Broadly neutralizing antibodies against HIV
Inventors
SAJADI, Mohammad • Lewis, George K. • DEVICO, Anthony
Assignees
University of Maryland Baltimore • US Department of Veterans Affairs
Publication Number
US-11760789-B2
Publication Date
2023-09-19
Expiration Date
2038-06-22
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Abstract
The present invention provides broadly neutralizing antibodies against HIV, compositions comprising the same and methods of use thereof.
Core Innovation
The invention provides broadly neutralizing antibodies against HIV, compositions comprising these antibodies, and methods of their use. The invention isolates anti-HIV antibodies capable of neutralizing at least 95% to 100% of HIV pseudoviruses listed in Table 1 with IC50 values of less than 50μg/mL. Specific antibodies such as N49P6, N49P7, N49P7.1, N49P9, and N49P11, or antigen binding fragments thereof, exhibit extremely broad and potent neutralizing activity across multiple clades of HIV-1, including viruses resistant to other broadly neutralizing antibodies.
The problem addressed relates to the need for new therapies for the treatment and prevention of HIV infection. HIV is a genetically diverse virus that rapidly establishes chronic infection, with variability in viral envelope proteins challenging the development of effective humoral responses. Existing broadly neutralizing antibodies derived mainly from memory B cells may not fully represent neutralizing species in circulation, and previous approaches have not fully elucidated the polyclonal humoral environment or identified antibody species responsible for broad neutralization. Thus, there is a need to better characterize and isolate broadly neutralizing antibodies directly from plasma that can neutralize diverse HIV strains effectively.
To overcome these challenges, the invention employs combined genomic and proteomic approaches to isolate and characterize broadly neutralizing antibody lineages directly from plasma and bone marrow cells of HIV-infected subjects with extremely broad neutralizing activity (referred to as natural viral suppressors). The isolated antibody lineages exhibit unique features, such as targeting the CD4-binding site of gp120 with specific molecular interactions that permit broad recognition despite HIV envelope diversity. Structural analyses reveal that antibodies like N49P7 bypass the CD4-binding site Phe43 cavity while engaging highly conserved inner domain residues, contributing to pan-neutralization and informing novel immunoprophylaxis strategies.
Claims Coverage
The claims present four independent claims involving isolated anti-HIV antibodies with specific heavy and light chain variable regions and complementarity determining regions (CDRs), as well as their variants, compositions, host cells, and methods of use.
Non-naturally occurring anti-HIV antibodies defined by unique CDR sequences
The invention claims isolated anti-HIV antibodies that are non-naturally occurring and comprise heavy chain variable regions with specific CDR H1, H2, and H3 amino acid sequences, and light chain variable regions with specific CDR L1, L2, and L3 sequences, wherein the antibodies differ from specified SEQ ID NOs for heavy and light chains.
Anti-HIV antibodies comprising defined heavy and light chain variable regions or their variants
Isolated anti-HIV antibodies comprising heavy and light chain variable (VH and VL) regions selected from a group of SEQ ID NOs (153, 155, 161, 163, 165, 167, 225, 227, 293, 295) or variants with 1-4 conservative amino acid substitutions.
Anti-HIV antibodies comprising specified heavy and light chain amino acid sequences or antigen binding fragments
Isolated anti-HIV antibodies comprising heavy chain amino acid sequences of SEQ ID NOs: 153, 161, 165, 225, 293 and corresponding light chain sequences, or antigen binding fragments thereof.
Host cells expressing the claimed anti-HIV antibodies
Isolated host cells engineered to express the antibodies defined by the preceding claims.
Engineered cells expressing the claimed anti-HIV antibodies
Engineered cells, including immune cells such as B cells, expressing any of the claimed anti-HIV antibodies.
Pharmaceutical compositions comprising the claimed antibodies
Pharmaceutical compositions comprising one or more of the claimed anti-HIV antibodies and a pharmaceutically acceptable carrier.
Methods for treating or preventing HIV infection using the claimed compositions
Methods for treating or preventing HIV infection in a subject by administering an effective amount of compositions comprising the claimed anti-HIV antibodies.
Combination therapy with anti-HIV antibodies and other treatments
Methods wherein the compositions comprising the claimed antibodies are administered in combination with another therapy, including anti-retroviral therapy.
The independent claims define novel isolated anti-HIV antibodies characterized by specific CDR sequences and variable regions, corresponding amino acid sequences, engineered host cells expressing these antibodies, pharmaceutical compositions comprising them, and methods for treating or preventing HIV infection, optionally in combination with other therapies.
Stated Advantages
Antibodies exhibit extremely broad and potent neutralization against diverse HIV pseudoviruses, including strains resistant to other broadly neutralizing antibodies.
Low antibody concentrations are required to neutralize HIV, facilitating higher protection with lower antibody amounts.
Identification of native antibodies with very broad cross-reactivity and potency informs better understanding of HIV humoral immunity evolution and aids immunoprophylaxis strategies.
Documented Applications
Use of broadly neutralizing anti-HIV antibodies for therapeutic treatment, including treatment, cure, functional cure, or prevention of HIV infection.
Passive administration of anti-HIV antibodies or gene therapies encoding these antibodies for prophylaxis or therapy.
Use of the antibodies in diagnostic assays to detect HIV or anti-HIV antibodies in biological samples.
Formulation of pharmaceutical compositions comprising the antibodies for administration by various routes including intravenous, intramuscular, subcutaneous, and mucosal delivery.
Combination therapy administering the antibodies with other HIV immunogens, vaccines, or anti-retroviral drugs for enhanced treatment or prevention.
Potential use of antibody-drug conjugates, labeled antibodies for imaging, and antibody-bead conjugates for purification or selective binding of HIV envelope proteins or virus particles.
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