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-9796774-B2
Publication Date
2017-10-24
Expiration Date
2031-09-23
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Abstract
The present application relates novel HIV-1 broadly neutralizing antibodies. The antibodies of the present invention are further characterized by their ability to bind epitopes from the Env proteins. The invention also provides light and heavy chain variable region sequences. Compositions for prophylaxis, diagnosis and treatment of HIV infection are provided.
Core Innovation
The invention relates to novel human broadly neutralizing monoclonal antibodies specific for HIV-1, particularly those that can potently neutralize diverse HIV-1 isolates from multiple clades in vitro. The antibodies, such as VRC-PG-04 and VRC-PG-05, bind epitopes on the HIV-1 envelope glycoprotein Env, including conserved sites such as the CD4 binding site (CD4bs). These antibodies are characterized by high affinity binding to properly folded Env structures like resurfaced stabilized cores (RSC3), and display broad and potent neutralization at low antibody concentrations, facilitating their use in prophylaxis, therapy, and diagnosis of HIV infection.
The problem being addressed is the formidable challenges posed by HIV-1 in eliciting broadly neutralizing antibodies due to its genetic diversity, immune evasion strategies, and structural features of the Env glycoprotein that limit antibody binding. Existing broadly neutralizing antibodies show limited breadth and potency, often focused on certain clades or epitopes, and many immunogens fail to present the native trimeric Env in conformations that elicit broad neutralizing responses. The invention aims to overcome these issues by identifying and characterizing novel human monoclonal antibodies that neutralize HIV-1 broadly and potently by targeting conserved epitopes, and developing methods for their isolation, characterization, and use.
The invention further relates to methods of isolating such broadly neutralizing antibodies from single memory B cells of HIV-1 infected donors using antigen-specific sorting with modified Env probes like RSC3 and its knockout mutants, followed by cloning and expression of matched heavy and light chain antibody sequences. These methods allow for the recovery of antibodies such as VRC-PG-04 and VRC-PG-05, which show unique binding properties and potent neutralization. The invention encompasses compositions comprising these antibodies, nucleic acid sequences encoding them, vectors for expression, and methods of immunization or treatment using these antibodies alone or in combination with other therapeutic agents, including antiviral drugs.
Claims Coverage
The patent contains independent claims covering the isolated monoclonal antibody VRC-PG-05 and compositions and methods involving its nucleic acid encoding sequences and use in diagnosis.
Isolated monoclonal antibody comprising specific heavy and light chains
An isolated or non-naturally occurring VRC-PG-05 monoclonal antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 8 and a light chain amino acid sequence of SEQ ID NO: 16.
Vectors encoding the monoclonal antibody
Vectors containing and expressing nucleic acid molecules encoding the VRC-PG-05 monoclonal antibody.
Diagnostic compositions with labeled antibodies for HIV detection
Diagnostic compositions comprising a labeled VRC-PG-05 antibody or fragment thereof for detecting the presence of HIV immunogens, antigens or epitopes in a sample, including biological samples such as blood, semen, or vaginal fluid.
The independent claims define the invention over the isolated VRC-PG-05 monoclonal antibody with specific heavy and light chain sequences, the nucleic acid vectors encoding this antibody, and diagnostic compositions utilizing this antibody or its fragments for detection of HIV components. These claims encompass antibodies, their genetic constructs, and their diagnostic uses, covering both molecules and their applications.
Stated Advantages
The antibodies have broad and potent HIV-1 neutralizing activity across multiple clades and clinical isolates, requiring only low concentrations for effective neutralization.
The antibodies target conserved epitopes such as the CD4 binding site on the HIV-1 Env, improving the likelihood of efficacy against diverse viral strains.
Methods for isolating these antibodies enable recovery of highly affinity-matured, broadly neutralizing antibodies from HIV-1 infected donors.
The antibodies and their nucleic acid sequences provide compositions useful for prophylaxis, therapy, and diagnosis of HIV infection.
Documented Applications
Use as prophylactic or therapeutic agents to prevent or treat HIV infection by administering the antibodies or their fragments to patients in need.
Administration in combination with other therapeutic agents, including a range of antiviral drugs.
Use in diagnostic assays to detect HIV immunogens, antigens or epitopes in biological samples such as blood, semen, or vaginal fluid.
Use of nucleotide sequences and vectors encoding these antibodies for expression in vitro or in vivo, including as components of immunogenic compositions or vaccines to elicit immune responses against HIV.
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