><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV env Protein gp120><HTLV-III gp120><Homer 1><Homer1><Housing><Human><Human Immunodeficiency Viruses><Hybridomas><Hybrids><Immune><Immune Globulins><Immune response><Immunes><Immunization><Immunize><Immunoglobulin, F(ab) Fragment><Immunoglobulins><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunostimulation><In Vitro><Individual><LAV-HTLV-III><Laboratories><Licensing><Light><Light-Chain Immunoglobulins><Link><Llama><Logistics><Lymphadenopathy-Associated Virus><Malignant Neoplasms><Malignant Tumor><Medication><Medicine><Membrane><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Murine><Mus><Natural Selections><Nature><Outcome><Performance><Phage Display><Pharmaceutic Preparations><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phase><Phenotype><Photoradiation><Play><Process><Production><Property><Protein Gene Products><Proteins><Protocol><Protocols documentation><R & D><R&D><Recombinant DNA Technology><Research Resources><Resources><Role><SARS-CoV-2 S protein><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2 S protein><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SBIR><Self-Antigens><Services><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Shark><Small Business Innovation Research><Small Business Innovation Research Grant><Targeted Research><Technology><Testing><Therapeutic><Therapeutic Agents><Virus><Virus-HIV><Yeasts><animal resource><antibody based diagnostic><antibody biosynthesis><antibody diagnostic><antibody libraries><antigen antibody affinity><antigen binding><antigen bound><base><biologic><biologics><biopharmaceutical><biotherapeutic agent><clinical applicability><clinical application><clinical diagnostics><cohort><coronavirus disease 2019 S protein><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><cost><developmental><drug/agent><embryonic stem cell><environmental stresses><environmental stressor><experiment><experimental research><experimental study><flexibility><flexible><gene manipulation><genetic manipulation><genetically engineered><genetically engineered mouse model><genetically engineered murine model><genetically manipulate><genetically perturb><gp120><gp120 ENV Glycoprotein><gp120(HIV)><host response><hybrid antibody><hydrophilicity><immune system response><immunogen><immunogenicity><immunoglobulin biosynthesis><immunoresponse><improved><in vivo><in-vivo diagnostics><interest><malignancy><medical diagnostic><membrane structure><microbe pathogen><microbial pathogen><model of animal><model organism><mouse model><murine model><nanobodies><nanobody><neoplasm/cancer><neutralizing antibody><novel><pathogen><pathogenic microbe><preservation><research and development><sdAb><sensor><single domain antibodies><social role><standard of care><stem cell of embryonic origin><validation studies><virus host interaction>