Bivalent, bispecific binding proteins for prevention or treatment of HIV infection
Inventors
Yang, Zhi-Yong • Nabel, Gary J. • Xu, Ling • Beninga, Jochen • Kruip, Jochen • Rao, Ercole • LEUSCHNER, Wulf Dirk • Beil, Christian • Lange, Christian
Assignees
Sanofi SA • National Institutes of Health NIH • US Department of Health and Human Services
Publication Number
US-11129905-B2
Publication Date
2021-09-28
Expiration Date
2036-10-24
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Abstract
Provided herein are bivalent, bispecific binding proteins that specifically bind to two different HIV-1 Env protein epitopes.
Core Innovation
The invention provides trispecific and/or trivalent binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins. A first pair of polypeptides possess dual variable domains having a cross-over orientation forming two antigen binding sites, and a second pair possesses a single variable domain forming a third antigen binding site. These binding proteins comprise specific structures for the polypeptide chains including linked immunoglobulin variable domains and constant domains, and amino acid linkers. The polypeptides of the first two chains form a cross-over light chain-heavy chain pair.
The background highlights challenges in treating HIV/AIDS with neutralizing antibodies, particularly the occurrence of breakthrough infection due to the high mutation rate of HIV-1 viruses. Early weeks after HIV-1 transmission establish viral reservoirs including latently infected cells which persist despite current combination antiretroviral therapy, leading to incurable lifelong infection. Although newly discovered anti-HIV-1 neutralizing antibodies with improved breadth and potency provide treatment options, breakthrough infections remain a major issue that the invention seeks to address.
Claims Coverage
The claims outline multiple inventive features primarily focused on bispecific binding proteins targeting two different HIV-1 Env protein epitopes using specific heavy and light chain variable domains.
Bispecific binding protein targeting two HIV-1 Env epitopes with defined variable domains
A bispecific binding protein comprising two distinct binding sites targeting different HIV-1 Env protein epitopes, where the first binding site includes VH1 and VL1 with specific amino acid sequences (SEQ ID NOs: 506 and 519), and the second binding site includes VH2 and VL2 with specific sequences (SEQ ID NOs: 504 and 518).
Alternative bispecific binding protein with swapped variable domains
A bispecific binding protein with the first binding site comprising VH1 and VL1 having amino acid sequences SEQ ID NOs: 503 and 513, and the second binding site comprising VH2 and VL2 with sequences SEQ ID NOs: 506 and 519, indicating interchangeable arrangements of variable domains.
Bispecific binding protein with combined HIV-1 Env epitopes
A bispecific binding protein that combines variable domains VH1 and VL1 with sequences SEQ ID NOs: 506 and 519 for the first binding site, and VH2 and VL2 with sequences SEQ ID NOs: 503 and 513 for the second binding site, providing specific pairing combinations to target different Env epitopes.
The claims cover bispecific binding proteins containing defined heavy and light chain variable domains arranged in pairs to specifically bind two different HIV-1 Env protein epitopes, with disclosed variations in variable domain compositions and pairings enhancing specificity and versatility.
Stated Advantages
The trispecific binding proteins target multiple epitopes on the HIV-1 Env glycoprotein, providing improved neutralizing capabilities compared to monospecific or bispecific antibodies, thereby reducing the likelihood of viral escape and breakthrough infections.
The trispecific binding proteins exhibit stable monomeric forms suitable for therapeutic use and demonstrate binding affinities similar or superior to parental antibodies.
The T-cell engager trispecific binding proteins activate CD4+ and CD8+ T cells robustly and induce lysis of HIV-1 infected cells, suggesting potential to reduce or eliminate latent viral reservoirs.
Trispecific binding proteins show favorable pharmacokinetic profiles in vivo, remaining detectable for at least 14 days and in some cases up to 35 days after administration.
Documented Applications
Use of trispecific binding proteins for prevention and treatment of HIV infection in patients, either alone or co-administered with standard anti-retroviral therapy.
Therapeutic application in neutralizing HIV virions and eliminating latently and/or chronically HIV-infected cells in humans.
Diagnostic uses including competitive binding assays, immunoprecipitation assays, and in vivo imaging using labeled trispecific binding proteins.
Use in developing T-cell engagers to activate immune response targeting HIV-infected cells and in reducing latent viral reservoirs.
Methods of producing trispecific binding proteins using host cells expressing nucleic acid vectors encoding the binding protein polypeptide chains.
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