HIV-1 broadly neutralizing antibodies
Inventors
Mascola, John • Burton, Dennis R. • Koff, Wayne • Kwong, Peter • Nabel, Gary • Phogat, Sanjay K. • Poignard, Pascal Raymond Georges • Simek-Lemos, Melissa Danielle De Jean St. Marcel • Wu, Xueling • Zhou, Tongqing • Yang, Zhi-Yong
Assignees
Scripps Research Institute • International AIDS Vaccine Initiative Inc • US Department of Health and Human Services
Publication Number
US-9382311-B2
Publication Date
2016-07-05
Expiration Date
2031-09-23
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Abstract
The present application relates broadly neutralizing monoclonal antibodies directed against HIV-1. In particular, monoclonal antibodies VRC-PG04 and VRC-PG05 are disclosed.
Core Innovation
The invention relates to broadly neutralizing human monoclonal antibodies that target HIV-1, specifically monoclonal antibodies VRC-PG04 and VRC-PG05. These antibodies neutralize HIV-1 in vitro and recognize conserved epitopes on the HIV-1 envelope glycoprotein, particularly at the structurally conserved CD4 receptor binding site, as identified using resurfaced stabilized core (RSC) Env probes. The antibodies have heavy and light chain complementarity determining regions (CDRs) with specific amino acid sequences disclosed in the patent, demonstrating potent and broad neutralization across multiple HIV-1 clades.
The problem being solved is the difficulty in eliciting broad and potent neutralizing antibodies against HIV-1 due to the virus’s extensive genetic variability and multiple immune evasion strategies. Existing antibodies isolated from infected donors tend to have limited breadth and potency, especially against non-clade B viruses, and epitopes targeted by previous antibodies have failed to consistently elicit broad neutralizing responses when used in immunogens. The invention addresses these issues by providing novel monoclonal antibodies isolated through antigen-specific memory B-cell sorting using modified Env structures, which exhibit potent neutralization with broad cross-clade reactivity.
The invention further encompasses the use of these antibodies, or fragments thereof, for therapeutic or prophylactic treatment of HIV infection, including methods of administration, compositions comprising the antibodies, and nucleic acid molecules encoding them. The antibodies can be used alone or in combination with other anti-HIV agents, potentially enhancing treatment efficacy. Additionally, the invention covers isolated antibodies, variants thereof, and their use in diagnostic compositions to detect HIV antigens or antibodies.
Claims Coverage
The patent includes one independent claim focused on monoclonal antibodies and their variants, along with dependent claims covering diagnostic compositions and nucleic acid vectors.
Isolated human monoclonal antibodies neutralizing HIV-1
An isolated or non-naturally occurring human monoclonal antibody that neutralizes HIV-1 virus in vitro, selected from VRC-PG04 or VRC-PG05.
Diagnostic composition using labeled monoclonal antibodies
A diagnostic composition comprising a labeled antibody or fragment thereof of the isolated monoclonal antibodies (VRC-PG04 or VRC-PG05) to detect HIV immunogens, antigens, or epitopes in a sample, including biological samples such as blood, semen, or vaginal fluid.
Isolated VRC-PG-04 monoclonal antibody with defined sequences
An isolated or non-naturally occurring VRC-PG-04 monoclonal antibody comprising specific heavy chain amino acid sequences (SEQ ID NO: 6, 21 or 22) and a light chain sequence (SEQ ID NO: 14).
Variants of VRC-PG-04 monoclonal antibody with specific sequences
An isolated or non-naturally occurring variant of VRC-PG-04 monoclonal antibody comprising heavy chain sequences selected from SEQ ID NOS: 21 or 22 and light chain sequences selected from SEQ ID NOS: 33 or 34.
Vectors encoding VRC-PG-04 antibodies
Vectors containing and expressing nucleic acid molecules encoding the VRC-PG-04 monoclonal antibody or its variants as defined in the claims, enabling recombinant expression.
The independent claims cover isolated monoclonal antibodies VRC-PG-04 and VRC-PG-05 that neutralize HIV-1, with dependent claims expanding coverage to diagnostic compositions using these antibodies, specific sequence-defined antibody variants, and nucleic acid vectors encoding them. The inventive features focus on broad and potent HIV-1 neutralizing activity and methods for detection and recombinant expression.
Stated Advantages
The antibodies exhibit broad and potent neutralizing activity against diverse HIV-1 isolates across multiple clades, including clades A, B, and C.
High potency is achieved requiring low concentrations of antibody (e.g., less than about 1 μg/ml) for effective neutralization.
The antibodies can be used therapeutically or prophylactically and in combination with other antiviral agents, potentially improving HIV infection treatment.
The antibodies enable diagnostic detection of HIV antigens or antibodies with specificity.
The use of antigen-specific B-cell sorting with modified Env probes allows efficient isolation of novel broadly neutralizing antibodies targeting conserved epitopes.
Documented Applications
Prophylactic or therapeutic treatment of HIV-1 infection by administering a therapeutically effective amount of VRC-PG04 or VRC-PG05 antibodies or fragments thereof to patients in need.
Use in diagnostic methods to detect HIV immunogens, antigens, or epitopes in biological samples such as blood, semen, or vaginal fluid using labeled antibodies or fragments thereof.
Nucleic acid molecules and vectors encoding the antibodies for recombinant expression in vitro or in vivo, including vaccine and immunogenic composition applications to elicit immune responses.
Combination therapies involving at least one antibody of the invention and a second therapeutic agent, including anti-viral agents.
Use of antibody combinations targeting different epitopes for enhanced immunization or therapeutic effects against HIV infection.
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