Human monoclonal antibodies protective against bubonic plague
Inventors
Amemiya, Kei • Dimitrov, Dimiter S. • Xiao, Xiaodong
Assignees
United States Department of the Army
Publication Number
US-8722046-B2
Publication Date
2014-05-13
Expiration Date
2029-04-08
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Abstract
In this application are described fully human monoclonal antibodies which specifically recognize F1 or V antigen of Y. pestis and epitopes recognized by these monoclonal antibodies. Also provided are mixtures of antibodies of the present invention, as well as methods of using individual antibodies or mixtures thereof for the detection, prevention, and/or therapeutical treatment of plague infections in vitro and in vivo.
Core Innovation
This invention describes fully human monoclonal antibodies that specifically recognize the F1 or V antigen of Yersinia pestis (Y. pestis), the causative agent of plague, and the epitopes recognized by these monoclonal antibodies. The antibodies include those designated as m252 against F1 antigen, and m253 and m254 against V antigen. These antibodies, individually or in mixtures, can be used for detection, prevention, and therapeutic treatment of plague infections both in vitro and in vivo.
The invention addresses the problem wherein existing treatments for plague, such as antibiotics and live attenuated vaccines, have limitations including adverse effects and the emergence of multiple-antibiotic-resistant strains of Y. pestis. Mouse monoclonal antibodies have shown protective effects but raise concerns about immune reactions in humans. There is thus a need for fully human anti-plague monoclonal antibodies to avoid immune responses and provide an alternative treatment.
The application reports the isolation of three fully human monoclonal antibodies from a naive human phage-displayed Fab library: one targeting the F1 antigen (m252) and two targeting the V antigen (m253, m254). Administration of the anti-F1 antibody alone showed good protective effects in mice, and while the anti-V antibodies alone were not protective, a clear synergistic protective effect was observed when all three were used in combination. The combination was effective even when administered up to two days post-infection, marking a significant advancement toward adjunctive therapy for Y. pestis infection in humans.
Claims Coverage
The patent includes multiple inventive features primarily centered on compositions comprising human monoclonal antibodies targeting F1 and V antigens of Y. pestis and their uses in detection and treatment.
Composition comprising specific human F1 antibodies
A composition including F1 antibodies characterized by having the amino acid sequence of SEQ ID NO: 3, SEQ ID NO:5, or antibody fragments retaining the complementarity determining regions (CDRs) of these sequences.
Composition comprising specific human V antibodies
A composition including V antibodies characterized by having the amino acid sequences of SEQ ID NO: 9 and SEQ ID NO:11, or antibody fragments retaining the CDRs of these sequences.
Composition comprising alternative specific human V antibodies
A composition including V antibodies defined by amino acid sequences SEQ ID NO: 13 and SEQ ID NO: 15, or antibody fragments retaining the CDRs of these sequences.
Combination of two different V antibodies
A composition combining two V antibodies: one with the amino acid sequences of SEQ ID NO: 13 and SEQ ID NO:15, and a second with the sequences of SEQ ID NO: 9 and SEQ ID NO:11, or corresponding CDR-retaining fragments.
Pharmaceutical compositions of antibody combinations
Pharmaceutical compositions comprising the above-described F1 and/or V antibodies, alone or in combination, formulated with pharmaceutically acceptable carriers.
Methods for detecting Y. pestis using antibody compositions
Methods for detecting Y. pestis or its F1 or V antigens in a sample comprising incubating the sample with effective amounts of the antibody compositions to form antibody-antigen complexes followed by detection of these complexes as indicators of bacterial presence.
Methods for treating Y. pestis infection using antibody compositions
Methods for treating Y. pestis infection by administering to a patient in need therapeutically effective amounts of pharmaceutical compositions comprising the defined human monoclonal antibodies targeting F1 and/or V antigens.
The claims cover compositions containing fully human monoclonal antibodies specific to Y. pestis F1 and V antigens, their pharmaceutical formulations, and methods for detecting and treating Y. pestis infection using these compositions, emphasizing the use of combinations of defined antibody sequences or fragments retaining their complementarity determining regions.
Stated Advantages
The fully human antibodies are safer and avoid immune reactions associated with mouse monoclonal antibodies.
The combination of human anti-F1 and anti-V antibodies produces a synergistic effect, improving protective efficacy against Y. pestis infection.
Administration of these antibodies can provide both prophylactic and therapeutic protection, including effectiveness when administered up to two days post infection.
These antibodies have potential for rapid intravenous application in humans to augment current antibiotic treatments.
Documented Applications
Use in detection of Y. pestis infection by assaying samples for formation of antibody-antigen complexes.
Prophylactic and therapeutic treatment of Y. pestis infections in humans and animal models via administration of human monoclonal antibodies or their mixtures.
Development of pharmaceutical compositions and diagnostic kits containing these human monoclonal antibodies for plague infection management.
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