Antibodies that modulate immunity to drug resistant and latent MTB infections

Inventors

Fischer, Gerald W. • Daum, Luke T. • Schuman, Richard F. • Sei, Clara J.

Assignees

Longhorn Vaccines and Diagnostics LLC

Abstract

The invention is directed to compositions and methods for stimulating, enhancing or modulating the immune system of a patient before or after infection by a pathogen, and in particular multidrug resistant (MDR) MTB and extremely drug resistant (XDR) MTB. Compositions of the invention contain non-naturally occurring antigens that generate an effective cellular and/or humoral immune response to MTB and/or antibodies that are specifically reactive to MTB antigens. The greater activity of the immune system generated by a vaccine of the invention increases generation of memory T cells that provide for a greater and/or extended response to an MTB infection. Responses involve an increased generation of antibodies that enhance immunity against MTB infection and promote an enhanced phagocytic response. Monoclonal antibodies produced by the non-naturally occurring antigens enhance phagocytosis and killing of mycobacteria by phagocytic cells, enhance clearance of MTB from the blood and modulate immunity and cytokine responses.

Core Innovation

The invention provides immunological compositions and vaccines directed to multidrug-resistant (MDR), extremely drug-resistant (XDR), and latent Mycobacterium tuberculosis (MTB) using non-naturally occurring, chemically and/or physically altered MTB antigens and antibodies reactive to epitopes altered after killing. The antibodies bind to an epitope of an antigen from a drug-resistant Mycobacterium organism, where the organism has been killed by chemical treatment, heat treatment, alcohol treatment, glutaraldehyde treatment, sonication, or a combination, and the epitope is chemically or physically altered as a result of being killed compared with the naturally occurring epitope.

For surface-directed antibodies, the invention specifies binding to an epitope of an antigen on the surface of the drug-resistant Mycobacterium organism, where the organism has been killed by the same chemical/physical treatments and the surface is chemically or physically altered as a result of being killed. The antigen targets include surface and cell-wall components and related antigens such as peptidoglycan, mycolic acid, lipoarabinomannan, and heat-shock proteins including the 16 kD HSPX, as well as synthetic/composite peptide antigens including MTB-influenza peptide composites.

The compositions include antibody formats and immune-modulating approaches, including monoclonal antibodies and antibody isotypes (IgA, IgD, IgE, IgG, IgM), and antibody portions such as Fab and Fc. The description further states functional outcomes including stimulation of cellular and humoral responses, increased memory T cells and antibody titers, enhancement of opsonization/phagocytosis and complement-associated killing, promotion of clearance of MTB from blood, and modulation of cytokine responses including IL-4 and IFN-γ.

Claims Coverage

The independent claims cover antibodies that bind epitopes on drug-resistant Mycobacterium organisms after chemical/physical killing, and distinguish whether the epitope is associated with general antigen versus a surface antigen. The coverage is based on two inventive features tied to epitope alteration after killing and, for the second independent claim, surface antigen alteration and resulting immune effects.

Overall, the claim set centers on antibodies that recognize epitopes created by killing-induced chemical/physical alteration of drug-resistant Mycobacterium antigens, with a separate independent focus on surface antigens whose surfaces are altered after killing. Dependent scope further specifies organism species, antigen constituent types, antibody isotypes/regions, phagocytosis/killing effects, blood clearance, and includes a vaccine application using the claimed antibody.

Stated Advantages

Documented Applications