Dosage and scheduling regimens for broad-spectrum neutralizing antibodies

Abstract

Provision of administration and scheduling regimens for broad-spectrum neutralizing antibodies. [Solution] A method is provided for administering a long-acting broad-spectrum anti-HIV antibody twice a year, for example, Q6M, Q24W, Q25W, or Q26W. In another embodiment, a method is provided for doing so in a human subject requiring treatment or prophylaxis of HIV. In some embodiments, the method includes (a) co-administering (i) an effective dose of 10-1074-LS (dinrilvimab, GS-2872) and (ii) an effective dose of 3BNC117-LS (telopavimab, GS-5423) at a first time point, and (b) co-administering an effective dose of 10-1074-LS and an effective dose of 3BNC117-LS at a second time point at least about 24 weeks after the first time point, for example, at least about 25 weeks, for example, at least about 26 weeks.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims the interests of U.S. Provisional Application No. 63 / 373,597, filed on 26 August 2022, and U.S. Provisional Application No. 63 / 514,711, filed on 20 July 2023, pursuant to Section 119(e) of the U.S. Patent Act, which are incorporated herein by reference in their entirety for all purposes.

[0002] Sequence List This application includes a sequence listing, which is filed electronically in XML format and is incorporated herein by reference in its entirety. The XML copy created on July 20, 2023, is named 1445-WO-PCT_sequencelisting.XML and has a size of 512,134 bytes. [Background technology]

[0003] Human immunodeficiency virus type 1 (HIV-1) HIV infection causes serious, life-threatening illnesses and remains one of the leading causes of morbidity and mortality worldwide. In the United States, approximately 1 million people are infected with HIV (people with HIV, PWH), and globally, there are over 38 million. (UNAIDS.Fact Sheet-Global HIV Statistics (2021). Advances in antiretroviral (ARV) therapy (ART) for HIV suppress viral replication and preserve immunological function. This has resulted in significant improvements in morbidity and mortality by preventing disease progression to AIDS. However, current treatment strategies have not been able to eliminate the virus and cure HIV-1 infection.

[0004] While current combination ARTs for the treatment of HIV-1 infection are effective and well-tolerated, these medications must be taken daily and require near-perfect adherence to minimize the emergence of drug-resistant variants. As a result, "treatment fatigue," defined as "a decreased desire and motivation to maintain vigilance in adhering to the treatment regimen," can occur among patients prescribed chronic or lifelong treatments (Claborn, et al., Psychol Health Med (2015) 20(3):255-65), which can lead to non-adherence and treatment failure. Therefore, there remains a significant medical need for ARVs that can be administered less frequently (i.e., long-acting drug products), thereby providing alternative treatment options for individuals infected with HIV-1.

[0005] Lenacapavir is a novel, first-in-class, multi-step selective inhibitor of HIV-1 capsid function, targeted for the treatment of HIV-1 infection. Lenacapavir possesses potent antiviral activity and does not exhibit overlapping resistance with any approved products. Lenacapavir has low human clearance and is being developed as a long-acting ARV for the treatment and prophylaxis of HIV-1. Lenacapavir has the potential to meet unmet high medical needs in patient-hospitalized areas (PWH) where long-acting treatment or a novel mechanism of action can be beneficial. Monoclonal antibodies (mAbs) that have neutralizing activity against the HIV-1 envelope glycoprotein have been identified (Burton and Mascola, Nat Immunol (2015) 16(6):571-6), parenteral administration of broadly neutralizing mAbs resulted in a significant reduction in plasmaviremia in untreated PWH, and broadly neutralizing antibodies (broadly neutralizing) were detected before analytical treatment was discontinued. Virological suppression was maintained in virologically suppressed PWH patients treated with antibodies (bNAb) (Caskey, et al., Nature (2015) 522(7557):487-91; Caskey, et al., Nat Med (2017) 23(2):185-91; Mendoza, et al., Nature (2018) 561:479-84). Antibodies can act for extended periods and have the potential to alleviate challenges to daily therapy or lifelong adherence. Antibodies may also be involved in the immune system, potentially contributing to a beneficial HIV-specific immune response (Niessl, et al., Nat Med (2020) 26(2):222-7), including the possibility of clearing latent infected cells (Gaebler, et al., Nature (2022) 606(7913):368-374) that are not achieved with ARV drugs. As biologics, bNAbs can save patients from the adverse effects associated with chronic ARV therapy. However, HIV-1 is a diverse virus, and its variants exhibit varying levels of susceptibility to any given bNAb. Therefore, the bNAbs identified to date have an imperfect range when measured by their ability to neutralize the diversity of HIV-1 isolates (Nishimura, et al., Nature (2017) 543(7646): 559-63). 3BNC117 and 10-1074 are two of the most potent bNAbs identified and clinically tested (Mouquet, et al., Proc Natl Acad Sci USA (2012) 109(47): E3268-77, Scheid, et al., Science (2011) 333(6049): 1633-7). However, viral resistance to bNAb can develop after antibody titers have declined (Bar-On, et al., Nat Med (2018) 24:1701-7). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] UNAIDS. Fact Sheet - Global HIV Statistics 2021 [Non-Patent Document 2] Claborn, et al., Psychol Health Med (2015) 20(3): 255 - 65 [Non-Patent Document 3] Burton and Mascola, Nat Immunol (2015) 16(6): 571 - 6 [Non-Patent Document 4] Caskey, et al., Nature (2015) 522(7557): 487 - 91 [Non-Patent Document 5] Caskey, et al., Nat Med (2017) 23(2): 185 - 91 [Non-Patent Document 6] Mendoza, et al., Nature (2018) 561: 479 - 84 [Non-Patent Document 7] Gaebler, et al., Nature (2022) 606(7913): 368 - 374 [Non-Patent Document 8] Niessl, et al., Nat Med (2020) 26(2): 222 - 7 [Non-Patent Document 9] Nishimura , et al., Nature (2017) 543(7646): 559 - 63 [Non-Patent Document 10] Mouquet, et al., Proc Natl Acad Sci U S A (2012) 109(47): E3268 - 77 [Non-Patent Document 11] Scheid, et al., Science (2011) 333(6049): 1633 - 7 [Non-Patent Document 12] Bar-On, et al., Nat Med (2018) 24: 1701 - 7 [Summary of the Invention] [Means for Solving the Problems] [[ID=�2]]

[0007] In one embodiment, a method is provided for treating or prophylactically treating HIV in human subjects requiring such treatment. In some embodiments, the method includes (a) co-administering, at a first time point, (i) an effective amount of a first antibody that competes with or contains VH and VL regions that bind to the epitopes of gp120 in a high-mannose patch containing a third variable loop (V3) and / or N332 oligomannose glycan, and (ii) an effective amount of a second antibody that competes with or contains VH and VL regions that bind to the epitopes of gp120 containing a CD4 binding site (CD4bs), wherein both the first and second antibodies include Fc amino acid substitutions to extend the serum half-life; and (b) co-administering, at a second time point at least about 24 weeks after the first time point, for example, at least about 25 weeks, for example, at least about 26 weeks later, an effective amount of the first antibody and an effective amount of the second antibody. In some embodiments, the first and second antibodies have the following amino acids at their indicated positions (EU index numbering): (i) tyrosine at position 252, threonine at position 254 and glutamic acid (YTE) at position 256, (ii) leucine at position 428 and serine at position 434 (LS), (iii) lysine at position 433 and phenylalanine at position 434, (iv) glutamine at position 250 and 428 The molecule contains an Fc region comprising (v) leucine at position 1(QL), (v) glutamine at position 307, valine at position 311, and valine at position 378 (DF215), (vi) aspartic acid at position 256, aspartic acid at position 286, arginine at position 307, valine at position 311, and valine at position 378 (DF228), or (vii) aspartic acid at position 309, histidine at position 311, and serine at position 434 (DHS).In some embodiments, the first antibody is GS-2872 (also known as dinrilvimab), 10-1074, 10-1074-J, GS-9722, GS-9721, PGT-121, PGT-121.66, PGT-121.414, PGT-122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-128, PGT-130, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-138, PGT-139, VRC24, 2G12, BG18, 354BG8, 354BG1 8, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1, and VRC29.03 compete with or include the VH and VL regions of antibodies, and the second antigen-binding molecule is GS-5423, 3BNC117, GS-9723, 3BNC60, b12, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b01 The antibodies compete with or include the VH and VL regions of antibodies selected from VRC08, VRC0801, NIH45-46, PGV04 (VRC-PG04), CH103, 44-VRC13.01, 1NC9, 12A12, N6, 1-18, N49-P7, NC-Cow1, IOMA, CH235, and CH235.12, N49P6, N49P7, N49P11, N49P9, and N60P25. In some embodiments, the first antibody competes with or includes the VH and VL regions of 10-1074, and the second antibody competes with or includes the VH and VL regions of 3BNC117. In some embodiments, the first antibody comprises 10-1074-LS (also known as dinrilvimab, GS-2872), and the second antibody comprises 3BNC117-LS (also known as teropavimab, GS-5423). In some embodiments, the first and second antibodies are co-administered every 6 months (Q6M). In some embodiments, the first and second antibodies are co-administered every 24 weeks (Q24W). In some embodiments, the first and second antibodies are co-administered every 25 weeks (Q25W).In some embodiments, the first antibody and the second antibody are co-administered every 26 weeks (Q26W). In some embodiments, the first antibody and the second antibody are administered intravenously independently in doses ranging from about 500 mg to about 3000 mg, for example, about 550 mg to about 2900 mg, for example, about 600 mg to about 2800 mg, for example, about 650 mg to about 2700 mg, for example, about 700 mg to about 2600 mg, for example, about 850 mg to about 2550 mg. In some embodiments, the first antibody is administered intravenously at a dose of 2550 mg, and the second antibody is administered intravenously at a dose of 2550 mg. In some embodiments, the first antibody is administered intravenously at a dose of 850 mg, and the second antibody is administered intravenously at a dose of 1275 mg. In some embodiments, the first antibody is administered intravenously at a dose of 850 mg, and the second antibody is administered intravenously at a dose of 1700 mg. In some embodiments, the first antibody is administered intravenously at a dose of 850 mg, and the second antibody is administered intravenously at a dose of 2550 mg. In some embodiments, the method further comprises co-administration of one or more long-acting HIV drugs. In some embodiments, the one or more long-acting HIV drugs are long-acting capsid inhibitors, long-acting integrase strand transfer inhibitors (INSTIs), long-acting non-nucleoside reverse transcriptase inhibitors (NNRTIs), and long-acting nucleoside inhibitors. nucleoside reverse transcriptase inhibitor (NRT) I) and selected from long-acting protease inhibitors (PIs) In some embodiments, one or more long-acting HIV drugs include long-acting capsid inhibitors. In some embodiments, the long-acting capsid inhibitor is selected from lenacapavir, VH4004280, and VH4011499. In some embodiments, the long-acting capsid inhibitor includes lenacapavir. In some embodiments, lenacapavir is administered in doses ranging from 300 mg to 1000 mg. In some embodiments, lenacapavir is administered orally or subcutaneously. In some embodiments, the long-acting INSTI is selected from bictegravir, raltegravir, elvitegravir, dolutegravir, cabotegravir, GS-1720, GS-6212, GS-1219, GS-3242, and VH4524184. In some embodiments, the long-acting NNRTI is selected from rilpivirine, elsulfavirine, doravirine, and GS-5894. In some embodiments, the long-acting NRTI is selected from islatravir and its prodrugs, tenofovir alafenamide (TAF) and the prodrug of tenofovir, lovahovir etalafenamide, and GS-1614. In some embodiments, the long-acting protease inhibitor is selected from atazanavir, ritonavir, darunavir, GS-1156 and the prodrug of GS-1156, and combinations thereof. In some embodiments, the method further includes determining the susceptibility of a subject to HIV to one or both of the first and second antibodies. In some embodiments, the subject is viremia (i.e., HIV-1 (RNA > 50 copies / mL). In some embodiments, the subject is virologically suppressed (i.e., HIV-1 RNA < 50 copies / mL). In some embodiments, the subject is receiving antiretroviral therapy (ART). In some embodiments, antiretroviral therapy (ART) is discontinued before administration of the first and second antibodies, for example, before the first time point. In some embodiments, the human is acutely infected with HIV. In some embodiments, the subject has Fiebig stage IV or earlier HIV infection. In some embodiments, the subject is not serotonized. In some embodiments, the subject is recently infected with HIV. In some embodiments, the antibody is administered to a subject with Fiebig stage V or Fiebig stage VI HIV infection. In some embodiments, the subject is chronically infected with HIV. In some embodiments, the subject is infected with HIV clade B virus.

[0008] In another embodiment, a method is provided for treating or prophylactically treating HIV in human subjects requiring such treatment. In some embodiments, the method includes (a) co-administering (i) an effective dose of 10-1074-LS (dinrilvimab, GS-2872) and (ii) an effective dose of 3BNC117-LS (telopavimab, GS-5423) at a first time point, and (b) co-administering an effective dose of 10-1074-LS and an effective dose of 3BNC117-LS at a second time point at least about 24 weeks after the first time point, for example, at least about 25 weeks, for example, at least about 26 weeks. In some embodiments, 10-1074-LS and 3BNC117-LS are co-administered every 6 months (Q6M). In some embodiments, 10-1074-LS and 3BNC117-LS are co-administered every 24 weeks (Q24W). In some embodiments, 10-1074-LS and 3BNC117-LS are co-administered every 25 weeks (Q25W). In some embodiments, 10-1074-LS and 3BNC117-LS are co-administered every 26 weeks (Q26W). In some embodiments, 10-1074-LS and 3BNC117-LS are co-administered twice over a year. In some embodiments, 10-1074-LS and 3BNC117-LS are co-administered four times over a two-year period. In some embodiments, 10-1074-LS and 3BNC117-LS are co-administered six times over a three-year period. In some embodiments, 10-1074-LS and 3BNC117-LS are co-administered eight times over a four-year period. In some embodiments, 10-1074-LS is administered intravenously at a dose of 30 mg / kg, and 3BNC117-LS is administered intravenously at a dose of 30 mg / kg. In some embodiments, 10-1074-LS is administered intravenously at a dose of 10 mg / kg, and 3BNC117-LS is administered intravenously at a dose of 30 mg / kg. In some embodiments, 10-1074-LS and 3BNC117 are administered intravenously independently in doses ranging from about 500 mg to about 3000 mg, for example, about 550 mg to about 2900 mg, for example, about 600 mg to about 2800 mg, for example, about 650 mg to about 2700 mg, for example, about 700 mg to about 2600 mg, for example, about 850 mg to about 2550 mg.In some embodiments, 10-1074-LS is administered intravenously at a dose of 2550 mg, and 3BNC117-LS is administered intravenously at a dose of 2550 mg. In some embodiments, 10-1074-LS is administered intravenously at a dose of 850 mg, and 3BNC117-LS is administered intravenously at a dose of 1275 mg. In some embodiments, 10-1074-LS is administered intravenously at a dose of 850 mg, and 3BNC117-LS is administered intravenously at a dose of 1700 mg. In some embodiments, 10-1074-LS is administered intravenously at a dose of 850 mg, and 3BNC117-LS is administered intravenously at a dose of 2550 mg. In some embodiments, the serum concentrations of 10-1074-LS and 3BNC117-LS are at least 10 μg / mL 26 weeks after the first time point. In some embodiments, the plasma or serum concentration of HIV RNA is less than 50 copies / mL after 26 weeks from the first time point. In some embodiments, the method further comprises co-administration of one or more long-acting HIV drugs. In some embodiments, one or more long-acting HIV drugs are selected from long-acting capsid inhibitors, long-acting integrase chain transfer inhibitors (INSTIs), long-acting non-nucleoside reverse transcriptase inhibitors (NNRTIs), long-acting nucleoside reverse transcriptase inhibitors (NRTIs), and long-acting protease inhibitors (PIs). In some embodiments, the long-acting capsid inhibitor is selected from lenacapavir, VH4004280, and VH4011499. In some embodiments, the long-acting capsid inhibitor includes lenacapavir. In some embodiments, lenacapavir is administered in doses ranging from 300 mg to 1000 mg. In some embodiments, lenacapavir is administered orally or subcutaneously. In some embodiments, the long-acting INSTI is selected from bictegravir, raltegravir, elvitegravir, dolutegravir, cabotegravir, GS-1720, GS-6212, GS-1219, GS-3242, and VH4524184. In some embodiments, the long-acting NNRTI is selected from rilpivirine, elsulfavirine, doravirine, and GS-5894.In some embodiments, the long-acting NRTI is selected from islatravir and its prodrugs, tenofovir alafenamide (TAF) and tenofovir prodrugs, lovahovir etalafenamide, and GS-1614. In some embodiments, the long-acting protease inhibitor is selected from atazanavir, ritonavir, darunavir, GS-1156 and GS-1156 prodrugs, and combinations thereof. In some embodiments, the method further includes determining the susceptibility of a subject to HIV to one or both of 10-1074-LS and 3BNC117-LS. In some embodiments, the subject is viremia. In some embodiments, the subject is virologically suppressed. In some embodiments, the subject is receiving antiretroviral therapy (ART). In some embodiments, antiretroviral therapy (ART) is discontinued before administration of 10-1074-LS and 3BNC117-LS. In some embodiments, the human is acutely infected with HIV. In some embodiments, the subjects have Fiebig stage IV or earlier HIV infection. In some embodiments, the subjects are not seroconverted to antibodies. In some embodiments, the subjects are recently infected with HIV. In some embodiments, the antibodies are administered to subjects with Fiebig stage V or Fiebig stage VI HIV infection. In some embodiments, the subjects are chronically infected with HIV. In some embodiments, the subjects are infected with HIV clade B virus.

[0009] In further embodiments, a kit is provided. In some embodiments, the kit comprises one or more unit doses of a first antibody bound to HIV gp120 V3 glycan and a second antibody bound to HIV gp120 CD4bs, wherein the first and second antibodies have serum half-life-extending amino acid substitutions, and the first and second antibodies are formulated for administration twice a year (e.g., every six months (Q6M), every 26 weeks (Q26W), every 25 weeks (Q25W), or every 24 weeks (Q24W)). In some embodiments, one or more unit doses of the first antibody and the second antibody are independently in the range of about 500 mg to about 3000 mg, for example, about 550 mg to about 2900 mg, for example, about 600 mg to about 2800 mg, for example, about 650 mg to about 2700 mg, for example, about 700 mg to about 2600 mg, for example, about 850 mg to about 2550 mg. The unit doses may be the same or different as needed. In some embodiments, the kit comprises one or more unit doses of 3BNC117-LS (telopavimab, GS-5423) and 10-1074-LS (dinriluvimab, GS-2872), and 3BNC117-LS (telopavimab) and 10-1074-LS (dinriluvimab) are formulated for administration twice a year (e.g., every 6 months (Q6M), every 26 weeks (Q26W), every 25 weeks (Q25W), or every 24 weeks (Q24W)). In some embodiments, the unit doses of 10-1074-LS and 3BNC117-LS are independently in the range of about 500 mg to about 3000 mg, for example, about 550 mg to about 2900 mg, for example, about 600 mg to about 2800 mg, for example, about 650 mg to about 2700 mg, for example, about 700 mg to about 2600 mg, for example, about 850 mg to about 2550 mg. In some embodiments, one or more unit doses of 10-1074-LS are 2550 mg, and one or more unit doses of 3BNC117-LS are 2550 mg. In some embodiments, one or more unit doses of 10-1074-LS are 850 mg, and one or more unit doses of 3BNC117-LS are 1275 mg. In some embodiments, one or more unit doses of 10-1074-LS are 850 mg, and one or more unit doses of 3BNC117-LS are 1700 mg.In some embodiments, one or more unit doses of 10-1074-LS are 850 mg, and one or more unit doses of 3BNC117-LS are 2550 mg. In some embodiments, 10-1074-LS and 3BNC117-LS are formulated for intravenous administration. In some embodiments, one or more unit doses are contained in one or more containers. In some embodiments, one or more containers are selected from vials, ampoules, and pre-filled syringes. In some embodiments, the kit further comprises one or more long-acting HIV drugs in one or more unit doses. In some embodiments, one or more long-acting HIV drugs in one or more unit doses are selected from long-acting capsid inhibitors, long-acting integrase chain transfer inhibitors (INSTIs), long-acting non-nucleoside reverse transcriptase inhibitors (NNRTIs), long-acting nucleoside reverse transcriptase inhibitors (NRTIs), and long-acting protease inhibitors (PIs). In some embodiments, the long-acting capsid inhibitor is selected from lenacapavir, VH4004280, and VH4011499. In some embodiments, the long-acting capsid inhibitor includes lenacapavir. In some embodiments, the unit dose of lenacapavir is in the range of 300 mg to 1000 mg. In some embodiments, lenacapavir is formulated for oral or subcutaneous administration. In some embodiments, the long-acting INSTI is selected from bictegravir, raltegravir, elvitegravir, dolutegravir, cabotegravir, GS-1720, GS-6212, GS-1219, GS-3242, and VH4524184. In some embodiments, the long-acting NNRTI is selected from rilpivirine, elsulfavirine, doravirine, and GS-5894. In some embodiments, the long-acting NRTI is selected from islatravir and its prodrugs, tenofovir alafenamide (TAF) and tenofovir prodrugs, lovahovir etalafenamide, and GS-1614. In some embodiments, the long-acting protease inhibitor is selected from atazanavir, ritonavir, darunavir, GS-1156 and GS-1156 prodrugs, and combinations thereof.

Brief Description of the Drawings

[0010] [Figure 1A] Figure 1A shows the study scheme of the Phase 1b trial GS-US-536-5816 (NCT04811040 on ClinicalTrials.gov). Figure 1B shows the participant allocation. All randomized participants were included in the safety analysis (N = 21), and participants who received the complete study regimen (oral LEN, SC LEN, and bNAb) were included in the efficacy analysis (N = 20). Figure 1C shows the virological efficacy outcomes at week 26 of the Phase 1b trial by the FDA snapshot algorithm. Eighteen out of 20 participants maintained viral suppression with the study regimen until week 26. One participant withdrew at week 12 with HIV-1 RNA < 50 copies / mL. One participant had a virological rebound confirmed at week 16 and was re-suppressed with baseline oral ART. [Figure 1B] Figure 1A shows the study scheme of the Phase 1b trial GS-US-536-5816 (NCT04811040 on ClinicalTrials.gov). Figure 1B shows the participant allocation. All randomized participants were included in the safety analysis (N = 21), and participants who received the complete study regimen (oral LEN, SC LEN, and bNAb) were included in the efficacy analysis (N = 20). Figure 1C shows the virological efficacy outcomes at week 26 of the Phase 1b trial by the FDA snapshot algorithm. Eighteen out of 20 participants maintained viral suppression with the study regimen until week 26. One participant withdrew at week 12 with HIV-1 RNA < 50 copies / mL. One participant had a virological rebound confirmed at week 16 and was re-suppressed with baseline oral ART. [Figure 1C]Figure 1A shows the study scheme of the Phase 1b trial GS-US-536-5816 (NCT04811040 on ClinicalTrials.gov). Figure 1B shows the participant allocation. All randomized participants were included in the safety analysis (N = 21), and participants who received the full study regimen (oral LEN, SC LEN, and bNAb) were included in the efficacy analysis (N = 20). Figure 1C shows the virological efficacy outcomes at week 26 of the Phase 1b trial by the FDA snapshot algorithm. 18 out of 20 participants maintained viral suppression with the study regimen until week 26. One participant withdrew at week 12 with HIV-1 RNA < 50 copies / mL. One participant had a virological rebound confirmed at week 16 and was re-suppressed with baseline oral ART.

[0011] [Figure 2] Shows the pharmacokinetics of teropavimab (TAB), zinlirvimab (ZAB), and lenacapavir (LEN) in the Phase 1b trial.

[0012] [Figure 3A] Simulated Cmax (Figures A and B) and Cmin (Figures C and D) 26 weeks after IV administration of 30 mg / kg or 2550 mg of GS-5423 every 6 months (Figures A and C) and 10 mg / kg, 30 mg / kg, 850 mg, or 2550 mg of GS-2872 every 6 months (Figures B and D) are shown. Box: interquartile range, horizontal line: median, whiskers: 1.5 times the interquartile range, not exceeding the minimum and maximum values, dots: outliers. [Figure 3B] Simulated Cmax (Figures A and B) and Cmin (Figures C and D) 26 weeks after IV administration of 30 mg / kg or 2550 mg of GS-5423 every 6 months (Figures A and C) and 10 mg / kg, 30 mg / kg, 850 mg, or 2550 mg of GS-2872 every 6 months (Figures B and D) are shown. Box: interquartile range, horizontal line: median, whiskers: 1.5 times the interquartile range, not exceeding the minimum and maximum values, dots: outliers. [Figure 3C]Figures A and C show the simulated C-maximum (Figures A and B) and C-minimum (Figures C and D) after 26 weeks of IV administration of GS-5423 at 30 mg / kg or 2550 mg every 6 months and GS-2872 at 10 mg / kg, 30 mg / kg, 850 mg, or 2550 mg every 6 months. Box: Interquartile range, horizontal line: median, whiskers: 1.5 times the interquartile range, not exceeding the minimum and maximum values, dots: outliers. [Figure 3D] Figures A and C show the simulated C-maximum (Figures A and B) and C-minimum (Figures C and D) after 26 weeks of IV administration of GS-5423 at 30 mg / kg or 2550 mg every 6 months and GS-2872 at 10 mg / kg, 30 mg / kg, 850 mg, or 2550 mg every 6 months. Box: Interquartile range, horizontal line: median, whiskers: 1.5 times the interquartile range, not exceeding the minimum and maximum values, dots: outliers.

[0013] [Figure 4A] The simulated median (line) and 5th to 95th percentile (shaded area) concentration-time profiles for GS-5423 (telopavimab) (Figure 3A) and GS-2872 (dinrilvimab) (Figure 3B) at different doses administered every 6 months are shown. [Figure 4B] The simulated median (line) and 5th to 95th percentile (shaded area) concentration-time profiles for GS-5423 (telopavimab) (Figure 3A) and GS-2872 (dinrilvimab) (Figure 3B) at different doses administered every 6 months are shown.

[0014] [Figure 5]A schematic diagram of a PK-PD viral dynamics model for evaluating the prediction of concentrations and washout periods for GS-5423 (3BNC117-LS, telopavimab, TAB) and GS-2872 (10-1074-LS, dinriluvimab, ZAB) is shown. C1 and C2, serum concentrations of 3BNC117 / TAB and 10-1074 / ZAB, respectively; EC50, drug 1 and EC50, drug 2, concentrations that yield the 50% maximum effect of 3BNC117 / TAB and 10-1074 / ZAB, respectively; fi, initial fraction of the i-th viral compartment; kg, maximum viral replication rate constant; kdel, drug 1 and kdel, drug 2, viral elimination rate constants for 3BNC117 / TAB and 10-1074 / ZAB, respectively; rd, i, viral elimination rate for the i-th viral compartment; rg, i, replication rate for the i-th viral compartment VL1, TAB, telopavimab; VL1, copy of the virus susceptible to both 3BNC117 / TAB and 10-1074 / ZAB; VL2, copy of the virus susceptible to 3BNC117 / TAB and copy of the virus resistant to 10-1074 / ZAB; VL3, copy of the virus susceptible to 10-1074 / ZAB and copy of the virus resistant to 3BNC117 / TAB; VL4, copy of the virus resistant to both 3BNC117 / TAB and 10-1074 / ZAB (assumed to be 0); VL total, total viral load; VLss, steady-state viral load; ZAB, dinrilvimab.

[0015] [Figure 6] This shows observed bNAb serum concentrations versus predicted bNAb serum concentrations from the PK model. bNAb, broad-spectrum neutralizing antibody; PK, pharmacokinetics; TAB, telopavimab; ZAB, dinrilvimab. Circles represent individual data points. Solid lines represent LOESS (locally estimated scatter plot smoothing) fit. Dashed lines represent identity lines.

[0016] [Figure 7]This shows the model-predicted PK profile after a single 30 mg / kg IV infusion. IV refers to intravenous administration, PWH, and individuals with HIV. A hypothetical population of 1000 individuals was simulated using population PK models from 3BNC117, 10-1074, TAB, and ZAB. Solid and dashed lines represent the model-predicted median for monotherapy and combination therapy, respectively, and shaded areas represent the 90% prediction interval for the population.

[0017] [Figure 8] This shows model-predicted versus observed viral dynamics after bNAb treatment in individuals with HIV-positive viremia. Q5th, 5th percentile; Q50th, 50th percentile; Q95th, 95th percentile. 100 trial simulations were performed on the same number of subjects as the original dataset used to model the fitting. Predicted quantiles were calculated from the median of quantiles across all trial replications. Arrows represent bNAb administration.

[0018] [Figure 9] This shows the model predicted time to viral rebound during ATI after bNAb treatment versus observed time. ATI, analytical treatment discontinuation; bNAb, broad-spectrum neutralizing antibody; CI, confidence interval. Dosage in the ATI trial: NCT02446847, 30 mg / kg of 3BNC117 administered twice every 3 weeks, or 30 mg / kg of 3BNC117 administered up to four times every 2 weeks; NCT02825797, 30 mg / kg of 3BNC117 and 30 mg / kg of 10-1074 administered up to three times every 3 weeks; NCT03526848, 30 mg / kg of 3BNC117 and 30 mg / kg of 10-1074 administered three times every 2 weeks, followed by up to four more doses every 4 weeks (Group 1, ATI started on day 2; Group 2, ATI started at week 26 [one participant started at week 21]). 100 trial simulations were performed on the same number of subjects as the original dataset used for model fitting. The solid blue line (shaded region) represents the median (2.5–97.5 percentile) across all trial repeats. The arrows represent bNAb administration. The red dotted line indicates the start of ATI.

[0019] [Figure 10] This graph shows model-predicted viral rebound kinetics after single-dose TAB / ZAB combination therapy at different ATI initiation times. PD and pharmacodynamics are also shown. The horizontal dotted line indicates the viral rebound threshold (200 cp / mL). A hypothetical population of 1000 individuals was simulated using a population PK-PD model. The solid line represents the model-predicted median, and the shaded area represents the 90% prediction interval for the population. Arrows indicate bNAb administration. The red dashed line indicates the initiation of ATI.

[0020] [Figure 11] This graph shows the simulated bNAb serum concentrations over time and their ratios to in vivo EC50 after single-dose IV administration of TAB 30 mg / kg and ZAB 10 mg / kg. EC50 is the concentration that yields 50% of the maximum drug effect. A hypothetical population of 1000 individuals was simulated using a population PK model. The solid line represents the median predicted by the model, and the shaded area represents the 90% prediction interval for the population. The ratios were calculated based on EC50 values ​​estimated from the PK-PD model (25.4 μg / mL for TAB and 32.2 μg / mL for ZAB). The black dashed line indicates the earliest proposed onset time of ATI.

[0021] [Figure 12] The trial scheme for Phase 2 trial GS-US-539-5939 is shown below. [Modes for carrying out the invention]

[0022] 1. Introduction Therefore, this method is partly based on the discovery that co-administration of a first broad-spectrum anti-HIV neutralizing antibody (bNAb) that binds to the gp120 epitope in a high-mannose patch containing a third variable loop (V3) and / or N332 oligomannose glycan, and a second bNAb that binds to the gp120 epitope containing a CD4 binding site (CD4bs) with an Fc amino acid substitution that prolongs the serum half-life, can be administered twice a year (e.g., Q6M, Q24W, Q25W, Q26W) and achieve therapeutic efficacy. To date, bNAbs have been administered every three months or more, even when they have an Fc amino acid substitution that prolongs the serum half-life.

[0023] In general, the method involves co-administering (i) an effective amount of a first antibody that competes with or contains the VH and VL regions that bind to the epitopes of gp120 in a high-mannose patch containing a third variable loop (V3) and / or N332 oligomannose glycan, and (ii) an effective amount of a second antibody that competes with or contains the VH and VL regions that bind to the epitopes of gp120 containing a CD4 binding site (CD4bs), wherein both the first and second antibodies contain Fc amino acid substitutions to extend the serum half-life; and then, at a second time point at least about 24 weeks after the first time point, for example, at least about 25 weeks, for example, at least about 26 weeks later, an effective amount of the first antibody and an effective amount of the second antibody are co-administered.

[0024] 3BNC117 and 10-1074 are modified to increase their half-life, resulting in GS 5423 (telopavimab, 3BNC117-LS) and GS-2872 (dinrilvimab, 10-1074-LS), enabling the maintenance of high bNAb concentrations over extended periods. Combination therapy consisting of long-acting bNAbs and ARV drugs can overcome the limitations of bNAbs alone and provide a safe, long-acting treatment option for PWH. The modified LS versions contain two amino acid substitutions in Fc: a methionine-to-leucine substitution at Fc position 428 (M428L) and an asparagine-to-serine substitution at Fc position 434 (N434S) (EU numbering). These substitutions enhance antibody binding affinity to the neonatal Fc receptor (FcRn), extending the bNAb half-life in vivo. Affinity binding to other Fc receptors remains unchanged. These modifications do not alter the fragment antigen-binding domain (Fab) of bNAb, and therefore do not alter their interaction with antigens or their safety profile.

[0025] 2. Broad-spectrum neutralizing antibodies administered as co-administration a. General broad-spectrum neutralizing antibodies HIV-1 is the main family of HIV, accounting for 95% of all infections worldwide. HIV-2 is mainly found in some West African countries.

[0026] HIV viruses are classified into specific groups: M, N, O, and P, of which M is the "major" group and accounts for the majority of HIV / AIDS cases worldwide. Based on their genetic sequences, the M group is further subdivided into subtypes (also called clades) based on their prevalence in different geographical locations.

[0027] Group M "subtypes" or "clades" are subtypes of HIV-1 group M defined by genetic sequence data. Examples of group M subtypes include subtypes A through K. Some of the subtypes are known to be more virulent or resistant to different drugs. There are also "circulating recombinations" or CRFs, which result from recombination between viruses of different subtypes, each of which is assigned a number. CRF12_BF is, for example, a recombination between subtypes B and F. Subtype A is common in West Africa. Subtype B is the dominant form in Europe, America, Japan, Thailand, and Australia. Subtype C is the dominant form in South Africa, East Africa, India, Nepal, and parts of China. Subtype D is generally found only in East and Central Africa. Subtype E has never been identified as a non-recombinant and has only been found recombined with subtype A as CRF01_AE. Subtype F is found in Central Africa, South America, and Eastern Europe. Subtype G (and CRF02_AG) is found in Africa and Central Europe. Subtype H is limited to Central Africa. Subtype I was originally used to describe the strain now described as CRF04_cpx, where cpx represents a "complex" recombination of several subtypes. Subtype J is found mainly in North Africa, Central Africa, and West Africa, and the Caribbean subtype K is limited to the Democratic Republic of Congo and Cameroon. These subtypes may be further divided into sub-subtypes such as A1 and A2, or F1 and F2. In 2015, subtype The CRF19 strain, a recombinant of subtypes A, D, and G possessing protease D, was found to be strongly associated with rapid progression to AIDS in Cuba.

[0028] This disclosure provides a method involving the administration of a human anti-HIV neutralizing antibody (e.g., broad-spectrum neutralizing antibody) that targets the gp120 polypeptide on the surface of HIV-infected cells. Neutralizing antibodies against viral envelope proteins provide adaptive immune protection against HIV-1 exposure by blocking infection of susceptible cells. Broad-spectrum neutralization indicates that the antibody can neutralize HIV-1 isolates from different clades. Therefore, the anti-HIV gp120 binding antibodies described herein have cross-clade binding activity.

[0029] In certain embodiments, the administered antibody is or is derived from a human neutralizing antibody (e.g., monoclonal) targeting HIV-1. The “neutralizing antibody” is capable of neutralizing the ability of HIV to initiate and / or sustain infection in host and / or target cells in vitro. This disclosure provides a neutralizing monoclonal human antibody in which the antibody recognizes an antigen from HIV, e.g., the gp120 polypeptide. In certain embodiments, the “neutralizing antibody” can inhibit the entry of the HIV-1 virus, e.g., SF162 and / or JR-CSF, with a neutralization index greater than 1.5 or greater than 2.0 (Kostrikis L. Get al., J. Virol., 70(1):445-458 (1996)).

[0030] In some embodiments, the administered antibody is or is derived from a human broad-spectrum neutralizing antibody (e.g., monoclonal) targeting HIV-1. “Broad-spectrum neutralizing antibody” means an antibody that neutralizes two or more HIV-1 virus species (from diverse clades and different strains within a clade) in a neutralization assay. A broad-spectrum neutralizing antibody may neutralize at least two, three, four, five, six, seven, eight, nine, or more different strains of HIV-1, where the strains belong to the same or different clades. In certain embodiments, a broad-spectrum neutralizing antibody may neutralize multiple HIV-1 species belonging to at least two, three, four, five, or six different clades. In certain embodiments, the inhibitory concentration of the anti-HIV gp120 V3-glycan-binding antibody or antigen-binding fragment may be less than approximately 0.0001 μg / ml, less than approximately 0.001 μg / ml, less than approximately 0.01 μg / ml, less than approximately 0.1 μg / ml, less than approximately 0.5 μg / ml, less than approximately 1.0 μg / ml, less than approximately 5 μg / ml, less than approximately 10 μg / ml, less than approximately 25 μg / ml, less than approximately 50 μg / ml, or less than approximately 100 μg / ml to neutralize approximately 50% of the ingested virus in the neutralization assay.

[0031] gp120 The envelope glycoprotein gp120 (or gp41) is a 120 kDa glycoprotein that is part of the outer layer of HIV. It presents itself as a viral membrane spike, consisting of three molecules of gp120 that bind together and are fixed to the membrane by the gp41 protein. Gp120 is essential for viral infection because it facilitates HIV entry into host cells through interaction with cell surface receptors. These receptors include DC-SIGN, heparan sulfate proteoglycan, and the CD4 receptor. Binding to CD4 on helper T cells induces the initiation of a cascade of higher-order structural changes in gp120 and gp41, which results in the fusion of the virus with the host cell membrane.

[0032] Gp120 is encoded by the HIVenv gene. The env gene encodes a gene product of approximately 850 amino acids. The primary env product is the protein gp160, which is cleaved in the endoplasmic reticulum by the cellular proteasephrin into gp120 (approximately 480 amino acids) and gp41 (approximately 345 amino acids).

[0033] Broad-spectrum neutralizing antibodies include, for example, Walsh and Seaman, Front Immunol. (2021) 12:712122; Julg and Barouch, Semin Immunol. (2021) 51:101475; Hsu, et al., Front Immunol. (2021) 12:710044; Karuna and Corey, Annu Rev Med. (2020) 71:329-346; Haynes, et al., Sci Transl Med. (2019) 11(516):eaaz2686; Dashti, et al., Trends Mol Med. (2019) 25(3):228-240; McCoy, Retrovirology (2018) 15:70; Sok and Burton, Nat Immunol. 2018 This is outlined in 19(11):1179-1188, Possas, et al., Expert Opin Ther Pat. 2018 Jul;28(7):551-560, and Stephenson and Barouch, Curr HIV / AIDS Rep (2016) 13:31-37, which are incorporated herein by reference in their entirety for all purposes.

[0034] b. Antibodies targeted to the V3 glycan region of HIV gp120 The V3 glycan site on gp120 is formed partly by a portion of the CCR5 coreceptor site and partly by surrounding camouflage glycans (the so-called "high mannose patch") (Sok, et al., Immunity (2016) 45, 31-45). Broad-spectrum neutralizing antibodies (bnAbs) against the V3 glycan site are the most common of all antibodies found in HIV infection (Walker, et al., PLoS Pathog. (2010) 6:e1001028 (2010), Landais, et al., PLoS Pathog. (2016) 12:e1005369, Georgiev, et al. Science (2013) 340:751-756). The consensus sequence of the V3 region of gp120 (Milich et al., J Virol., 67(9):5623-5634(1993) is provided below: CTRPNNNTRKSIHIGPGRAFYTTGEIIGDIRQAHC(Sequence ID 1).

[0035] The amino acid sequence of an exemplary gp160 polypeptide from the HIV clone WITO is provided below (the V3 hypervariable loop is shown in bold, and the possible N-linked glycosylation site at N332 is shown in bold and underlined). [ka]

[0036] The amino acid sequences of exemplary gp160 polypeptides of HIV clones identified in NCBI Ref Seq No. NP_057856.1 are provided below (the V3 hypervariable loop is shown in bold, and the possible N-linked glycosylation site at N332 is shown in bold and underlined). [ka]

[0037] The amino acid sequence of an exemplary gp120 polypeptide from an HXB2 subtype B HIV-1 isolate (corresponding to residues 1-511 of GenBank accession number K0345; NCBI Ref Seq No. NP_057856.1) is provided below (the V3 hypervariable loop is shown in bold, and the possible N-linked glycosylation site at N332 is shown in bold and underlined; the signal peptide is shown underlined). [ka]

[0038] The amino acid sequence of an example gp120 polypeptide is provided below: [ka]

[0039] The amino acids of another example gp120 polypeptide (see bioafrica.net / proteomics / ENV-GP120prot.html) are provided below. TEKLWVTVYY GVPVWKEATT TLFCASDAKA YDTEVHNVWA THACVPTDPN PQEVVLVNVT ENFNMWKNDM VEQMHEDIIS LWDQSLKPCV KLTPLCVSLK CTDLKNDTNT NSSSGRMIME KGEIKNCSFN ISTSIRGKVQ KEYAFFYKLD IIPIDNDTTS YKLTSCNTSV ITQACPKVSF EPIPIHYCAP AGFAILKCNN KTFNGTGPCT NVSTVQCTHG IRPVVSTQLL LNGSLAEEEV VIRSVNFTDN AKTIIVQLNT SVEINCTRPN NNTRKRIRIQ RGPGRAFVTI GKIGNMRQAH CNISRAKWNN TLKQIASKLR EQFGNNKTII FKQSSGGDPE IVTHSFNCGG EFFYCNSTQL FNSTWFNSTW STEGSNNTEG SDTITLPCRI KQIINMWQKV GKAMYAPPIS GQIRCSSNIT GLLLTRDGGN SNNESEIFRP GGGDMRDNWR SELYKYKVVK IEPLGVAPTK AKRRVVQREK R(Sequence ID 6)

[0040] Genomic diversity among independent human immunodeficiency virus type 1 (HIV-1) isolates is less pronounced among consecutive isolates from the same patient, and even within a single patient isolate, which is a well-known characteristic of HIV-1. While this sequence heterogeneity is distributed throughout the genome, the majority of it is located in the env gene. Comparison of putative amino acid sequences from several different isolates showed that the sequence heterogeneity clusters in five variable regions (designated V1-V5) of the surface glycoprotein gp120. The V3 region, despite being only 35 amino acids long, exhibits considerable sequence variability. Interestingly, despite this variability, the V3 region is associated with CD4 + It contains determinants that mediate interactions with cells. Increased gp120 variability leads to higher levels of viral replication, suggesting increased viral adaptability in individuals infected with diverse HIV-1 variants. Variability at potential N-linked glycosylation sites (PNGS) also contributes to increased viral adaptability. PNGS allow the binding of long-chain carbohydrates to the highly variable region of gp120. Therefore, the number of PNGS in the environment can influence viral adaptability by providing more or less sensitivity to neutralizing antibodies.

[0041] Examples of broad-spectrum neutralizing antibodies that bind to gp120 in a high-mannose patch containing a third variable loop (V3) and / or N332 oligomannose glycan and can be used in the methods described herein include, but are not limited to, GS-9722 (elipovimab), GS-9721, PGT-121, PGT-121.66, PGT-121.414, PGT-122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-128, PGT-130, PGT-133, PGT-1324, PGT-125, PGT-126, PGT-124 Includes GT-135, PGT-136, PGT-137, PGT-138, PGT-139, 10-1074, 10-1074-LS (zinliluvimab, GS-2872), 10-1074-J, VRC24, 2G12, BG18, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1 and VRC29.03. Further broad-spectrum neutralizing antibodies that bind to gp120 in a third variable loop (V3) containing N332 oligomannose glycan and / or in a high-mannose patch and can be used in the method described herein include, for example, International Publication Nos. 2012 / 030904; 2014 / 063059; 2016 / 149698; 2017 / 106346; 2018 / 075564; 2018 / 125813; 2018 / 237148; 2019 / 226829; 2020 / 023827; 2020 / 056145; and Kerwin, et al., J Pharm Sci. 2020. These are described in Jan;109(1):233-246, which are incorporated herein by reference in their entirety for all purposes.

[0042] Tables A1-A4 provide exemplary sequences of the complementarity determining region (CDR) of antibodies targeting the HIV gp120 V3 glycan region. Table B provides exemplary sequences of the VH and VL regions of antibodies targeting the HIV gp120 V3 glycan region. Table A1-1 Table A1-2 Table A1-3 Table A1-4 Table A2-1 Table A2-2 Table A2-3 Table A2-4 Table A3-1 Table A3-2 Table A3-3 Table A3-4 Table A4-1 Table A4-2 Table A4-3 Table A4-4 Table B-1 Table B-2 Table B-3 Table B-4 Table B-5

[0043] In some embodiments, the anti-HIV gp120 V3 glycan-conjugated antibody comprises VH, which includes VH-CDR1, VH-CDR2, and VH-CDR3; and VL, which includes VL-CDR1, VL-CDR2, and a second VH-CDR3, wherein VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 include the sequences described below: SEQ ID NOs: 7, 8, 9, 10, 11, and 12; SEQ ID NOs: 7, 13, 9, 10, 11, and 12; SEQ ID NOs: 14, 15, 16, 17, 11, and 18. , Sequence IDs 14, 19, 20, 17, 11 and 18, Sequence IDs 21, 22, 23, 24, 25 and 26, Sequence IDs 21, 22, 27, 24, 25 and 26, Sequence IDs 28, 29, 30, 31, 32 and 33, Sequence IDs 34, 35, 36, 37, 25 and 38, Sequence IDs 39, 40, 41, 42, 43 and 44, Sequence IDs 45, 46, 47, 48, 49 and 50, Sequence IDs 45, 51, 52, 53, 49 and 54, Sequence IDs 55, 56, 57, 58, 59 and 44, Sequence IDs Numbers 60, 46, 61, 58, 49 and 44, Sequence IDs 62, 63, 64, 65, 66 and 67, Sequence IDs 68, 69, 70, 71, 72 and 73, Sequence IDs 74, 75, 76, 77, 78 and 73, Sequence IDs 79, 80, 81, 82, 83 and 73, Sequence IDs 84, 85, 86, 87, 88 and 89, Sequence IDs 84, 90, 91, 92, 93 and 89, Sequence IDs 84, 85, 86, 95, 96 and 89, Sequence IDs 84, 97, 98, 99, 100, and 101, SEQ ID NOs. 84, 97, 98, 99, 100, and 102, SEQ ID NOs. 84, 97, 98, 103, 100, and 89, SEQ ID NOs. 84, 104, 91, 92, 93, and 89, SEQ ID NOs. 84, 97, 98, 99, 100, and 105, SEQ ID NOs. 106, 107, 108, 109, 110, and 111, SEQ ID NOs. 106, 112, 113, 109, 114, and 115 or SEQ ID NOs. 106, 116, 117, 109, 118, and 119 (CDR by Kabat).

[0044] In some embodiments, the anti-HIV gp120 V3 glycan-binding antibody comprises VH, which includes VH-CDR1, VH-CDR2, and VH-CDR3; and VL, which includes VL-CDR1, VL-CDR2, and a second VH-CDR3, wherein VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 include the sequences described below: SEQ ID NOs: 120, 121, 9, 10, 11, and 12; SEQ ID NOs: 122, 123, 16, 17, 11, and 18; SEQ ID NOs: 124, 125, 20, 17, 11, and 18, SEQ ID NOs: 126, 127, 23, 24, 25, and 26, SEQ ID NOs: 126, 127, 27, 24, 25, and 26, SEQ ID NOs: 128, 192, 30, 31, 32, and 33, SEQ ID NOs: 130, 131, 36, 37, 25, and 38, SEQ ID NOs: 132, 133, 41, 42, 43, and 44, SEQ ID NOs: 134, 135, 47, 48, 49, and 50, SEQ ID NOs: 134, 136, 52, 53, 49, and 54, SEQ ID NOs: 137, 56, 57, 58, 59, and 44, SEQ ID NOs: 138, 135 , 61, 58, 49, and 44, SEQ ID NOs: 139, 140, 64, 65, 66, and 67, SEQ ID NOs: 141, 142, 70, 71, 72, and 71, SEQ ID NOs: 143, 144, 76, 77, 78, and 73, SEQ ID NOs: 145, 144, 81, 82, 83, and 73, SEQ ID NOs: 146, 147, 86, 87, 88, and 89, SEQ ID NOs: 148, 147, 86, 87, 88, and 89, SEQ ID NOs: 149, 150, 91, 92, 93, and 89, SEQ ID NOs: 148, 147, 86, 95, 96, and 8 9, SEQ ID NOs: 149, 151, 98, 99, 100, and 101; SEQ ID NOs: 149, 151, 98, 99, 100, and 102; SEQ ID NOs: 149, 151, 98, 103, 100, and 89; SEQ ID NOs: 149, 151, 98, 99, 100, and 105; SEQ ID NOs: 152, 153, 108, 109, 110, and 111; SEQ ID NOs: 154, 155, 113, 109, 114, and 115; or SEQ ID NOs: 154, 156, 117, 109, 118, and 119 (CDR by Chothia).

[0045] In some embodiments, the anti-HIV gp120 V3 glycan-binding antibody comprises VH, which includes VH-CDR1, VH-CDR2, and VH-CDR3, and VL, which includes VL-CDR1, VL-CDR2, and a second VH-CDR3, wherein VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 include the sequences described below: SEQ ID NOs: 157, 158, 159, 160, 161, and 12; SEQ ID NOs: 162, 163, 164, 165, 161, and 18; SEQ ID NOs: 162, 163, 166, 165, 161, and 18; SEQ ID NOs: 167, 16 8, 169, 165, 161, and 18; SEQ ID NOs: 170, 171, 172, 173, 161, and 26; SEQ ID NOs: 170, 171, 174, 173, 161, and 26; SEQ ID NOs: 175, 176, 177, 178, 161, and 38; SEQ ID NOs: 179, 180, 181, 182, 183, and 33; SEQ ID NOs: 184, 185, 186, 187, 188, and 44; SEQ ID NOs: 189, 190, 191, 192, 193, and 50; SEQ ID NOs: 189, 194, 195, 196, 193, and 54; SEQ ID NOs: 197, 198, 199, 200, and 20 1, and 44, Sequence IDs 202, 203, 204, 200, 193, and 44, Sequence IDs 205, 206, 207, 208, 209, and 67, Sequence IDs 210, 211, 212, 213, 214, and 73, Sequence IDs 215, 216, 217, 218, 219, and 73, Sequence IDs 220, 216, 221, 222, 223, and 73, Sequence IDs 224, 225, 86, 226, 227, and 89, Sequence IDs 228, 225, 86, 226, 227, and 89, Sequence IDs 229, 230, 91, 231, 232, and 89, Sequence ID 229, 233, 91, 231, 232 and 89, Sequence IDs 228, 225, 86, 234, 235 and 89, Sequence IDs 229, 236, 98, 231, 232 and 101, Sequence IDs 229, 236, 98, 231, 232 and 102, Sequence IDs 229, 236, 98, 237, 232 and 89, Sequence IDs 229, 238, 91, 231, 232 and 89, Sequence IDs 229, 236, 98, 231, 232 and 105, Sequence IDs 239, 240, 108, 241, 242 and 111, Sequence IDs 243, 244, 113, 241, 245,and 115, or sequence numbers 243, 246, 117, 241, 242, and 119 (CDR by IMGT).

[0046] In some embodiments, the anti-HIV gp120 V3 glycan-conjugated antibody comprises VH, which includes VH-CDR1, VH-CDR2, and VH-CDR3, and VL, which includes VL-CDR1, VL-CDR2, and a second VH-CDR3, wherein VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 include the sequences described below: SEQ ID NOs: 247, 248, 249, 250, 251, and 252, SEQ ID NOs: 247, 253, 249, 250, 251, and 252, SEQ ID NOs: 254, 255, 256, 257, 251, and 258, SEQ ID NOs: 259, 260, 261, 257, 251, and 258, Sequence IDs 262, 263, 264, 265, 266, and 267, Sequence IDs 262, 263, 268, 265, 266, and 267, Sequence IDs 269, 270, 271, 272, 273, and 274, Sequence IDs 275, 276, 277, 278, 279, and 280, Sequence IDs 281, 282, 283, 284, 285, and 286, Sequence IDs 287, 288, 289, 290, 291, and 286, Sequence IDs 287, 292, 293, 294, 291, and 295, Sequence IDs 296, 297, 2 98, 299, 300, and 286, Sequence IDs 301, 288, 302, 299, 291, and 286, Sequence IDs 303, 304, 305, 306, 307, and 308, Sequence IDs 309, 310, 311, 312, 313, and 314, Sequence IDs 315, 316, 317, 318, 319, and 314, Sequence IDs 320, 321, 322, 323, 324, and 314, Sequence IDs 325, 326, 327, 328, 329, and 330, Sequence IDs 331, 326, 327, 328, 329, and 330, Sequence IDs 332, 333, 334, 3 35, 336, and 330, Sequence IDs 332, 337, 334, 335, 336, and 330, Sequence IDs 331, 326, 327, 338, 339, and 330, Sequence IDs 340, 341, 342, 335, 343, and 344, Sequence IDs 340, 341, 342, 335, 345, 346, Sequence IDs 340, 341, 342, 347, 348, and 330, Sequence IDs 332, 349, 334, 335, 336, and 330, Sequence IDs 340, 341, 342, 335, 345, and 350, Sequence IDs 351, 352, 353, 354, 355,and 356, as well as sequence numbers 357, 358, 359, 354, 360, and 361, or sequence numbers 357, 362, 363, 354, 364, and 356 (CDR by Honegger).

[0047] Exemplary embodiments of CDR sequences of anti-HIV gp120 V3 glycan-binding antibodies useful in the methods described herein are provided in Tables A1 to A4.

[0048] In some embodiments, the anti-HIV gp120 V3 glycan-binding antibody comprises VH and VL, which include amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the described amino acid sequence, respectively, as selected from the following SEQ ID NOs. Sequence IDs 365 and 366, 367 and 368, 369 and 370, 371 and 372, 373 and 374, 375 and 376, 377 and 378, 379 and 380, 381 and 382, ​​383 and 384, 385 and 386, 387 and 388, 389 and 390, 391 and 392, 393 and 394, 395 and 396, 397 and 398, Sequence numbers 399 and 400, SEQ ID NOs. 401 and 402, SEQ ID NOs. 403 and 404, SEQ ID NOs. 405 and 406, SEQ ID NOs. 407 and 408, SEQ ID NOs. 409 and 410, SEQ ID NOs. 411 and 412, SEQ ID NOs. 413 and 414, SEQ ID NOs. 415 and 416, SEQ ID NOs. 417 and 418, SEQ ID NOs. 419 and 420, SEQ ID NOs. 421 and 422, SEQ ID NOs. 423 and 424, SEQ ID NOs. 425 and 426, SEQ ID NOs. 427 and 428, SEQ ID NOs. 429 and 430, or SEQ ID NOs. 431 and 432. Exemplary embodiments of variable domain VH and VL sequences of anti-HIV gp120 V3 glycan-binding antibodies useful in the methods described herein are provided in Table B.

[0049] In some embodiments, the anti-HIV gp120 V3 glycan-binding antibody is 10-1074-LS. The heavy and light chain amino acid sequences of 10-1074-LS are provided below as SEQ ID NOs. 433 and 434. Heavy chain QVQLQESGPGLVKPSETLSVTCSVSGDSMNNYYWTWIRQSPGKGLEWIGYISDRESATYNPSLNSRVVISRDTSKNQLSLKLNSVTPADTAVYYCATARRGQRIYGVVSFGEFFYYY SMDVWGKGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG (Sequence ID 433) Light chain SYVRPLSVALGETARISCGRQALGSRAVQWYQHRPGQAPILLIYNNQDRPSGIPERFSGTPDINFGTRATLTISGVEAGDEADYYCHMWDSRSGFSWSFGGATRLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS(Sequence ID 434)

[0050] c. Antibodies targeted to the CD4bs region of HIV gp120 The CD4 binding site (CD4bs) includes structurally conserved sites located within β1-α1, loop D, β20-β21 (crosslinking sheet), and β24-α5 of gp120, which determine CD4 binding and are involved in the epitope of CD4bs-binding antibodies (Qiao, et al., Antiviral Res. 2016 Aug;132:252-61). The CD4bs of gp120 form a higher-order structural epitope that is recognized by anti-CD4bs antibodies with one or more amino acid residues selected from Thr278, Asp279, Ala281, Thr283, Asp368, Trp427, Glu460, Ser461, Glu462, Leu452, Leu453, and Arg476. The amino acid residues and positional numbering are based on the HXB2 subtype B HIV-1 isolate corresponding to residues 1-511 of NCBI sequence number NP_057856.1 provided below. Residues that may contribute to gp120 CD4bs are shown in bold and underlined: Thr278, Asp279, Asn280, Ala281, Thr283, Asp368, Trp427, Leu452, Leu453, Gly459, Glu464, Ser465, Glu466, Ile467, Gly472, Gly473, and Arg476. [ka]

[0051] Three-dimensional models showing the amino acid residues contributing to gp120 CD4bs can be found, for example, in Canducci, et al., Retrovirology. 2009 Jan 15;6:4, Falkowska, et al., J Virol. 2012 Apr;86(8):4394-403, and Li, et al., J. Virol. 2012 Oct;86(20):11231-41, Gristick, et al., Nat Struct Mol Biol. 2016 Oct;23(10):906-915, Kwon, et al., Nat Struct Mol Biol. 2015 Jul;22(7):522-31, Liu, et al., Nat Struct Mol Biol. 2017 Apr;24(4):370-378, and Chen, et al., Science. 2009 Nov. Provided in 20;326(5956):1123-7 and Lyumkis, et al., Science. 2013 Dec 20;342(6165):1484-90. In some embodiments, the antibody variants described herein compete with the anti-CD4bs antibodies GS-9723, GS-5423, b12, CH103, 1NC9, 12A12, VRC01, VRC07-523, N6, 3BNC117, NIH45-46 and / or PGV04 (VRC-PG04) for binding to gp120CD4bs. In some embodiments, the antibody variants described herein overlap with or bind to the same epitopes as the anti-CD4bs antibodies GS-9723, GS-5423 (telopavimab), b12, CH103, 1NC9, 12A12, VRC01, VRC07-523, N6, 3BNC117, NIH45-46 and / or PGV04 (VRC-PG04).

[0052] Gp120 is encoded by the HIVenv gene. The env gene encodes a gene product of approximately 850 amino acids. The primary env product is the protein gp160, which is cleaved in the endoplasmic reticulum by the cellular proteasephrin into gp120 (approximately 480 amino acids) and gp41 (approximately 345 amino acids).

[0053] The following provides the amino acid sequence of an exemplary gp160 polypeptide of the HIV clone identified by NCBI reference sequence number NP_057856.1 (CD4bs is shown in bold and underlined): [ka]

[0054] The amino acid sequence of an exemplary gp120 polypeptide from an HXB2 subtype B HIV-1 isolate (corresponding to residues 1-511 of GenBank accession number K0345; NCBI reference sequence number NP_057856.1) is provided below (CD4bs is shown in bold and underlined). [ka]

[0055] The amino acid sequence of an example gp120 polypeptide is provided below: [ka]

[0056] The amino acids of another example gp120 polypeptide (see bioafrica.net / proteomics / ENV-GP120prot.html) are provided below. [ka]

[0057] In certain embodiments of the methods described herein, a subject is administered an antibody that binds to the HIV gp120 protein within the CD4bs region, for example, to an epitope or region of the gp120 CD4 binding site. In certain embodiments, the administered antibody binds to the HIV-1 antigen expressed on the cell surface, eliminating or killing the infected cell.

[0058] Examples of broad-spectrum neutralizing antibodies that bind to gp120 in CD4bs and can be used in the methods described herein include, but are not limited to, antibodies selected from the group consisting of 3BNC117, GS-9723, GS-5423, 3BNC60, b12, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b01, VRC08, VRC0801, NIH45-46, PGV04 (VRC-PG04); CH103, 44-VRC13.01, 1NC9, 12A12, N6, 1-18, N49-P7, NC-Cow1, IOMA, CH235 and CH235.12, N49P6, N49P7, N49P11, N49P9, and N60P25.

[0059] Tables C1-C4 provide exemplary sequences of complementarity-determining regions (CDRs) of antibodies targeting the HIV gp120CD4bs region, which are useful in the methods described herein. Table D provides exemplary sequences of VH and VL of antibodies targeting the HIV gp120CD4bs region, which are useful in the methods described herein. [Table C1] [Table C2] [Table C3] [Table C4] [Table D-1] [Table D-2]

[0060] In some embodiments, the anti-HIV gp120 CD4bs-conjugated antibody comprises VH, which includes VH-CDR1, VH-CDR2, and VH-CDR3, and VL, which includes VL-CDR1, VL-CDR2, and a second VH-CDR3, wherein VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 include the sequences described below: SEQ ID NOs: 442, 443, 444, 445, 446, and 447, SEQ ID NOs: 448, 443, 449, 445, 447 46 and 447, Sequence IDs 450, 451, 452, 453, 454 and 455, Sequence IDs 450, 456, 452, 453, 454, 455, Sequence IDs 457, 458, 459, 453, 454 and 455, Sequence IDs 460, 461, 462, 463, 464 and 465, Sequence IDs 466, 467, 468, 469, 470 and 471, or Sequence IDs 472, 473, 474, 475, 476 and 477 (CDR by Kabat).

[0061] In some embodiments, the anti-HIV gp120 CD4bs-conjugated antibody comprises VH, which includes VH-CDR1, VH-CDR2, and VH-CDR3, and VL, which includes VL-CDR1, VL-CDR2, and a second VH-CDR3, wherein VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 include the sequences described below: SEQ ID NOs: 478, 479, 480, 481, 482, and 483; SEQ ID NOs: 484, 479, 485, 481, 48 2 and 483, SEQ ID NOs: 486, 487, 488, 489, 490 and 483, SEQ ID NOs: 486, 491, 488, 489, 490 and 483, SEQ ID NOs: 492, 487, 493, 489, 490 and 483, SEQ ID NOs: 494, 495, 496, 497, 498 and 499, SEQ ID NOs: 500, 501, 502, 503, 504 and 505, or SEQ ID NOs: 506, 507, 508, 509, 510 and 511 (CDR by Chothia).

[0062] In some embodiments, the anti-HIV gp120 CD4bs-conjugated antibody comprises VH, which includes VH-CDR1, VH-CDR2, and VH-CDR3, and VL, which includes VL-CDR1, VL-CDR2, and a second VH-CDR3, wherein VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 include the sequences described below: SEQ ID NOs: 512, 513, 514, 481, 482, and 447; SEQ ID NOs: 515, 513, 516, 481, 48 2 and 447, Sequence IDs 517, 518, 519, 520, 490 and 455, Sequence IDs 517, 522, 519, 520, 521 and 455, Sequence IDs 522, 523, 524, 520, 490 and 455, Sequence IDs 525, 526, 527, 528, 498 and 465, Sequence IDs 529, 530, 531, 532, 504 and 471, or Sequence IDs 533, 534, 535, 536, 510 and 477 (CDR by IMGT).

[0063] In some embodiments, the anti-HIV gp120 CD4bs-conjugated antibody comprises VH, which includes VH-CDR1, VH-CDR2, and VH-CDR3, and VL, which includes VL-CDR1, VL-CDR2, and a second VH-CDR3, wherein VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 include the sequences described below: SEQ ID NOs. 538, 539, 540, 541, 542, and 483, SEQ ID NOs. 543, 539, 544, 541, 545 and 483, Sequence IDs 546, 547, 548, 549, 550 and 483, Sequence IDs 546, 551, 548, 549, 550 and 483, Sequence IDs 555, 556, 557, 558, 559 and 499, Sequence IDs 560, 561, 562, 563, 564 and 505, Sequence IDs 566, 567, 568, 569, 569 and 511 (CDR by Honegger).

[0064] In some embodiments, the anti-HIV gp120 CD4bs-conjugated antibody comprises VH and VL, each containing an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the described amino acid sequence, such as SEQ ID NOs. 571 and 572, SEQ ID NOs. 573 and 574, SEQ ID NOs. 575 and 576, SEQ ID NOs. 577 and 578, SEQ ID NOs. 579 and 580, SEQ ID NOs. 581 and 582, SEQ ID NOs. 583 and 584, SEQ ID NOs. 585 and 586, 587 and 588.

[0065] In some embodiments, the anti-HIV gp120 CD4bs-conjugated antibody is 3BNC117-LS. The heavy and light chain amino acid sequences of 3BNC117-LS are provided below as SEQ ID NOs. 589 and 590. Heavy chain QVQLLQSGAAVTKPGASVRVSCEASGYNIRDYFIHWWRQAPGQGLQWVGWINPKTGQPNNPRQFQGRVSLTRHASWDFDTFSFYMDLKALRSDDTAVYFCARQRSDYWDDFDVWGS GTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG (Sequence ID 589) Light chain DIQMTQSPSSLSASVGDTVTITCQANGYLNWYQQRRGKAPKLLIYDGSKLERGVPSRFSGRRWGQEYNLTINNLQPEDIATYFCQVYEFVVPGTRLDLKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 590)

[0066] d. Fc amino acid substitutions that increase serum half-life In some embodiments, the Fc region or Fc domain of the anti-HIV gp120 bNAb includes amino acid modifications that promote an increase in the serum half-life of the antibinding molecule. Amino acid substitutions that increase the half-life of the antibody have been described. In one embodiment, one or both of the Fc regions or Fc domains of the heavy chain include a methionine-to-tyrosine substitution at position 252 (EU numbering), a serine-to-threonine substitution at position 254 (EU numbering), and a threonine-to-glutamic acid substitution at position 256 (EU numbering). See, for example, U.S. Patent No. 7,658,921. This type of variant, named "YTE," exhibits a four-fold increased half-life compared to the wild-type version of the same antibody (Dall'Acqua et al. J Biol Chem, 281:23514-24 (2006); Robbie et al. Antimicrob Agents Chemotherap., 57(12):6147-6153 (2013)). In certain embodiments, the Fc region or Fc domain of one or both heavy chains contains an IgG constant domain with one, two, or three or more amino acid substitutions among the amino acid residues at positions 251-257, 285-290, 308-314, 385-389, and 428-436 (EU numbering). Alternatively, M428L and N434S ("LS") amino acid substitutions can increase the pharmacokinetic half-life of the multispecific antigen-binding molecule. In other embodiments, the Fc region or Fc domain of one or both heavy chains includes the M428L and N434S substitution (EU numbering). In other embodiments, the Fc region or Fc domain of one or both heavy chains includes the T250Q and M428L (EU numbering) amino acid substitution, as described, for example, in U.S. Patent Nos. 7,217,797 and 7,217,798. In other embodiments, the Fc region or Fc domain of one or both heavy chains includes the H433K and N434F (EU numbering) amino acid substitution, as described, for example, in U.S. Patent No. 8,163,881.In other embodiments, the Fc region or Fc domain of one or both heavy chains includes, for example, the T307Q / Q311V / A378V(DF215) or T256D / N286D / T307R / Q311V / A378V(DF228)(EU numbering) amino acid substitution, as described in U.S. Patent Publication No. 2020-0277358. In some embodiments, the Fc region or Fc domain of one or both heavy chains includes aspartic acid at position 309, histidine at position 311, and serine (DHS) at position 434, as described in U.S. Patent No. 11059892.

[0067] 3. Scheduling regimen In general, the method involves treating or prophylactically treating HIV in human subjects requiring it by co-administering twice a year an effective amount of bNAb bound to a high-mannose patch containing the gp120 epitope and / or N332 oligomannose glycan within a third variable loop (V3), and an effective amount of bNAb bound to the gp120 epitope containing a CD4 binding site (CD4bs), both bNAbs having Fc amino acid substitutions to extend their serum half-lives. In various embodiments, the frequency of co-administration may be once every 6 months (i.e., Q6M), once every 24 weeks (i.e., Q24W), once every 25 weeks (i.e., Q25W), or once every 26 weeks (i.e., Q26W).

[0068] "Subject," "individual," or "patient" refers to any mammal, including humans and non-human primates. In some embodiments, the mammal is a human.

[0069] "Effective dose" or "therapeutic effective dose" refers to the amount of antibody sufficient to treat or produce a beneficial result in cells, tissues, or subjects when administered alone or in combination with another therapeutic agent. The amount constituting the "effective dose" varies depending on the antibody and its specific use, as well as the condition and severity of the subject being treated, the mode of administration, and age, but can be routinely determined by those skilled in the art, taking into account their knowledge and this disclosure. The therapeutic effective dose further refers to the amount of antibody sufficient to treat, prevent or improve an infectious or disease condition, or the progression of an infectious or disease, and sufficient to increase the rate of treatment, cure, prevention, or improvement of such condition. When applied to an individual antibody administered alone, the therapeutic effective dose refers to the active ingredient alone. When applied to a combination, the therapeutic effective dose refers to the combined amount of active ingredients that produce a therapeutic effect, whether administered in combination, sequentially, or simultaneously. In some embodiments, the therapeutically effective dose allows for an effective blood or serum concentration of the antibody at the time of the second or subsequent administration (for example, 6 months, 24 weeks, 25 weeks, or 26 weeks after the first or previous administration).

[0070] In certain embodiments, the anti-HIV gp120 V3 glycan-binding antibody and the anti-HIV gp120 CD4bs-binding antibody described herein are administered intravenously in therapeutically effective doses ranging from about 500 mg to about 3000 mg, for example, about 550 mg to about 2900 mg, for example, about 600 mg to about 2800 mg, for example, about 650 mg to about 2700 mg, for example, about 700 mg to about 2600 mg, for example, about 850 mg to about 2550 mg, respectively. In some embodiments, the anti-HIV gp120 V3 glycan-binding antibody (e.g., 10-1074-LS) is administered intravenously at a dose of 850 mg. In some embodiments, the anti-HIV gp120 V3 glycan-binding antibody (e.g., 10-1074-LS) is administered intravenously at a dose of 2550 mg. In some embodiments, the anti-HIV gp120 CD4bs-conjugated antibody (e.g., 3BNC117-LS) is administered intravenously at a dose of 1700 mg. In some embodiments, the anti-HIV gp120 CD4bs-conjugated antibody (e.g., 3BNC117-LS) is administered intravenously at a dose of 2550 mg. In some embodiments, the anti-HIV gp120 V3 glycan-conjugated antibody (e.g., 10-1074-LS) is administered intravenously at a dose of 2550 mg, and the anti-HIV gp120 CD4bs-conjugated antibody (e.g., 3BNC117-LS) is administered intravenously at a dose of 2550 mg. In some embodiments, the anti-HIV gp120 V3 glycan-conjugated antibody (e.g., 10-1074-LS) is administered intravenously at a dose of 850 mg, and the anti-HIV gp120 CD4bs-conjugated antibody (e.g., 3BNC117-LS) is administered intravenously at a dose of 2550 mg. In some embodiments, the anti-HIV gp120 V3 glycan-conjugated antibody (e.g., 10-1074-LS) is administered intravenously at a dose of 850 mg, and the anti-HIV gp120 CD4bs-conjugated antibody (e.g., 3BNC117-LS) is administered at a dose of 1700 mg. In some embodiments, the anti-HIV gp120 V3 glycan-conjugated antibody (e.g., 10-1074-LS) is administered intravenously at a dose of 850 mg, and the anti-HIV The gp120 CD4bs-conjugated antibody (e.g., 3BNC117-LS) is administered at a dose of 1275 mg. In some embodiments, the anti-HIV gp120 V3 glycan-conjugated antibody (e.g., 10-1074-LS) is administered intravenously at a dose of 10 mg / kg, and the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody (e.g., 3BNC117-LS) are administered intravenously at a dose of 30 mg / kg.

[0071] As used herein, “to treat,” “to treat,” or “treatment” encompasses treatment of the disease, injury, or condition of interest (e.g., HIV-1 infection in a subject (e.g., a mammal such as a human having the disease or condition of interest)) and includes: (i) inhibiting the progression of the disease, injury, or condition, i.e., stopping its onset; (ii) reducing or alleviating the disease, injury, or condition, i.e., causing a regression of the disease or condition; or (iii) alleviating the symptoms resulting from the disease, injury, or condition. As used herein, the terms “disease,” “disorder,” and “condition” may be used interchangeably. As used herein, “inhibition,” “treatment,” “to treat,” and “remission” may be used interchangeably and refer to, for example, cessation of symptoms, extension of survival, partial or complete improvement of symptoms, and partial or complete eradication of the condition, disease, or disorder.

[0072] As used herein, “prevent” or “prevent” includes (i) preventing or inhibiting the occurrence of a disease, injury or condition in an object, in particular, if such object is susceptible to the condition but has not yet been diagnosed with the condition; or (ii) reducing the likelihood of a disease, injury or condition occurring in an object.

[0073] Co-administration includes co-administration of the anti-HIV gp120 V3 glycan-conjugated antibody and the anti-HIV gp120 CD4bs-conjugated antibody as described herein, as well as administration of a unit dose. For example, the anti-HIV gp120 V3 glycan-conjugated antibody and the anti-HIV The gp120 CD4bs-conjugated antibody may be administered simultaneously or within seconds, minutes, hours, or days of each other's administration. In some embodiments, the unit doses of the anti-HIV gp120 V3 glycan-conjugated antibody and the anti-HIV gp120 CD4bs-conjugated antibody disclosed herein are administered within a few hours of each other (e.g., within 1-12 hours, 1-24 hours, 1-36 hours, 1-48 hours, 1-60 hours, 1-72 hours).

[0074] In certain embodiments, the anti-HIV gp120 V3 glycan-conjugated antibody and the anti-HIV gp120 CD4bs-conjugated antibody described herein are combined into a unit dosage form, either separately or as a mixture, for co-administration to a patient, for example, as a liquid or suspension dosage form for intravenous, intramuscular, or subcutaneous administration.

[0075] In certain embodiments, the anti-HIV gp120 V3 glycan conjugate and the anti-HIV gp120 CD4bs conjugate are formulated separately or as a mixture as a liquid solution or suspension that may optionally contain one or more other agents useful for treating HIV (e.g., HIV capsid inhibitors, e.g., lenacapavir). In certain embodiments, the liquid solution or suspension may contain other active ingredients for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0076] In certain embodiments, such liquid solutions or suspensions are suitable for administration twice a year, for example, once every six months (i.e., Q6M), once every 24 weeks (i.e., Q24W), once every 25 weeks (i.e., Q25W), and once every 26 weeks (i.e., Q26W).

[0077] In some embodiments, after one or more co-administrations of 10-1074-LS and 3BNC117-LS, the serum concentrations of 10-1074-LS and 3BNC117-LS are at least 10 μg / mL 26 weeks after the first time point or 26 weeks after the most recent co-administration.

[0078] In some embodiments, after one or more co-administrations of 10-1074-LS and 3BNC117-LS, serum HIV RNA concentrations are less than 50 copies / mL 26 weeks after the first time point or 26 weeks after the most recent co-administration.

[0079] 4. Patient Selection Stages of infectious disease In various embodiments, the human subjects are adults, adolescents, or infants. The subjects may be symptomatic (e.g., viremia) or asymptomatic (e.g., acute infection or ART suppression). In some embodiments, the human subjects are acutely infected with HIV or have recently been infected. In certain embodiments, the subjects are not seroconverted to antibodies. In some embodiments, the human subjects are chronically infected with HIV. The subjects may or may not be receiving an antiretroviral therapy (ART) regimen.

[0080] Patients can be classified into Fiebig stages I-VI based on the sequential acquisition of positive HIV-1 clinical diagnostic assays (viral RNA measured by PCR, and p24 and p31 viral antigens measured by enzyme-linked immunosorbent assay (ELISA)). The p24 antigen is a viral core protein that ephemerally appears in the blood during the elevation phase, after HIV-1 RNA levels have risen above 10,000 copies / mL, before detectable HIV antibodies are produced. In Fiebig stage I, only HIV-1 RNA can be detected in the blood during the elevation of viremia. Fiebig stage II begins approximately 7 days after a positive result from a test detecting the p24 antigen. In Fiebig stage III, IgM anti-HIV-1 antibodies can be detected using a highly sensitive enzyme-mediated immunoassay (EIA) (e.g., third-generation EIA) within approximately 5 days after a positive p24 antigen test result. Stage III typically occurs 1-2 weeks after the onset of acute retroviral symptoms. Fiebig stage IV occurs approximately 3 days after a Western blot test shows inconclusive progression and an EIA test shows a positive result. A clearly positive Western blot test, transition to Fiebig stage V, generally occurs 7 days or approximately 1 month after the initial infection. Fiebig stages of HIV infection are described, for example, in Fiebig, et al., AIDS. (2003) 17(13):1871-9, Cohen, et al., J Infect Dis. (2010) 202 Suppl 2:S270-7, and McMichael, et al., Nature Reviews Immunology (2010) 10:11-23, which are incorporated herein by reference in their entirety for all purposes. In some embodiments, the biological sample being evaluated is derived from a human subject with HIV infection at Fiebig stage IV or earlier, e.g., Fiebig stage I, Fiebig stage II, Fiebig stage III, or Fiebig stage IV. In some embodiments, the biological sample being evaluated is from a human subject with HIV infection of Fiebig stage V or Fiebig stage VI.

[0081] HIV susceptibility in subjects to one or both bNAbs In some embodiments, the method further includes the step of obtaining a biological sample (e.g., blood, serum, plasma, semen, lymph nodes) from the subject. In some embodiments, the method involves receiving a report of HIV gp120 amino acid residues located at designated positions of interest, e.g., positions 332 and 325, and one or more amino acid positions from the group consisting of 63, 179, 320, and 330, where the amino acid positions refer to Sequence ID No. 4.

[0082] In various embodiments, the method further includes the step of identifying patients who are most likely to benefit from therapy with one or both antibodies targeting the V3 glycan region of HIV gp120 and / or antibodies targeting the CD4bs of HIV gp120. In some embodiments, the susceptibility of a subject to one or both antibodies targeting the V3 glycan region of HIV gp120 and / or antibodies targeting the CD4bs of HIV gp120 is determined by a bNAb IC90 of ≤2 μg / mL in a PhenoSense mAb assay (monogram).

[0083] HIV susceptible to anti-HIV gp120 V3-glycan antibody In some embodiments, the patient is identified by receiving a report of the HIV species infecting the patient, which identifies the HIV gp120 amino acid residues located at designated target amino acid positions, e.g., positions 332 and 325, and one or more amino acid positions in the group consisting of positions 63, 179, 320 and 330, where the amino acid positions refer to Sequence ID No. 4 (above, corresponding to residues 1-511 of HXB2 subtype B HIV-1 isolate (GenBank accession number K0345, NCBI Ref Seq No. NP_057856.1)). An assay useful for determining whether a subject is likely to be susceptible to an anti-HIV gp120 V3-glycan antibody containing 10-1074-LS is described, for example, in International Publication No. 2020 / 236753, which is incorporated herein by reference in its entirety for all purposes.

[0084] In some embodiments, the patient is identified by performing one or more assays (e.g., polynucleotide sequencing or polypeptide sequencing) to determine the amino acid sequence of gp120 or the amino acid residue present at a designated amino acid position of interest in the gp120 protein of the HIV species infecting the patient. Identification of the full-length or partial sequence of the gp120 protein obtained from the subject can be determined at the polynucleotide level or the polypeptide level. In some embodiments, the amino acid present at the target gp120 residue position is determined at the polypeptide level.

[0085] In various embodiments, the method involves identifying a subject infected with HIV or an HIV population expressing gp120, including N332 glycan, D325, and T63, where amino acid positions refer to SEQ ID NO: 4.

[0086] In various embodiments, the method involves identifying a subject infected with HIV or an HIV population expressing gp120, including N332 glycan, D325, and L179, where amino acid positions refer to SEQ ID NO: 4.

[0087] In various embodiments, the method involves identifying a subject infected with HIV or an HIV population expressing gp120, including N332 glycan, D325, and T320, where amino acid positions refer to SEQ ID NO: 4.

[0088] In various embodiments, the method involves identifying a subject infected with HIV or an HIV population expressing gp120, including N332 glycan, D325, and H330, where amino acid positions refer to SEQ ID NO: 4.

[0089] In various embodiments, the method involves identifying a subject infected with HIV or an HIV population expressing gp120, including N332 glycan, D325, T63, and L179, where amino acid positions refer to SEQ ID NO: 4.

[0090] In various embodiments, the method involves identifying a subject infected with HIV or an HIV population expressing gp120, including N332 glycan, D325, T63, and T320, where amino acid positions refer to SEQ ID NO: 4.

[0091] In some embodiments, the subjects are infected with HIV clade B virus. In various embodiments, the method involves identifying subjects infected with HIV or an HIV population expressing gp120 containing N332 glycan, D325, T63, and H330, where amino acid positions refer to SEQ ID NO: 4. In various embodiments, the method involves identifying subjects infected with HIV or an HIV population expressing gp120 containing N332 glycan, D325, T63, L179, T320, and H330, where amino acid positions refer to SEQ ID NO: 4.

[0092] In various embodiments, the method involves identifying a subject infected with HIV or an HIV population expressing gp120, including N332 glycan, D325, T320, and H330, where amino acid positions refer to SEQ ID NO: 4.

[0093] In various embodiments, the method involves identifying a subject infected with HIV or an HIV population expressing gp120, comprising N332 glycan, D325, L179, T320, and H330, where amino acid positions refer to SEQ ID NO: 4. In some embodiments, the subject is infected with HIV clade A and / or HIV clade C virus. In some embodiments, the subject is infected with HIV clade A, clade B, and / or HIV clade C virus.

[0094] In various embodiments, the method involves identifying a subject infected with HIV or an HIV population expressing gp120, including N332 glycan, D325, T63, L179, and T320, where amino acid positions refer to SEQ ID NO: 4.

[0095] In various embodiments, the method involves identifying a subject infected with HIV or an HIV population expressing gp120, including N332 glycan, D325, T63, L179, and H330, where amino acid positions refer to SEQ ID NO: 4.

[0096] HIV susceptible to anti-HIV gp120 CD4bs antibody In some embodiments, patients are identified by receiving a report of the HIV species infecting them, which identifies the HIV gp120 amino acid residues located at a designated target amino acid position, e.g., position 201, and one or more amino acid positions in the group consisting of positions 102, 108, 281, 318, and 353, with the amino acid positions referring to SEQ ID NO: 439. In some embodiments, patients are identified by performing one or more assays (e.g., polynucleotide sequencing or polypeptide sequencing) to determine the amino acid sequence of gp120, or the amino acid residues located at the designated target amino acid position of the gp120 protein of the HIV species infecting the patient. Identification of the full-length or partial sequence of the gp120 protein obtained from the subject can be determined at the polynucleotide level or the polypeptide level. In some embodiments, the amino acids located at the target gp120 residue position are determined at the polypeptide level. An assay useful for determining whether a subject is likely to be susceptible to an anti-HIV gp120 CD4 binding site antibody, including 3BNC117-LS, is described, for example, in International Publication No. 2022 / 103758, which is incorporated herein by reference in its entirety for all purposes.

[0097] In various embodiments, the method involves identifying a subject infected with HIV or an HIV population expressing gp120, including I201 and F353, where amino acid positions refer to SEQ ID NO: 439.

[0098] In various embodiments, the method involves identifying a subject infected with HIV or an HIV population expressing gp120, including I201, I108, and F353, where amino acid positions refer to SEQ ID NO: 439.

[0099] In various embodiments, the method involves identifying a subject infected with HIV or an HIV population expressing gp120, including I201, I108, A281, and F353, where amino acid positions refer to SEQ ID NO: 439.

[0100] In various embodiments, the method involves identifying a subject infected with HIV or an HIV population expressing gp120, including I201, E102, I108, A281, and F353, where amino acid positions refer to SEQ ID NO: 439.

[0101] In various embodiments, the method involves identifying a subject infected with HIV or an HIV population expressing gp120, including I201, E102, I108, A281, Y318, and F353, where amino acid positions refer to SEQ ID NO: 439.

[0102] In some embodiments, the subject is infected with HIV clade (also known as HIV subtype) B virus. In some embodiments, the subject is infected with HIV clade (also known as HIV subtype) A and / or HIV clade (also known as HIV subtype) C virus. In some embodiments, the subject is infected with HIV clade (also known as HIV subtype) A, clade B and / or HIV clade (also known as HIV subtype) C virus.

[0103] Determination of the target gp120 amino acid. The determination of amino acid residues in the HIVgp120 sequence of a subject at specified positions of the subject, e.g., 332 and 325, and one or more amino acid positions from the group consisting of 63, 179, 320 and 330 (see SEQ ID NO: 3 for amino acid positions), can be performed at the polynucleotide or polypeptide level. At the polynucleotide level, HIV RNA or proviral DNA isolated from one or more biological samples can be sequenced using methods known in the art. In some embodiments, HIV RNA or proviral DNA isolated from two or more biological samples of a subject are sequenced. In some embodiments, the two or more biological samples are obtained from different tissue sources, e.g., blood, peripheral blood mononuclear cells, lymph nodes and / or semen. In some embodiments, the two or more biological samples are obtained at different time points, e.g., 1, 2, 3, 4, 5, 6, 7, or 8 weeks apart, or 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months apart.

[0104] If necessary, primers that anneal to and amplify the HIVenv coding sequence, particularly the CD4bs region of gp120, can be used. In some embodiments, nested sets of primers can be used. In various embodiments, RNA can be directly sequenced or reverse transcriptase polymerase chain reaction (RT-PCR) can be performed. In some embodiments, Sanger sequencing can be performed, for example, when sequencing to determine amino acid residues in the CD4bs region, or when sequencing samples from patients in the early Fiebig stages of the disease, e.g., before Fiebig stage III, e.g., Fiebig stage I or II. In various embodiments, single genome amplification (SGA) and sequencing are performed. Methods for amplification (SGA) and sequencing of plasma HIV virion RNA are described, for example, in Salazar-Gonzalez, et al. (2008) J Virol 82:3952-3970 and Keele, et al., Proc Natl Acad Sci US A. (2008) 105(21):7552-7. The application of SGA to determine amino acid sequence variations of the HIV gp120 sequence, which can be used in the methods described herein, is described, for example, in Bar, et al., N Engl J This is described in Med. (2016) 375(21):2037-2050 and Mendoza, et al, Nature. (2018) 561(7724):479-484. In various embodiments, high-throughput, next-generation sequencing (NGS), massively parallel, or deep sequencing techniques are used to sequence gp120, including at least the CD4bs region, from a population of HIV species in one or more biological samples from a single patient or subject. In such cases, multiple nucleic acid sequences encoding at least the CD4bs region of gp120 are sequenced and aligned. In some embodiments, the entire length of gp120 is sequenced. Exemplary platforms for performing NGS sequencing that can be used to determine the gp120 sequence of HIV species in one or more patient-derived biological samples include Illumina (Solexa) (illumina.com), Ion torrent: Proton / PGM sequencing (thermofisher.com), SOLiD (thermofisher.com), and single-molecule real-time (SMRT) sequencing (Pacific Biosciences, pacb.com). Methods for isolating and sequencing HIV gp120 containing at least the CD4bs region from patients, which can be applied by this method, are described, for example, in Shioda, et al., J Virol. (1997) 71(7): 4871-81, Colon, et al, J Virol Antivir Res. (2015) 4(3). pii: 143 (PMID: 27358904), Kafando et al, PLoS One. (2017) 12(12): e0189999, Hebberecht et al., PLoS One. (2018) 13(4): e0195679, Andrews, et al, Sci Rep. (2018) 8(1): 5743, and Landais, et al. Immunity. (2017) 47(5): 990-1003. If necessary, shorter sequence reads ("contigs") of nucleic acid sequences can be assembled into longer sequences that include at least the CD4bs region of gp120.Methods for contig assembly of HIV genome sequences that can be applied in this method are described, for example, in Huang, et al., Bioinformation. (2018) 14(8):449-454, Hiener, et al., J Vis Exp. (2018) Oct 16; (140). doi:10.3791 / 58016, and Wymant, et al., Virus Evol. (2018) May 18; 4(1):vey007. doi:10.1093 / ve / vey007.

[0105] 5. Combination therapy In one particular embodiment, a method is provided for treating or preventing HIV infection in a person who has or is at risk of having an infection, comprising administering to the person a therapeutically effective amount of anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody disclosed herein in combination with one or more additional therapeutic agents (e.g., one, two, three, four, one or two, one to three, or one to four).

[0106] In one embodiment, a pharmaceutical composition is provided comprising an anti-HIV gp120 V3 glycan and an anti-HIV gp120 CD4bs-conjugated antibody, as disclosed herein, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents and pharmaceutically acceptable carriers, diluents, or excipients.

[0107] In a particular embodiment, a method for treating HIV infection is provided, comprising administering to a patient in need of treatment a therapeutically effective amount of anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody or its antigen-conjugated fragment, in combination with one or more additional therapeutic agents suitable for treating HIV infection.

[0108] In certain embodiments, anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody or its antigen-binding fragment are combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody or its antigen-binding fragment are combined with two additional therapeutic agents. In other embodiments, anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody or its antigen-binding fragment are combined with three additional therapeutic agents. In further embodiments, anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody or its antigen-binding fragment are combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents (e.g., one or more broad-spectrum anti-HIV neutralizing antibodies), and / or they may be selected from different classes of therapeutic agents.

[0109] Administration of HIV combination therapy In certain embodiments, the anti-HIV gp120 V3 glycan and the anti-HIV gp120 CD4bs conjugate antibody or its antigen-binding fragment are co-administered with one or more additional therapeutic agents. The co-administration of the anti-HIV gp120 CD4bs conjugate antibody and one or more additional therapeutic agents as described herein generally refers to the simultaneous or sequential administration of the anti-HIV gp120 CD4bs conjugate antibody and one or more additional therapeutic agents so that therapeutically effective amounts of both are present in the patient's body. If administered sequentially, the combination may be administered in two or more doses.

[0110] Co-administration includes the parallel administration and administration of anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody or its antigen-binding fragment, as described herein, before or after the administration of a unit dose of one or more additional therapeutic agents. For example, anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody or its antigen-binding fragment, as described herein, may be administered within seconds, minutes, hours, or days of the administration of one or more additional therapeutic agents. In some embodiments, a unit dose of anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents within seconds, minutes, hours, or days. Alternatively, a unit dose of one or more additional therapeutic agents may be administered first, followed by a unit dose of anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody disclosed herein within seconds, minutes, hours, or days. In other embodiments, a unit dose of the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents after a certain period of time (e.g., 1-12 hours, 1-24 hours, 1-36 hours, 1-48 hours, 1-60 hours, 1-72 hours). In yet another embodiment, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the anti-HIV gp120 CD4bs conjugated antibody disclosed herein after a certain period of time (e.g., 1-12 hours, 1-24 hours, 1-36 hours, 1-48 hours, 1-60 hours, 1-72 hours).

[0111] In certain embodiments, the anti-HIV gp120 V3 glycan-conjugated antibody and the anti-HIV gp120 CD4bs-conjugated antibody disclosed herein are combined with one or more additional therapeutic agents in single dosage forms for co-administration to a patient, such as solid, liquid, or suspension forms for oral, intravenous, intramuscular, or subcutaneous administration.

[0112] In certain embodiments, the anti-HIV gp120 V3 glycan and the anti-HIV gp120 CD4bs conjugated antibody are formulated as a liquid solution or suspension that may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the liquid solution or suspension may contain other active ingredients for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0113] In certain embodiments, such liquid solutions or suspensions are suitable for administration twice a year, for example, every six months (Q6M), every 26 weeks (Q26W), every 25 weeks (Q25W), or every 24 weeks (Q24W).

[0114] HIV combination therapy In the embodiments described above, additional therapeutic agents may be anti-HIV agents. Exemplary anti-HIV therapeutic agents that may be combined or co-administered include: a third anti-HIV antibody, an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an HIV capsid inhibitor, a nucleocapsid protein 7 (NCp7) inhibitor, and HIV Tat or Rev inhibitors, Tat-TAR-P-TEFb immunomodulators (e.g., immunostimulators), immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), cell therapies (chimeric antigen receptor T cells, CAR-T, and genetically modified T cell receptors, TCR-T, autologous T cell therapy, modified B cells, NK cells, etc.), latent infection reactivators, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, fatty acid synthase inhibitors, HIV vif gene modulator, Vif dimerizing antagonist, HIV-1 virus infectivity factor inhibitor, HIV-1 Nef modulator, TNF alpha ligand inhibitor, HIV Nef inhibitor, Hck tyrosine kinase modulator, mixed lineage kinase-3 (MLK-3) inhibitor, HIV-1 splicing inhibitor, integrin antagonist, nucleoprotein inhibitor, splicing agent modulator, COMM domain-containing protein 1 modulator, HIV ribonuclease H inhibitor, IFN antagonist, retrocycline modulator, CD3 antagonist, CDK-4 inhibitor, CDK-6 inhibitor, CDK-9 inhibitor, cytochrome P450Examples of HIV-mediated inhibitors include, but are not limited to, HIV-3 inhibitors, CXCR4 modulators, dendritic ICAM-3 grabbing nonintegrin-1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, HPK1 (MAP4K1) inhibitors, proprotein convertase PC9 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD, and NADH-oxidase inhibitors, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P-glycoprotein modulators, RNA polymerase modulators, TAT protein inhibitors, prolyl endopeptidase inhibitors, phospholipase A2 inhibitors, pharmacokinetic enhancers, HIV gene therapies, HIV vaccines, anti-HIV peptides, and combinations thereof.

[0115] In some embodiments, additional therapeutic agents are selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, incubation period reversals, HIV capsid inhibitors, HIV Tat or Rev inhibitors, immunomodulators (e.g., immunostimulators), immunotherapeutic agents, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, as well as "antibody-like" therapeutic proteins, and combinations thereof.

[0116] In some embodiments, additional therapeutic agents or additional multiple therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latent infection reactivators, HIV bNAbs, TLR7, TLR8, and TLR9 agonists, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, bispecific antibodies that mobilize T cells and NK cells, chimeric T cell receptors that target HIV antigens, pharmacokinetic enhancers, and other drugs for treating HIV, as well as combinations thereof.

[0117] In some embodiments, additional therapeutic agents or additional multiple therapeutic agents are selected from dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir, and combinations thereof.

[0118] Additional anti-HIV antibodies In some embodiments, the anti-HIV gp120 V3 glycan-conjugated antibody and the anti-HIV gp120 CD4bs-conjugated antibody disclosed herein are further combined with one or more additional anti-HIV antibodies. In some embodiments, one or more additional antibodies bind to an epitope or region of gp120 selected from the group consisting of (i) the second variable loop (V2) and / or the tip of the Env trimer, (ii) the gp120 / gp41 interface, or (iii) the silent surface of gp120. The aforementioned epitopes or gp120 regions conjugated by broad-spectrum neutralizing antibodies are described, for example, in McCoy, Retrovirology (2018) 15:70; Sok and Burton, Nat Immunol. 2018 19(11):1179-1188; Possas, et al., Expert Opin Ther Pat. 2018 Jul;28(7):551-560; and Stephenson and Barouch, Curr HIV / AIDS Rep (2016) 13:31-37, which are incorporated herein by reference in their entirety for all purposes.

[0119] In some embodiments, combination therapy involves co-administration of an anti-HIV gp120 V3 glycan-conjugated antibody and an anti-HIV gp120 CD4bs-conjugated antibody with an additional anti-HIV broad-spectrum neutralizing antibody or bNAb (i.e., a neutralizing antibody that neutralizes multiple HIV-1 virus strains). Various bNAbs are known in the art and can be used as combination therapies. Further exemplary bNAbs to be used include those comprising VH and VL that bind to or compete with an epitope or region of gp120 selected from the group consisting of (i) a second variable loop (V2) and / or the tip of the Env trimer, (ii) the gp120 / gp41 interface, or (iii) the silent surface of gp120.

[0120] In some embodiments, the combination therapy includes an antibody that binds to the gp120 epitope or region in the second variable loop (V2) and / or the tip of the Env trimer, and competes with, or contains, the CDR and / or VH and VL regions derived from an antibody selected from the group consisting of PG9, PG16, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGT-145, CH01, CH59, PGDM1400, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E, and VRC38.01.

[0121] In some embodiments, the combination therapy includes antibodies that bind to an epitope or region of gp120 at the gp120 / gp41 interface and compete with, or contain, the CDR and / or VH and VL regions from an antibody selected from the group consisting of PGT-151, CAP248-2B, 35O22, 8ANC195, ACS202, VRC34, and VRC34.01.

[0122] In some embodiments, the combination therapy includes an antibody that binds to an epitope or region of the gp120 silent surface and competes with or contains a second VH and VL region derived from the antibody VRC-PG05.

[0123] In some embodiments, the combination therapy includes an antibody that binds to an epitope or region of gp41 in the membrane proximal region (MPER) and competes with or contains a second VH and VL region from an antibody selected from the group consisting of 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2, and LN01. In some embodiments, the combination therapy includes an antibody that binds to an epitope or region of KLIC (disclosed as "KLIC" in Sequence ID No. 496), which is an invariant site of the transmembrane protein gp41, and competes with or contains a second VH and VL region from a clone 3 human monoclonal antibody (Cl3hmAb) (Protheragen). See, for example, Vanini, et al., AIDS. (1993) 7(2):167-74.

[0124] In some embodiments, the combination therapy includes an antibody that binds to an epitope or region of the gp41 fusion peptide and competes with or contains a second VH and VL region derived from an antibody selected from the group consisting of VRC34 and ACS202.

[0125] In some embodiments, the combination therapy includes a multispecific antibody that binds to the HIV antigen, such as a bispecific or trispecific antibody. Examples of HIV bispecific and trispecific antibodies include MGD014, B12BiTe, BiIA-SG, TMB-bispecific, SAR-441236, VRC-01 / PGDM-1400 / 10E8v4, 10E8.4 / iMab, and 10E8v4 / PGT121-VRC01.

[0126] Prior to administration, bNAbs may be modified to possess enhanced drug-like properties, reduced immunogenicity, enhanced ADCC, and appropriate pharmacokinetic properties. Such antibodies have been shown to bind to HIV envelope glycoproteins expressed on the surface of virions or infected cells, mediating both direct neutralization of the virus and potent NK, monocyte, and PBMC killing of these cells. This property allows the antibody to treat HIV infection by neutralizing the virus, potentially leading to the killing and elimination of latent HIV-infected cells in infected individuals, resulting in a sterile cure for HIV.

[0127] In various embodiments, all antibodies administered in combination with anti-HIV antibody therapy may have Fc and / or post-translational modifications that increase serum half-life and / or enhance effector activity, as described above.

[0128] In various embodiments, anti-HIV gp120 CD4bs-conjugated antibodies or antigen-binding fragments, and optionally combined bNAbs, can be delivered in vivo from administered mRNA or genetically modified B cells, for example, to be expressed in vivo. Examples of bNAbs delivered in vivo include AAV8-VRC07; mRNA encoding the anti-HIV antibody VRC01; and genetically modified B cells encoding 3BNC117 (Hartweger et al, J. Exp. Med. 2019, 1301).

[0129] HIV combination drugs In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody described herein are combined with one, two, three, four or more additional anti-HIV therapeutic agents. Examples of anti-HIV combination drugs that can be co-administered include, but are not limited to, ATRIPLA® (efavirenz, tenofovir disoproxil fumarate and emtricitabine), COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and Emtricitabine); TRUVADA (registered trademark) (Tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY (registered trademark) (Tenofovir alafenamide and emtricitabine); ODEFSEY (registered trademark) (Tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA (registered trademark) (Tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA (registered trademark) (D Lunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat); efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alaf Enamide hemifmarate, emtricitabine, cobicistat, and elvitegravir; tenofovir analogues; COMBIVIR® (zidovudine and lamivudine, AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®, lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine);BIKTARVY® (vicregravir + emtricitabine + tenofovir alafenamide), DOVATO® (dolutegravir + lamivudine), TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and ritonavir (ATZ+RTV); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; PREZCOB IX (registered trademark) (darunavir and cobicistat); dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dolutegravir + lamivudine, lamivudine + abacavir + zidov Zin, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, ACC-008 (ACC-007 + lamivudine + tenofovir disoproxil fumarate), VM-1500 + emtricitabine + tenofovir disoproxil, and tenofovir Examples include disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, lopinavir + ritonavir + abacavir + lamivudine, and lamivudine; cabotegravir + rilpivirine; 3-BNC117 + albuvirtide, (elsulfavirine; VM-1500), VM-1500A, renacapavir + islatravir (oral and injectable), and dual-target HIV-1 reverse transcriptase / nucleocapsid protein 7 inhibitors.

[0130] Other HIV drugs Other drugs used to treat HIV include, but are not limited to, aspergrin C, gamimune, methenkephalin, naltrexone, prolastin, REP9, VSSP, H1viral, SB-728-T, 1,5-dicameoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, Bevirimat, A BBV-382, Obefazimod (ABX-464), AG-1105, APH-0812, APH0202, Briostatin-1, Briostatin-23, Briostatin analog, SUW-133, BIT-225, BRII-732, BRII-778, Kozivir CYT-107, CS-TATI-1, Fluoro-beta-D-arabinose nucleic acid (FANA) modified antisense oligonucleotide, FX-101, Grifficin, HGTV-43, HPH-116, HRS-5685, HivCide-I, Hydroxychloroquine, IMB-10035, IMO-3100, IND-02, JL-18008, LADAVRU, LLDT-8, MK-1376, MK-2048, MK-4250, MK-8507, MK-8558, Islatravir (MK-8591), NOV-205, OB-00 2H, ODE-Bn-TFV, PA-1050040(PA-040), PC-707, PGN-007, QF-036, S-648414, SCY-635, SB-9200, SCB-719, TR -452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, DIACC-1010, Fasnall, Immuglo, 2-CLIP Examples include S peptide, HRF-4467, thrombospongin analog, TBL-1004HI, VG-1177, xl-081, AVI-CO-004, rfhSP-D, [18F]-MC-225, URMC-099-C, RES-529, Verdinexor, IMC-M113V, IML-106, antiviral fc conjugate (AVC), WP-1096, WP-1097, Gammora, ISR-CO48, ISR-48, ISR-49, MK-8527, cannabinoids, ENOB-HV-32, T-1144, VIR-576, Nipapovil, Covimlo, WP-1122, ZFP-362, and ABBV-1882.

[0131] HIV protease inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with an HIV protease inhibitor. Examples of HIV protease inhibitors include, but are not limited to, amprenavir, atazanavir, brekanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, ASC-09+ritonavir, AEBL-2, DG-17, elnonavir (GS-1156), TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, GRL-02031, and TMC-310911. Examples of additional HIV protease inhibitors are described, for example, in U.S. Patent No. 10,294,234 and U.S. Patent Application Publications 2020030327 and 2019210978.

[0132] HIV ribonuclease H inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with an HIV ribonuclease H inhibitor. Examples of HIV ribonuclease H inhibitors that can be combined include, but are not limited to, NSC-727447.

[0133] HIV Nef inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with an HIV Nef inhibitor. Examples of HIV Nef inhibitors that can be combined include, but are not limited to, FP-1.

[0134] HIV reverse transcriptase inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with a non-nucleoside inhibitor or a non-nucleotide inhibitor. Examples of reverse transcriptase HIV non-nucleoside or non-nucleotide inhibitors include, but are not limited to, dapivine, delaviridine, delaviridine mesylate, doravirine, difluoro-biphenyl-diarylpyrimidine (DAPY), efavirenz, etravirine, GS-5894, lentinan, nevirapine, rilpivirine, ACC-007, ACC-018, AIC-292, F-18, KM-023, PC-1005, M1-TFV, M2-TFV, VM-1500A-LAI, PF-3450074, elsulfavirine (sustained-release oral), doravirine + islaravir (fixed-dose combination / oral tablet), elsulfavirine (long-acting nano-suspension for injection), and elsulfavirine (VM-1500).

[0135] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with an HIV nucleoside or nucleotide inhibitor. Examples of reverse transcriptase HIV nucleoside or nucleotide inhibitors include, but are not limited to, adefovir, adefovir dipivoxil, azuvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir octadecyloxyethyl ester (AGX-1009), tenofovir amib fenamide fumarate (HS-10234), tenofovir disoproxil hemifumarate, VIDEX®, and VIDEX Examples include EC (registered trademark) (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, sensabudine, didanosine, erbucitabine, festinavir, fosalvudine tidoxine, CMX-157, dapivine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fodivudine tidoxil, lamivudine, phosphazide, stabudine, zalcitabine, zidovudine, lovahovir etalafenamide (GS-9131), GS-9148, GS-1614, GSK-4023991, MK-8504, islatravir, MK-8583, VM-2500, and KP-1461.

[0136] Additional examples of reverse transcriptase HIV nucleoside or nucleotide inhibitors are described in U.S. Patent Publication Nos. 2007049754, 2016250215, 2016237062, 2016251347, 2002119443, 2013065856, 2013090473, 2014221356, and International Publication No. 04096286, but are not limited to those described therein.

[0137] HIV integrase inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with an HIV integrase inhibitor. Examples of HIV integrase inhibitors include, but are not limited to, elvitegravir, elvitegravir (sustained-release microcapsules), curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicamoylquinic acid, 3,5-dicamoylquinic acid derivatives, oulintricarboxylic acid, oulintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrofostine, tyrofostine derivatives, quercetin, quercetin derivatives, raltegravir, PEGylated raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, Examples include carbotegravir (long-acting injectable), diketoquinoline-4-1 derivatives, GS-1720, GS-6212, GS-1219, GS-3242, VH4524184, integrase-LEDGF inhibitors, ledgin, M-522, M-532, MK-0536, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, S-365598, stilbendesulfonic acid, T169, STP-0404, VM-3500, XVIR-110, and ACC-017.

[0138] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with an HIV non-catalyzed site or an allosteric integrase inhibitor (NCINI). Examples of HIV non-catalyzed sites or allosteric integrase inhibitors (NCINIs) include, but are not limited to, CX-05045, CX-05168, and CX-14442.

[0139] Capsid inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with a capsid inhibitor. Examples of capsid inhibitors that can be combined with the agents of this disclosure include capsid polymerization inhibitors or capsid disruption compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamides, HIV p24 capsid protein inhibitors, lenacapavir (GS-6207), VH4004280, VH4011499, GS-CA1, AVI-621, AVI-101, AVI-201, AVI-301, and the AVI-CAN1-15 series, PF-3450074, as well as the compounds described in International Publication No. 2019 / 087016, U.S. Patent Application Publication Nos. 2014 / 0221356, 2016 / 0016973, 2018 / 0051005, and 2016 / 0108030.

[0140] HIV virus infectious factor inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with an HIV viral infectivity factor inhibitor. Examples of HIV viral infectivity factor inhibitors include 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide derivatives and Irino-L.

[0141] HIV entry inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with an HIV entry (fusion) inhibitor. Examples of HIV entry (fusion) inhibitors include AAR-501, LBT-5001, senicliviroc, CCR5 inhibitors, gp41 inhibitors, CD4 adhesion inhibitors, gp120 inhibitors, gp160 inhibitors, and CXCR4 inhibitors.

[0142] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with a CCR5 inhibitor. Examples of CCR5 inhibitors include aplaviroc, bicliviroc, maraviroc, maraviroc (long-acting nanoemulsion for injection), senicliviroc, leronlimab (PRO-140), adapavir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibody, B-07, MB-66, polypeptide C25P, TD-0680, thioraviroc, and vMIP (Haimipu).

[0143] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with a CXCR4 inhibitor. Examples of CXCR4 inhibitors include prelixafor, ALT-1188, N15 peptide, barishafortide, and vMIP (Haimipu).

[0144] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with a gp41 inhibitor. Examples of gp41 inhibitors include albuvirtide, enfvirtide, grifficin (gp41 / gp120 / gp160 inhibitor), BMS-986197, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, CPT-31, Cl3hmAb, lipovirtide, PIE-12 trimer, and shifvirtide.

[0145] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-binding antibody described herein are combined with a CD4 binding inhibitor. Examples of CD4 binding inhibitors include ivalizumab and CADA analogs.

[0146] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with a gp120 inhibitor. Examples of gp120 inhibitors include anti-HIV bactericides, Radha-108 (receptor) 3B3-PE38, BMS818251, BanLec, bentonite-based nanopharmaceuticals, fostemsavir tromethamine, IQP-0831, VVX-004, and BMS-663068.

[0147] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with a gp160 inhibitor. An example of a gp160 inhibitor that can be combined is funquinoline.

[0148] HIV maturation inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with an HIV maturation inhibitor. Examples of HIV maturation inhibitors include BMS-955176, GSK-3640254, VH-3739937 (GSK-3739937), HRF-10071, and GSK-2838232.

[0149] Latent infection reactivator In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with an HIV incubation period reversal agent. Examples of latent infection reactivators that can be combined with one or more multispecific antigen-binding molecules described herein include IL-15 receptor agonists (e.g., ALT-803; interleukin-15 / Fc fusion protein (e.g., XmAb24306); recombinant interleukin-15 (e.g., AM0015, NIZ-985); pegylated IL-15 (e.g., NKTR-255)); and Toll-like receptors (T). LR) agonists (TLR7 agonists, e.g., besatormod (GS-9620); TLR8 agonists, e.g., sergantrimod (GS-9688); TLR9 agonists, e.g., refitrimod (MGN-1703); histone deacetylase (HDAC) inhibitors; proteasome inhibitors such as Velcade; protein kinase C C, PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors (e.g., ZL-0580, apavetalone, etc.), ionomycin, IAP antagonists (inhibitors of apoptotic proteins such as APG-1387, LBW-242, etc.), SMAC mimetics (including TL32711, LCL161, GDC-0917, HGS1029, xebinapanth (AT-406)), Debio-1143, PMA, SAHA (suberoylanilide hydroxamic acid) Examples of PKC activators include suberoyl, anilide, and hydroxamic acid), NIZ-985, IL-15 regulatory antibodies (containing IL-15, IL-15 fusion protein, and IL-15 receptor agonists, e.g., ALT-803), JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors, e.g., largazole analogs, APH-0812, and GSK-343. Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG-lactone.

[0150] Toll-like receptor (TLR) agonist In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with agonists of Toll-like receptors (TLRs), such as TLR1 (NCBI gene ID: 7096), TLR2 (NCBI gene ID: 7097), TLR3 (NCBI gene ID: 7098), TLR4 (NCBI gene ID: 7099), TLR5 (NCBI gene ID: 7100), TLR6 (NCBI gene ID: 10333), TLR7 (NCBI gene ID: 51284), TLR8 (NCBI gene ID: 51311), TLR9 (NCBI gene ID: 54106) and / or TLR10 (NCBI gene ID: 81793).

[0151] Examples of TLR7 agonists that may be co-administered or combined with one or more multispecific antigen-binding molecules described herein include AL-034, DSP-0509, GS-9620 (Besatrimod), Besatrimod analogues, LHC-165, TMX-101 (Imiquimod), GSK-2245035, Reciquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and U.S. Patent Application Publication No. 20100143301 (Gilead U.S. Patent Publication No. 20110098248 (Gilead Sciences), and U.S. Patent Publication No. 20090047249 (Gilead Sciences), 2010143301, U.S. Patent Publication No. 20140045849 (Janssen), U.S. Patent Publication No. 20140073642 (Janssen), International Publication No. 2014 / 056953 (Janssen), International Publication No. 2014 / 076221 (Janssen), International Publication No. 2014 / 128189 (Janssen), U.S. Patent Publication No. 20140350031 (Janssen), International Publication No. 2014 / 023813 (Janssen), U.S. Patent Publication No. 20080234251 (Array Array Biopharma, U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (NoviraExamples include, but are not limited to, the compounds disclosed in Therapeutics and U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics).

[0152] The TLR7 / TLR8 agonists that can be co-administered are NKTR-262, tellatrimod, and BDB-001.

[0153] Examples of TLR8 agonists that may be co-administered or combined with one or more multispecific antigen-binding molecules described herein include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motlimod, resikimod, selgantrimod (GS-9688), VTX-1463, VTX-763, 3M-051, 3M-052, and U.S. Patent Application Publication No. 2017071944 (Gilead (Sciences), U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 20140073642 (Janssen), International Publication No. 2014 / 056953 (Janssen), International Publication No. 2014 / 076221 (Janssen), International Publication No. 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), International Publication No. 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Examples of compounds disclosed in U.S. Patent Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Publication No. 20140275167 (Novira Therapeutics), and U.S. Patent Publication No. 20130251673 (Novira Therapeutics) include, but are not limited to, those disclosed in U.S. Patent Publication No.

[0154] Examples of TLR9 agonists that may be co-administered include, but are not limited to, AST-008, covitrimod, CMP-001, IMO-2055, IMO-2125, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatrimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, refitrimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotrimod, and PUL-042. Examples of TLR3 agonists include lintatrimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1. Examples of TLR4 agonists include G-100 and GSK-1795091.

[0155] Histone deacetylase (HDAC) inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are administered together with a histone deacetylase inhibitor, such as an inhibitor of histone deacetylase 1 or histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR, gene ID: 9734). Examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, bellinostat, CKD-581, CS-055 (HBI-8000), CT-101, CUDC-907 (fimepinostat), entinostat, gibinostat, mosetinostat, panobinostat, prasinostat, xinostat (JNJ-26481585), resminostat, licorinostat, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamstine, remetinostat, and entinostat.

[0156] Cytochrome P450 3 inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with a cytochrome P450 3 inhibitor. Examples of cytochrome P450 3 inhibitors include, but are not limited to, those described in U.S. Patent No. 7,939,553.

[0157] RNA polymerase modulator In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with an RNA polymerase modulator. Examples of RNA polymerase modulators include, but are not limited to, those described in U.S. Patents 10,065,958 and 8,008,264.

[0158] Cyclin-dependent kinase (CDK) inhibitors or antagonists In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with inhibitors or antagonists of cyclin-dependent kinases (CDKs), such as cyclin-dependent kinase 4 (CDK4; NCBI gene ID: 1019), cyclin-dependent kinase 6 (CDK6; NCBI gene ID: 1021), and cyclin-dependent kinase 9 (CDK9; NCBI gene ID: 1025). In some embodiments, the CDK4 / CDK6 / CDK9 inhibitor or antagonist is selected from the group consisting of VS2-370.

[0159] Interferon gene stimulator (STING) ) Agonist In some embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with an interferon gene stimulator (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic diAMP.

[0160] RIG-I Agonist In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with an antagonist of DExD / H-box helicase 58 (DDX 58; also known as RIG-I, RIG1, RIGI, RLR-1, SGMRT2; NCBI gene ID: 23586). In some embodiments, the agents described herein are combined with a RIG-I modulator such as RGT-100, or a NOD2 modulator, e.g., SB-9200 (also known as GS 9992; Inarigivir), and IR-103. An exemplary RIG-I agonist is KIN1148, described by Hemann, et al., J Immunol May 1, 2016, 196(1 Supplement)76.1. Additional RIG-I agonists are described, for example, in Elion, et al., Cancer Res. (2018) 78(21): 6183-6195 and Liu, et al., J Virol. (2016) 90(20): 9406-19. RIG-I agonists are commercially available, for example, from invivogen (invivogen.com).

[0161] LAG-3 and TIM-3 inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein is combined with or co-administered with anti-TIM-3 (also known as hepatitis A virus cell receptor 2 antibody (HAVCR2; NCBI gene ID: 84868)), such as TSR-022, LY-3321367, MBG-453, or INCAGN-2390. In some embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein is combined with anti-LAG-3 (lymphocyte activation) (NCBI gene ID: 3902) antibody, such as lilatrimab (ONO-4482), LAG-525, MK-4280, REGN-3767, or INCAGN2385.

[0162] immune system therapy In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with immunotherapy. Examples of immunotherapies include Toll-like receptor (TLR) modulators such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Programmed cell death protein 1 (PD-1) modulator, programmed cell death ligand 1 (PD-L1) modulator, IL-15 modulator (e.g., IL-15 receptor agonist e.g., ALT-803; interleukin-15 / Fc fusion protein (e.g., XmAb24306), recombinant interleukin-15 (e.g., AM0015, NIZ-985), pegylated IL-15 (e.g., NKTR-255)), DermaVir, interleukin-7, Plaquenil (hydroxychloroquine), proleukin (aldesleukin, IL-2), interferon alpha, interferon alpha-2b, interferon alpha-n3, PEGylated interferon alpha, interferon gamma, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), ribavirin, polymer polyethyleneimine (polymer Examples include polyethyleneimine (PEI), gepon, IL-12, WF-10, VGV-1, MOR-22, BMS-936559, CYT-107, normuferon, peginterferon alpha-2a, peginterferon alpha-2b, RPI-MN, STING modulator, RIG-I modulator, NOD2 modulator, SB-9200, and IR-103.

[0163] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with a TLR agonist. Examples of TLR agonists include, but are not limited to, Besatrimod (GS-9620), Refitrimod, Chilsotrimod, Lintatrimod, DSP-0509, AL-034, G-100, Covitrimod, AST-008, Motrimod, GSK-1795091, GSK-2245035, VTX-1463, Sergantrimod (GS-9688), LHC-165, BDB-001, RG-7854, and Teratrimod.

[0164] Immune checkpoint receptor protein modulators In various embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and / or one or more stimulants, activators, or agonists of one or more stimulant immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can reliably regulate T cell or NK cell activation and prevent immune leaks in infected cells. Activation or stimulation of stimulant immune checkpoints can enhance the effects of immune checkpoint inhibitors in infection treatment agents. In various embodiments, immune checkpoint proteins or receptors regulate the T cell response (for example, as outlined in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, immune checkpoint proteins or receptors regulate the NK cell response (as outlined, e.g., Davis, et al., Semin Immunol. (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0165] Examples of immune checkpoint proteins or receptors that can be combined with the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein include, but are not limited to, the following: CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane domain and immunoglobulin domain-containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cytotoxic receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-related 2 (HHLA2, B7H7); Inducible T cell costimulatory molecule (ICOS, CD278); Inducible T cell costimulatory molecule ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated, BTLA); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-related protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); poliovirus receptor (Poliovirus Receptor, PVR) Cell adhesion molecule (PVR, CD155); Contains PVR-related immunoglobulin domain (PVRIG, CD112R); T cell immune receptor with Ig and ITIM domains (TIGIT); Contains T cell immunoglobulin and mucin domains 4 (TIMD4; TIM4); Hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); Galectin 9 (LGALS9); Lymphocyte activation 3 (LAG3, CD223); Signal transduction lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); Lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL1 6-binding protein 2 (ULBP2); UL16-binding protein 3 (ULBP3); retinoic acid initial transcript 1E (RAET1E; ULBP4); retinoic acid initial transcript 1G (RAET1G; ULBP5); retinoic acid initial transcript 1L (RAET1L; ULBP6); lymphocyte activation 3 (CD223); killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic terminal 1 (KIR, CD158E1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin-like receptor C3 (KLRC3, NKG2E); killer cell lectin-like receptor C4 (KLRC4, NKG2F);Killer cell immunoglobulin-like receptor, one Ig domain and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 2 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1); and hematopoietic progenitor cell kinase 1 (HPK1, MAP4K1).

[0166] In various embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with one or more T-cell inhibitory immune checkpoint protein or receptor blockers or inhibitors. Exemplary T cell suppressive immune checkpoint proteins or receptors include, but are not limited to, CD274 (CD274, PDL1, PD-L1); programmed cell death ligand 1 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated immunoglobulin-containing (PVRIG, CD112R); T cell immune receptor having Ig and ITIM domains (TIGIT); Lymphocyte activation 3 (LAG3, CD223); Hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); Galectin 9 (LGALS9); Killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic terminal 1 (KIR, CD158E1); Killer cell immunoglobulin-like receptor, 1 Ig domain and long cytoplasmic tail 2 (KIR2DL1); Killer cell immunoglobulin-like receptor, 2 Ig domains and long cytoplasmic tail 2 (KIR2DL2); Killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 2 (KIR2DL3); and Killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 1 (KIR3DL1). In various embodiments, the anti-HIV gp120 V3 glycan and anti-HIV described herein are used. The gp120 CD4bs-conjugated antibody is combined with one or more agonists or activators of one or more T cell-stimulating immune checkpoint proteins or receptors. Examples of T cell-stimulating immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell costimulatory molecules (ICOS, CD278); inducible T cell costimulatory molecule ligands (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). For example, see Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0167] In various embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with one or more NK cell inhibitory immune checkpoint protein or receptor blockers or inhibitors. Examples of NK cell suppressive immune checkpoint proteins or receptors include, but are not limited to, the following: killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, 1 Ig domain and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, 2 Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 2 (KIR2DL3); killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94). In various embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with one or more agonists or activators of one or more NK cell-stimulated immune checkpoint proteins or receptors. Examples of NK cell-stimulated immune checkpoint proteins or receptors include, but are not limited to, CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). For example, see Davis, et al., Semin Immunol. (2017) 31:64-75; Fang, et al., Semin Immunol. (2017) 31:37-54; and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0168] In some embodiments, one or more immune checkpoint inhibitors include protein inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4 (e.g., antibodies or fragments thereof, or antibody mimetics). In some embodiments, one or more immune checkpoint inhibitors include organic small molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4.

[0169] Examples of CTLA4 inhibitors that can be co-administered include ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, and PBI. Examples include, but are not limited to, -5D3H5, BPI-002, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0170] Examples of programmed cell death 1 (PDCD1; NCBI gene ID: 5133, CD279, PD-1, PD1) inhibitors that can be combined with or co-administered include zimberelimab (AB122, GLS-010, WBP-3055), pembrolizumab (KEYTRUDA®, MK-3475, SCH900475), and nivolumab (OPDIVO®, BMS-93). 6558, MDX-1106), semiprimab (LIBTAYO(registered trademark); semiprimab-rwlc, REGN-2810), pidilizumab (CT-011), AMG-404, MEDI0680 (AMP-514), spartalizumab (PDR001), tislerizumab (BGB-A317), tripalimab (JS-001), genolimuzumab (CBT-501, APL-501, GB 226), SHR-1201, Camrelizumab (SHR-1210), Syntilimab (TYVYT®, IBI-308), Dostallimab (TSR-042, WBP-285), Lambrolizumab (MK-3475); Sasanlimab (PF-06801591), Cetrelimab (JNJ-63723283), Cellpurlimab (HLX-10), Retifanlimab (MGA-012), Valstilimab (AGEN2034), Prorugolimab (BCD 100), buzigalimab (ABBV-181), voplaterimab (JTX-4014), AK-103 (HX-008), AK-105, CS-1003, BI-754091, LZM-009, Sym-021, BAT-1306, PD1-PIK, teboterimab (MGD013; PD-1 / LAG-3), RO-7247669 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), RO- Examples include, but are not limited to, 7121661 (PD-1 / TIM-3), RG7769 (PD-1 / TIM-3), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), and MEDI-5752 (CTLA4 / PD-1).In some embodiments, the first and / or second antigen-binding domains comprise the extracellular domain of human programmed cell death 1 ligand 2 (PD-L2) and bind to PD1 (e.g., AMP-224).

[0171] Examples of CD274 molecule (NCBI gene ID: 29126; B7-H, B7H1, PD-L1) inhibitors that can be combined or co-administered include atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®; MSB0010718C), emvafolimab (ASC22), durvalumab (IMFINZI®; MEDI-4736), BMS-936559 (MDX1105), cosivelimab (CK-301), rhodapolimab (LY 3300054), and valiblimab (BGB A333), emvafolimab (KN035), opcolimab (HLX20), manerimab (BCD135), CX-072, CBT-502 (TQB2450), MSB-2311, SHR-1316, sugemalimab (CS-1001; WBP3155), A167 (KL-A167, HBM9167), STI-A1015 (IMC-001), FAZ-053, BMS-936559 (MDX1105), INCB086550, GEN- Examples include, but are not limited to, 1046 (PD-L1 / 4-1BB), FPT-155 (CTLA4 / PD-L1 / CD28), M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-3 / PDL1), INBRX-105 (4-1BB / PDL1), and GNS-1480 (PD-L1 / EGFR). Furthermore, human-derived allogenes engineered to express chimeric antigen receptors (CARs) targeting PD-L1, such as PD-L1 t-HANK, are also included. Another example is heterogeneous natural killer cells.

[0172] In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 includes BPI-002.

[0173] In various embodiments, the antibodies described herein include domvanalimab, ralzapastotug, vivostrimab, osiperlimab, tilagolumab, and rillbegos. It is used in combination with anti-TIGIT antibodies such as Tomig, Berrestutug, Etigirimab, BMS-986207, RG-6058, or AGEN-1307.

[0174] Agonists or activators of members of the TNF receptor superfamily (TNFRSF). In various embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein is an agonist of one or more TNF receptor superfamily (TNFRSF) members, for example, TNFRSF1A (NCBI gene ID: 7132), TNFRSF1B (NCBI gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI gene ID: 7293), TNFRSF5 (CD40; NCBI gene ID: 958), TNFRSF6 (FAS, NCBI gene ID: 355), TNFRSF7 (CD27 TNFRSF8 (CD30, NCBI gene ID; 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID; 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID; 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID; 8795), TNFRSF10C (CD263, TRAILR3, NCBI gene ID; 8794) TNFRSF10D (CD264, TRAILR4, NCBI gene ID; 8793), TNFRSF11A (CD265, RANK, NCBI gene ID; 8792), TNFRSF11B (NCBI gene ID; 4982), TNFRSF12A (CD266, NCBI gene ID; 51330), TNFRSF13B (CD267, NCBI gene ID; 23495), TNFRSF13C (CD268, NCBI gene ID; 115650), TN It is administered together with FRSF16 (NGFR, CD271, NCBI gene ID; 4804), TNFRSF17 (BCMA, CD269, NCBI gene ID; 608), TNFRSF18 (GITR, CD357, NCBI gene ID; 8784), TNFRSF19 (NCBI gene ID; 55504), TNFRSF21 (CD358, DR6, NCBI gene ID; 27242), and TNFRSF25 (DR3, NCBI gene ID; 8718).

[0175] Exemplary anti-TNFRSF4(OX40) antibodies that may be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tavorixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and the antibodies described in International Publication Nos. 2016179517, 2017096179, 2017096182, 2017096281, and 2018089628.

[0176] Exemplary anti-TNFRSF5 (CD40) antibodies that may be co-administered include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0177] In some embodiments, the anti-TNFRSF7 (CD27) antibody varylumab (CDX-1127) is co-administered.

[0178] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include, but are not limited to, urelumab, utomirumab (PF-05082566), AGEN2373, and ADG-106.

[0179] Examples of co-administered anti-TNFRSF18(GITR) antibodies include, but are not limited to, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and antibodies described in International Publication Nos. 2017096179, 2017096276, 2017096189, and 2018089628. In some embodiments, antibodies or fragments thereof that simultaneously target TNFRSF4(OX40) and TNFRSF18(GITR) are co-administered. Such antibodies are described, for example, in International Publication Nos. 2017096179 and 2018089628.

[0180] Interleukin receptor agonists In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with interleukin receptor agonists, such as IL-2, IL-7, IL-15, IL-10, and IL-12 agonists. Examples of IL-2 receptor agonists include proleukin (aldesleukin, IL-2); pegylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707); benpegaldesleukin, AIC-284, and ALKS-423. Examples of IL-7 include CUI-101, Neo-2 / 15; IL-15 receptor agonists, such as ALT-803, NKTR-255, and hetIL-15, interleukin-15 / Fc fusion proteins, AM-0015, NIZ-985, SO-C101, IL-15 Synthorin (PEGylated IL-15), P-22339, and IL-15-PD-1 fusion protein N-809; and CYT-107.

[0181] Examples of interferon receptor agonists that can be combined with the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein include interferon alpha, interferon alpha-2b, interferon alpha-n3, PEGylated interferon alpha, interferon gamma, gepon, nucleoferon, pegylated interferon alpha-2a, pegylated interferon alpha-2b, and RPI-MN.

[0182] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with an Flt3 agonist such as GS-3583 or CDX-301.

[0183] Bispecific and tripspecific natural killer (NK) cell engineering Ja In various embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are used to target NK cell activating receptors, e.g., CD16A, type C lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H and NKG2F), innate cytotoxic receptors (NKp30, NKp44 and NKp46), killer cell type C lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (mediating antibody-dependent cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6 and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1 and A bispecific NK-cell engager (BiKE) or trispecific NK-cell engager (TriKE) (e.g., one without Fc) or a bispecific antibody (e.g. If necessary, it is combined with (having Fc). Examples of co-administered anti-CD16 bispecific antibodies, BiKE, or TriKE include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). The anti-CD16 binding bispecific molecule may or may not have Fc. Examples of co-administered bispecific NK cell engagers target CD16 and one or more HIV-related antigens, as described herein. BiKE and TriKE are described, for example, Felices, et al., Methods Mol Biol. (2016) 1441:333-346 and Fang, et al., Semin Immunol. (2017) 31:37-54. Examples of trispecific NK cell inducers (TRiKE) include OXS-3550, HIV-TriKE, and CD16-IL-15-B7H3 TriKe.

[0184] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivative (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0185] Phosphatidylinositol 3-kinase (PI3K) inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with a PI3K inhibitor. Examples of PI3K inhibitors include idelalisib, alpelisib, buparisib, CAI orotinate, copanlisib, duvelisib, gedatricib, neratinib, panulisib, perifosin, pictilisib, piraralisib, pukitinib mesylate, rigosertib, rigosertib sodium, sonolicid, taselicib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, Examples include DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474.

[0186] Alpha-4 / Beta-7 Antagonist In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with an alpha-4 / beta-7 antagonist. Examples of integrin alpha-4 / beta-7 antagonists include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast-methyl, and vedolizumab.

[0187] HPK1 / MAP4K1 inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with an inhibitor of mitogen-activated protein kinase 1 (MAP4K1, also known as hematopoietic progenitor kinase 1 (HPK1); NCBI gene ID: 11184). Examples of HPK1 inhibitors include, but are not limited to, ZYF-0272 and ZYF-0057.

[0188] Pharmacokinetic enhancers In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with a pharmacokinetic enhancer. Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

[0189] Additional treatments Examples of additional therapeutic agents include compounds disclosed in WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), US 2013 / 0165489 (University of Pennsylvania), US 2014 / 0221378 (Japan Tobacco), US 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences), and US 2013 / 091096 (Boehringer Ingelheim).

[0190] Combination therapy for HIV In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine), BIKTARVY® (vicregravir + emtricitabine + tenofovir alafenamide), COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA (registered trademark) (Tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY (registered trademark) (Tenofovir alafenamide and emtricitabine); ODEFSEY (registered trademark) (Tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA (registered trademark) (Tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); Adefovir; Adefovir dipivoxil; Cobicistat; Emtricitabine; Tenofovir; Tenofobi Ludisoproxil; Tenofovir disoproxil fumarate; Tenofovir alafenamide; Tenofovir alafenamide hemi fumarate; TRIUMEQ (registered trademark) (dolutegravir, abacavir, and lamivudine); Dolutegravir, abacavir sulfate, and lamivudine; Raltegravir; Raltegravir and lamivudine; Maraviroc; Enfuvirtide; ALUVIA (registered trademark) (KALETRA (registered trademark); Lopinavir and ritonavir); COMBIVIR (registered trademark) (Zidovudine and lamivudine; AZT+3TC); EPZICOM(registered trademark)(LIVEXA(registered trademark); abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR(registered trademark)(abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine;Prolastin; Hosamprenavir; Hosamprenavir Calcium Effervescent; Etravirine; Nelfinavir; Nelfinavir Mesylate; Interferon; Didanosine; Stavudine; Indinavir; Indinavir Sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir Mesylate; Aldesleukin; Zalcitabine; Tipranavir; Amprenavir; Delavirdine; Delavirdine Mesylate; Radha-108 (Receptol); Lamivudine and Tenofovir Disoproxil Fumarate; Efavirenz, Lamivudine, and Tenofovir Disoproxil Fumarate; Phosphazide; Lamivudine, Nevirapine, and Zidovudine; Abacavir; and Abacavir Sulfate, in combination with one, two, three, or four additional therapeutic agents selected therefrom.;

[0191] It will be understood by those skilled in the art that the additional therapeutic agents listed above may be included in two or more of the classes listed above. The particular classes are not intended to limit the functionality of these compounds listed in those classes.;

[0192] In some embodiments, the anti-HIV gpA20 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV protease inhibitor compound. In additional embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, the anti-HIV gp120 described herein V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody are combined with at least one HIV nucleoside inhibitor, integrase inhibitor, and pharmacokinetic enhancer of reverse transcriptase. In another embodiment, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with two HIV nucleoside inhibitors or nucleotide inhibitors of reverse transcriptase.

[0193] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0194] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0195] In some embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are administered in combination with or concurrently with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

[0196] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, the second additional therapeutic agent being emtricitabine.

[0197] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody described herein are combined with one or more additional therapeutic agents in therapeutically effective doses ranging from 1 mg to 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 1000 mg, or 1500 mg of the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody or its antigen-binding fragment, for example. In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody described herein are combined with one or more additional therapeutic agents in therapeutically effective doses ranging from about 0.1 mg / kg to about 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 8 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, or 50 mg / kg of the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody or its antigen-binding fragment. In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody described herein is combined with one or more additional therapeutic agents in therapeutically effective doses ranging from about 5 mg to about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, 250 mg, 300 mg, 500 mg, 1000 mg, or 1500 mg of the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody or its antigen-binding fragment.

[0198] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody described herein are combined with 5 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody described herein are combined with 5 to 10, 5 to 15, 5 to 20, 5 to 25, 25 to 30, 20 to 30, 15 to 30, or 10 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody described herein are combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody described herein are combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine.

[0199] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody described herein are combined with 200-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody described herein is combined with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300-400, or 250-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody described herein is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. The anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody described herein may be combined with the drugs provided herein in any dosage (e.g., 1 mg to 500 mg of anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs conjugated antibody), as each dosage combination described herein is specifically and individually enumerated.

[0200] Long-acting HIV inhibitors In some embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein can be co-administered with a long-acting HIV inhibitor. In various embodiments, the long-acting HIV inhibitor can be co-administered twice a year, for example, every six months (Q6M), every 24 weeks (Q24W), every 25 weeks (Q25W), or every 26 weeks (Q26W). Examples of long-acting HIV inhibitors that can be administered concomitantly or co-administered include, but are not limited to, long-acting capsid inhibitors such as lenacapavir; long-acting integrase inhibitors such as long-acting bictegravir (GS-9883), GS-6212, long-acting cabotegravir (LA), long-acting raltegravir (RAL); long-acting NRTIs such as EFdA / MK-8591 (4-ethinyl-2-fluoro-2-deoxyadenosine; islatravir) implants, tenofovir alafenamide fumarate (TAF) implants, injectable rovahovir etalafenaamide (GS-9131); long-acting NNRTIs such as GS-5894, long-acting dapivine (DPV), and long-acting rilpivirine Examples include erythrocytes (RPV), el-sulfavirine; also, VM-1500 LAI, maraviroc (LAI), and long-acting dolutegravir (RPV). Long-acting anti-HIV drugs are outlined in Singh, et al., Pharmaceuticals (2019) 12:62.

[0201] HIV vaccine In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with an HIV vaccine. Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, and HIV MAG vaccines. DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, adenovirus vector vaccines (e.g., Ad5, Ad26, or Ad35), Simian adenovirus (chimpanzee, gorilla, rhesus monkey, i.e., rhAd), adeno-associated virus vector vaccines, chimpanzee adenovirus vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), coxsackievirus vaccines, enterovirus vaccines, gorilla adenovirus vaccines, lentivirus vector vaccines, bipartite or tripartite arenavirus vaccines (e.g., LCMV, Pichinde), trimer-based HIV-1 vaccines, measles virus vaccines, flavivirus vector vaccines, tobacco mosaic virus vector vaccines, varicella-zoster virus vaccines, human parainfluenza virus 3 (PIV) 3) Vaccines, poxvirus vaccines (modified vaccinia virus Ankara (MVA), orthopoxvirus-derived NYVAC and avipoxvirus-derived ALVAC (canalipoxvirus) strains); fowlpox virus vaccines, rhabdovirus vaccines, such as vesicular stomatitis virus (VSV) and maraba virus; recombinant human CMV (r Examples include hCMV vaccines, alphavirus vaccines such as Semlik Forest virus, Venezuelan encephalitis virus, and Sindbisvirus (see, for example, Lauer, et al, Clin Vaccine Immunol (2017) 24(1):e00298-16); LNP-formulated mRNA therapeutic vaccines; and LNP-formulated self-replicating RNA / self-amplifying RNA vaccines.

[0202] Examples of HIV vaccines include, but are not limited to, AAVLP-HIV vaccine, AdC6-HIVgp140, AE-298p, anti-CD40.Env-gp140 vaccine, Ad4-EnvC150, BG505 SOSIP.664 gp140 adjuvant vaccine, BG505 SOSIP.GT1.1 gp140 adjuvant vaccine, ChAdOx 1.tHIVconsv1 vaccine, CMV-MVA triplex vaccine, ChAdOx 1.HTI, Chimigen HIV vaccine, ConM SOSIP.v7 gp 140, rgp120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAX B / E (gp120) (RV 144), and monomer gp120. HIV-1 subtype C vaccine, MPER-656 liposome subunit vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, Multiclade DNA recombinant adenovirus-5 rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-GP, Pennvax-G / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA-51, PolyICLC adjuvanted vaccine, TatImmune, GTU-multiHIV(FIT-06), ChAdV 63.HIV consv, gp 140[Delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-EnvF, SeV-Gag vaccine, AT-20, DNK-4, ad 35-Grin / ENV, TBC-M 4, HIVAX, HIVAX-2, N 123-VRC-34.01-induced epitope HIV vaccines, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV 1-PG9DP, GOVX-B11, GOVX-B21, GOVX-C55, TVI-HIV-1, Ad-4(Ad 4-env Clade C+Ad 4-mGag), Paxvax, EN 41-UGR7C, EN41-FPA2, ENOB-HV-11, ENOB-HV-12, exoVACC, PreVaxTat, AE-H, MYM-V 101, CombiHIVvac, ADVAX, MYM-V 201, MVA-CMDR, MagaVax, DNA-Ad 5 gag / pol / nef / nev(HVTN 505), MVATG-17401, ETV-01, CDX-1401, DNA and Sev vector vaccines expressing SCaVII, rcAD26.MOS1.HIV-Env, Ad26.Modified HIV vaccine, Ad26.Mod.HIV+MVA mosaic vaccine+gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, VIR-1111, IHV-001, and virus-like particle vaccines such as pseudovirion vaccine, CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-type DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccine, conjugate polypeptide vaccine, dendritic cell vaccine (DermaVir, etc.), gag DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), I i-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RN-activated HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, vaccine-4x+romidepsin, variant gp120 polypeptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI and MVA.HTI, MVA.tHIVconsv3, MVA.tHIVconsv4, VRC-HIVDNA 016-00-VP+VRC-HIVADV 014-00-VP, INO-6145, JNJ-9220, gp 145 C.6980; eOD-GT8 60-dose system vaccine, PD-201401, env(A,B,C,A / E) / gag(C)DNA vaccine, gp120(A,B,C,A / E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine (GLA-SE immunostimulatory), HIV p24gag basal-enhancing plasmid DNA vaccine, HIV-1 iglb12 neutralizing VRC-01 antibody-stimulating anti-CD4 vaccine, arenavirus vector vaccines (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimen, mRNA-based prophylactic vaccines, VPI-211, HIV ANTI-CD40.ENV GP140, HIV ANTI-CD40.HIV5PEP, multimer HIV gp120 vaccine TBL-1203HI, CH505 TF chTrimer, CD40.HIVRI.Env vaccine, VRC-HIVRGP096-00-VP, Drep-HIV-PT-1, BG505 MD39.3 mRNA, BG505 MD39.3 Examples include gp151 CD4KO mRNA, BG505 MD39.3 gp151 mRNA, mRNA-1644, mRNA-1547, mRNA-1574, and anti-HIV vaccines described in International Publication Nos. 2021011544 and International Publication Nos. 2022155258.

[0203] Combination therapy for contraception In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with a family control regime or a contraceptive regime. Therapeutic agents used for family control (contraception) include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinylestradiol, etinodiol, etonogestrel, levomefolate, levonorgestrel, linestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norlegestromine, norethindrone, nortinodrel, norgestimate, olmeroxifen, segestersone acetate, ulipristal acetate, and any combination thereof.

[0204] Gene therapy and cell therapy In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with gene or cell therapy regimens. Gene and cell therapies include, but are not limited to, gene modifications for silencing genes; genetic approaches for directly killing infected cells; injections of immune cells designed to replace a large portion of the patient's own immune system to enhance the immune response to infected cells, or to activate the patient's own immune system to kill infected cells, or to locate and kill infected cells; and genetic approaches for modifying cell activity to further alter the endogenous immune response to infection. Examples of cell therapies include LB-1903, ENOB-HV-01, ENOB-HV-21, ENOB-HV-31, GOVX-B01, HSPC-overexpressing ALDH1 (LV-800, HIV infection), AGT103-T, and SupT1 cell-based therapies. An example of dendritic cell therapy is AGS-004. CCR5 gene editing agents include, but are not limited to, SB-728T and SB-728-HSPC. Examples of CCR5 gene inhibitors include Cal-1 and lentiviral vector CCR5 shRNA / TRIM5 alpha / TAR decoy transduced autologous CD34-positive hematopoietic progenitor cells (HIV infection / HIV-associated lymphoma). In some embodiments, C34-CCR5 / C34-CXCR4 expressing CD4-positive T cells are co-administered with one or more multispecific antigen-binding molecules. In some embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-binding antibody described herein are co-administered with AGT-103 transduced autologous T cell therapy or AAV-eCD4-Ig gene therapy.

[0205] Gene Editor In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein are combined with gene editing agents, such as HIV-targeted gene editing agents. In various embodiments, the genome editing system can be selected from the group consisting of CRISPR / Cas9 complexes, zinc finger nuclease complexes, TALEN complexes, homing endonuclease complexes, and meganuclease complexes. Exemplary HIVs that target the CRISPR / Cas9 system include, but are not limited to, EBT-101 and XVIR-TAT.

[0206] CAR-T cell therapy In some embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody described herein can be co-administered with a population of immunoeffector cells genetically engineered to express a chimeric antigen receptor (CAR), the CAR comprising an HIV antigen-binding domain. The HIV antigen comprises the HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, a CD4 induction binding site on gp120, an N-glycan on gp120, V2 of gp120, and a membrane proximal region on gp41. The immunoeffector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof. The cells can be autologous or allogeneic. Examples of HIV CAR-Ts include A-1801, A-1902, convertible CAR-T, VC-CAR-T, CMV-N6-CART, anti-HIV duoCAR-T, anti-Env duoCAR T, anti-CD4 CART cell therapy, CD4 CAR+C34-CXCR4+CCR5 ZFN T cells, dual anti-CD4 CART-T cell therapy (CD4 CAR+C34-CXCR4 Examples include T cells, anti-CD4 MicAbody antibody + anti-MicAbody CAR T cell therapy (iNKG2D CAR, HIV infection), GP-120 CAR-T therapy, autologous hematopoietic stem cells genetically engineered to express CD4 CAR, and C46 peptide.

[0207] TCR-T cell therapy In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with a population of TCR-T cells. The TCR-T cells target a TCR-binding domain that targets a peptide derived from an HIV-derived peptide present on the surface of virus-infected cells, such as the Gag protein presented by HLA-A02 on the surface of HIV-infected cells, and a second antigen-binding domain that targets CD3, and is engineered to target IMC-M113V, which is a TCR bispecificity. * A02 to target a peptide derived from the Gag protein presented by, and a second antigen-binding domain that targets CD3, and is engineered to target IMC-M113V, which is a TCR bispecificity.

[0208] 6. Kit A kit comprising one or more unit doses of a first antibody that binds to HIV gp120 V3 glycan and a second antibody that binds to HIV gp120 CD4bs, wherein the first antibody and the second antibody have serum half-life extending amino acid substitutions, and the first antibody and the second antibody are formulated for administration twice a year (e.g., every 6 months (Q6M), every 26 weeks (Q26W), every 25 weeks (Q25W), or every 24 weeks (Q24W)), and a kit is further provided.

[0209] In certain embodiments, a kit comprising the anti-HIV gp120 V3 glycan binding antibody and anti-HIV gp120 CD4bs binding antibody described herein is combined in unit dosage form, separately or as a mixture, as a liquid or suspension dosage form for intravenous, intramuscular or subcutaneous administration, for co-administration to a patient.

[0210] In some embodiments, the unit doses of the first antibody that binds to HIV gp120 V3 glycan and the second antibody that binds to HIV gp120 CD4bs are independently in the range of about 500 mg to about 3000 mg, for example, about 550 mg to about 2900 mg, for example, about 600 mg to about 2800 mg, for example, about 650 mg to about 2700 mg, for example, about 700 mg to about 2600 mg, for example, about 850 mg to about 2550 mg. In some embodiments, the unit dose of the anti-HIV gp120 V3 glycan-binding antibody (e.g., 10-1074-LS) is 850 mg. In some embodiments, the unit dose of the anti-HIV gp120 V3 glycan-binding antibody (e.g., 10-1074-LS) is 2550 mg. In some embodiments, the unit dose of anti-HIV gp120 CD4bs-conjugated antibody (e.g., 3BNC117-LS) is 2550 mg. In some embodiments, the unit dose of both anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-conjugated antibody (e.g., 3BNC117-LS) is 1700 mg. In some embodiments, anti-HIV gp120 V3 glycan and anti-HIV gp120 The unit dose of the CD4bs-conjugated antibody (e.g., 3BNC117-LS) is 2550 mg for both. In some embodiments, the unit dose of the anti-HIV gp120 V3 glycan-conjugated antibody (e.g., 10-1074-LS) is 850 mg, and the unit dose of the anti-HIV gp120 CD4bs-conjugated antibody (e.g., 3BNC117-LS) is 2550 mg. In some embodiments, the unit dose of the anti-HIV gp120 V3 glycan-conjugated antibody (e.g., 10-1074-LS) is 850 mg, and the anti-HIV gp120 The unit dose of CD4bs-conjugated antibody (e.g., 3BNC117-LS) is 1700 mg. In some embodiments, the unit dose of anti-HIV gp120 V3 glycan-conjugated antibody (e.g., 10-1074-LS) is 850 mg, and the unit dose of anti-HIV gp120 CD4bs-conjugated antibody (e.g., 3BNC117-LS) is 1275 mg.

[0211] In some embodiments, the kit further comprises one or more unit doses of long-acting anti-HIV drugs. In some embodiments, one or more long-acting HIV drugs are selected from long-acting capsid inhibitors, long-acting integrase chain transfer inhibitors (INSTIs), long-acting non-nucleoside reverse transcriptase inhibitors (NNRTIs), long-acting nucleoside reverse transcriptase inhibitors (NRTIs), and long-acting protease inhibitors (PIs). In some embodiments, the long-acting capsid inhibitor includes lenacapavir. In some embodiments, the unit dose of lenacapavir is in the range of 300 mg to 1000 mg, for example, 300 mg, 600 mg, 900 mg, or 927 mg. If necessary, the unit dose of lenacapavir can be formulated for oral, subcutaneous, or intravenous administration. In some embodiments, the long-acting INSTI is selected from bictegravir, raltegravir, elvitegravir, dolutegravir, and cabotegravir. In some embodiments, the long-acting NNRTI is selected from rilpivirine, el-sulfavirine, doravirine, and GS-5894. In some embodiments, the long-acting NRTI is selected from islatravir and its prodrugs, tenofovir alafenamide (TAF) and tenofovir prodrugs, lovahovir etalafenamide, and GS-1614. In some embodiments, the long-acting protease inhibitor is selected from atazanavir, ritonavir, darunavir, GS-1156 and GS-1156 prodrugs, and combinations thereof.

[0212] In one embodiment, the kit comprises one or more pharmaceutical packs or one or more containers (e.g., vials, ampoules, pre-filled syringes) containing one or more components of the pharmaceutical compositions described herein, such as the anti-HIV gp120 V3 glycan-conjugated antibody and the anti-HIV gp120 CD4bs-conjugated antibody described herein. In some examples, the kit comprises the pharmaceutical compositions described herein. In one embodiment, a kit is provided comprising the anti-HIV gp120 V3 glycan-conjugated antibody and the anti-HIV gp120 CD4bs-conjugated antibody or the pharmaceutical composition thereof in combination with one or more (e.g., one, two, three, four, one or two, one to three or one to four) additional therapeutic agents (such as those disclosed above).

[0213] Optionally, any information relating to such containers may be a notice in the form prescribed by the government agency regulating the manufacture, use, or sale of a drug or biological product, and such notice shall reflect the approval by the agency for manufacture, use, or sale for human administration. [Examples]

[0214] The following examples are provided to illustrate, but not to limit, the claimed invention.

[0215] Example 1 Ph1b trial: 26-week primary outcome of long-acting broad-spectrum neutralizing antibody combined with lenacapavir. GS-US-536-5816 (NCT04811040 on ClinicalTrials.gov) is a randomized, blinded, proof-of-concept (POC) phase 1b trial evaluating the safety and efficacy of a single dose each of long-acting regimens of lenacapvir, telopavimab (GS5423, 3BNC117-LS, TAB), and dinriluvimab (GS2872, 10-1074-LS, ZAB) in adult HIV-1 infected patients who are virologically suppressed (HIV-1 RNA < 50 copies / mL) with oral ART.

[0216] Administration Participants were adults with HIV virological suppression ≥2 years on ART (HIV-1 RNA <50 copies / mL), susceptibility to both bNAbs by HIV proviral phenotype (PhenoSense mAb IC90 ≤2ug / mL, monogram Biosciences), and CD4 lowest point ≥350 and CD4 count ≥500 at baseline. Participants who provided written consent and met all eligibility criteria were randomized in a 1:1 ratio to one of two treatment groups based on the dose of GS 2872 (10 mg / kg or 30 mg / kg IV). All participants received GS-5423 (30 mg / kg IV) and oral lenacapavir 600 mg on days 1 and 2, and lenacapavir 927 mg for injection subcutaneously on day 1. Participants were clinically monitored every 4 weeks with plasma HIV-1 RNA until the primary endpoint at week 26. The primary endpoint was safety, and the secondary endpoint included virological results from FDA snapshot analysis.

[0217] In the initial human trial of 3BNC117-LS (NCT03254277), 39 participants received a single dose of 3BNC117-LS at doses ranging from 3 to 30 mg / kg (IV) or 150 or 300 mg (SC). Five participants received placebo. Of the 43 enrolled participants, five reported five response-type adverse events (AEs) within four weeks post-administration, all of which were grade 1 in severity: tenderness at the injection site (2%), headache (2%), malaise / fatigue (2%), and nausea (4%). In addition, 48 unreported AEs were reported by 28 of the 43 enrolled participants, with 29 of the reported events (58%) occurring within four weeks of administration of the investigational drug (intraperitoneal). Of the reported events, nine were grade 2 severity (17%), two were grade 3 severity (4%) (proteinuria and cellulitis requiring hospitalization for IV antibody), and one was grade 4 severity (hypokalemia). One participant was hospitalized with a transient ischemic attack secondary to right carotid artery thrombosis. Further evaluation revealed vascular anatomical abnormalities likely to contribute to the thrombotic event. This severe AE was not considered to be related to IP. The most commonly reported AEs were associated with upper respiratory tract infection (14%), nausea (4%), and dizziness (4%).

[0218] In the initial human trial of 10-1074-LS (NCT03554408), 77 participants were enrolled: 27 participants received a single dose of 10-1074-LS at doses ranging from 3 to 30 mg / kg (IV, n=15) or 140 or 280 mg (SC, n=12). Twelve additional participants received a single SC injection of a combination of 10-1074-LS and 3BNC117-LS, and 18 received three repeated SC injections of the antibody mixture every 12 weeks. Ten participants received a single intravenous infusion of 10-1074-LS and 3BNC117-LS at a dose of 30 mg / kg of each antibody. The remaining 10 participants received a placebo. As of July 2020, 20 requested adverse events (AEs) were reported by 15 of the 77 registered participants, all of which were grade 1 in severity: erythema / skin discoloration at the administration site (8%), pain (4%), induration (2%), headache (4%), fever (4%), malaise / fatigue (3%), and muscle pain (1%). In addition, 86 unreported AEs were reported by 46 participants. Of these, 86 AEs, 29 (33.7%), occurred within 4 weeks of IP administration. Of the reported unreported AEs, 10 were grade 2 in severity (11.6%), and 8 reported events were grade 3 in severity (9.3%): kidney stones (1%), elevated blood pressure (4%), decreased hemoglobin (1%), proteinuria (1%), and increased left-sided weakness (1%). Three participants who experienced a transient grade 3 increase in blood pressure on the day of IP administration had a pre-existing history of hypertension. The most common adverse events (AEs) were associated with upper respiratory tract infections (25%), localized musculoskeletal pain (8%), and gastroenteritis symptoms (8%).

[0219] NCT04811040 Overview of the Ph1b Test Participants discontinued their background oral ART regimen one day before receiving the investigational drug on day 1. Of the 124 screened participants, 55 were sensitive to both bNAbs, 21 were randomized, and 20 received the full study regimen. The median age was 44 years (IQR 34, 51), 14% were female, 14% were Black, 14% were Asian, 33% were Hispanic / Latino, and the median CD4 count was 909 (IQR 687, 1270).

[0220] At week 26, all participants resumed their background oral ART baseline regimen (or a suitable regimen selected by the principal investigator) and returned to the clinic for visits at weeks 38 and 52.

[0221] Approximately 20 participants were in the primary cohort. These were adults with HIV-1, no history of virologic failure (VF) or antiretroviral drug resistance, CD4 lowest point ≥ 350 cells / μL, and at least two years of first-line ART demonstrating virological suppression (HIV-1 RNA < 50 copies / mL) for at least 18 months prior to screening, and who were willing to change their ART regimen for the trial strategy. A schematic diagram of the study is provided in Figure 1.

[0222] Twenty-one participants were enrolled in the primary cohort and randomized. Twenty participants received the complete study regimen (10 in each treatment group), and one participant received oral lenacapavir but withdrew consent before completing the administration procedure. The median age of the participants was 44 years (range 25–61 years), 18 (86%) were male at birth, and all had HIV-1 RNA <50 copies / mL and CD4 count >500 cells / μL. The demographic and baseline characteristics of the enrolled participants are summarized in Table 1.

[0223] Therapeutic concentrations of telopavimab (TAB), dinriluvimab (ZAB), and lenacapavir (LEN) were maintained until week 26. These results are shown in Figure 1B. [Table 1]

[0224] Efficacy was evaluated at the primary endpoint at week 26 according to the FDA Snapshot algorithm. One participant in group 1 had confirmed HIV RNA ≥ 50 copies / mL at week 16 (confirmed as 155 copies / mL and 524 copies / mL) and was resuppressed by restarting baseline ART. One participant in group 2 withdrew consent at week 12 (HIV-1 RNA < 50 copies / mL). 18 / 20 (90%) of participants had HIV-1 RNA < 50 copies / mL at week 26. The primary efficacy results are summarized in Table 2 and Figure 1C. [Table 2] ^Resistance testing pending * I dropped out of the trial after 12 weeks. $AE / Reasons other than death or lack of effectiveness

[0225] There were no serious adverse events during treatment, no adverse events during treatment leading to discontinuation of the investigational drug or the study, and no deaths. The most common adverse event during treatment was injection site reactions associated with subcutaneous lenacapavir (LEN) administration (17 out of 20 patients, or 85%). Two participants had grade 3 AEs: one had injection site cellulitis, and the other had injection site erythema at the LEN injection site. The LEN + GS-5423 (telopavimab) + GS-2872 (dinriluvimab) combination was well tolerated with high efficacy for 6 months in selected virologically suppressed individuals living with HIV. These results are consistent with the conclusion that the LEN + GS-5423 (telopavimab) + GS-2872 (dinriluvimab) combination provides long-acting treatment for HIV with twice-yearly administration.

[0226] Example 2 Modeling to determine a uniform annual cycle that allows for two doses per year. In this example, the inventors performed population PK (popPK) modeling and simulation to predict the PK profiles of GS-5423 (telopavimab) and GS-2872 (dinriluvimab) based on weight-based administration and uniform administration at different doses. By comparing these profiles to target efficacy levels, the inventors determined the optimal dose range for GS-5423 and GS-2872 administered every six months in adults with HIV.

[0227] method PK data for GS-5423 (telopavimab; 3BNC117-LS, TAB) and GS-2872 (dinrilvimab; 10-1074-LS, ZAB) were obtained from four clinical studies in viremia or virally suppressed PWH (TAB: n=34, ZAB: n=36) who received a single intravenous dose of TAB (30 mg / kg) and / or ZAB (10 or 30 mg / kg) alone, in combination with LEN, or without LEN. The studies included YCO-0946 (NCT03254277) and YCO-0971 (NCT03554408). Serum concentrations of TAB and ZAB were measured using a validated Mesa Scale Discovery-electrochemiluminescence immunoassay. A two-compartment population PK model was developed to account for the PK data of GS-5423 and GS-2872 after IV and SC administration in HIV and HIV+ participants. See Joel S. Owen, Jill Fiedler-Kelly, "Introduction to Population Pharmacokinetic / Pharmacodynamic Analysis with Nonlinear Mixed Effects Models," Wiley; 1st edition, 2014 (ISBN: 9780470582299). PopPK models for TAB and ZAB were constructed using nonlinear mixed effects modeling. Covariate analysis was performed to identify significant covariates to the PK parameters of GS-5423 and GS-2872, including the effects of body weight, demographics, baseline characteristics, combination regimens, and disease status. Population PK models were simulated to predict the PK profiles of GS-5423 and GS-2872 after normalized administration of 30 or 10 mg / kg body weight or equivalent uniform doses administered intravenously every 6 months. Model simulations were performed to predict post-administration concentrations of TAB and ZAB on a flat versus body weight basis. The weight distribution is assumed to be consistent with previous studies in adults with HIV virologically suppressed by antiretroviral therapy (average weight 85 kg).

[0228] result Simulations based on PK modeling of data from four clinical studies, including YCO-0946 and YCO-0971, showed that fixed doses of 2550 mg or 850 mg of GS-5423 or GS-2872 were expected to produce similar exposures to 30 mg / kg or 10 mg / kg body weight-based doses, respectively, without a significant increase in PK variability (Figures 3A-3D). Therefore, considering that GS-5423 and GS-2872 alone or in combination up to 30 mg / kg were well tolerated in the ongoing study GS-US-536-5816 and previous studies in HIV+ participants, 2550 mg Doses up to IV are expected to be safe for both GS-5423 and GS-2872 in adults with HIV infection.

[0229] GS-5423 (TAB) and GS-2872 (ZAB) PK data in PWH were appropriately described by a two-compartment PopPK model. Increased body weight was associated with increased volume of distribution and clearance of both TAB and ZAB. PWH with viremia had a significant increase in clearance of TAB and ZAB compared to those suppressed at baseline. Model simulations suggest that a constant dose of 2550 mg results in similar exposure to 30 mg / kg for both TAB and ZAB, based on the body weight distribution in a recent phase 3 HIV study of adult PWH with a mean body weight of approximately 85 kg.

[0230] Previous studies of non-LS forms of each antibody in HIV+ participants who underwent interruption of analytical treatment (Mendoza, et al., Nature. (2018) 561(7724):479-484 and Gaebler, et al., Nature (2022) 606(7913):368-374) showed that virological suppression was generally maintained when serum concentrations of both antibodies exceeded 10 μg / mL. Based on PK simulations, 1700 mg of GS-5423 or 850 mg of GS-2872 is expected to maintain concentrations above 10 μg / mL in 99%–100% of subjects over 6 months (26 weeks) post-administration (Figures 4A–4B, Table 3). Therefore, the dose ranges of GS-5423 at 1700–2550 mg and GS-2872 at 850–2550 mg, administered intravenously every six months, are expected to be effective and safe dose ranges for both bNAbs. [Table 3]

[0231] Example 3 Evaluation of therapeutic concentrations of anti-HIV antibodies 3BNC117 / telopavimab and 10-1074 / dinriluvimab using PK-PD modeling and washout period prediction in HIV cure trials. 3BNC117 and 10-1074 induce a rapid decrease in viremia in people with HIV, and reduce the time to viral rebound in suppressed individuals with HIV during analytical treatment interruption (ATI). It has been shown to delay the interval (Caskey, et al. Nature. 2015;522:487-491, Caskey, et al. Nat Med. 2017;23:185-191, Scheid, et al. Nature. 2016;535:556-560, Mendoza, et al. Nature. 2018;561:479-484, Bar-On, et al. Nat Med. 2018;24:1701-1707, Gaebler, et al. Nature. 2022;606:368-374). The combinations of 3BNC117 / TAB and 10-1074 / ZAB, along with immunomodulators, are being studied for their potential to eliminate HIV carriers and induce long-term remission in people with HIV. However, due to their potent antiviral effects, insufficient washout periods before ATI can complicate the effectiveness assessment of the time to virological rebound in HIV cure studies. The aim of this study is to study the pharmacokinetics of these bNAbs through PK-PD viral dynamic modeling (pharmacokinetic, PK). The objectives were to characterize the pharmacokinetic-pharmacodynamic (PK-PD) relationship and to predict the required length of TAB / ZAB washout in HIV cure studies to evaluate post-treatment viral control in ATI.

[0232] method Population PK and PK-PD models were developed using a nonlinear mixed-effects modeling approach based on serum bNAb concentrations and / or viral dynamics data from six efficacy trials in people with HIV, as well as from three PK trials of 3BNC117 / TAB (GS-5423) and / or 10-1074 / ZAB (GS-2872) (Table 4). [Table 4]

[0233] bNAb concentrations were measured by ELISA assay, with the exception of study NCT03526848 (Gaebler, et al. Nature. 2022;606:368-374). For this study, concentrations measured by the TZM-bl assay (Sarzotti-Kelsoe, et al. J Immunol Methods. 2014;409:131-146) were converted to ELISA data using a log-linear correlation model calibrated based on data from study NCT02825797 (Mendoza, et al. Nature. 2018;561:479-484, Bar-On Y, et al. Nat Med. 2018;24:1701-1707), and PK was measured using both methods. The PK data for bNAb were modeled using a two-compartment linear PK model. Covariates (demographics, disease status, concomitant treatment) were tested using stepwise forward addition (α=0.01) and backward elimination (α=0.001) methods. The PK-PD model explains viral replication using the logistic growth function and viral elimination using primary kinetics, along with a nonlinear saturation (Emax) model to explain the relationship between bNAb concentration and viral elimination rate. Virus populations with different susceptibility or resistance to each bNAb were modeled to capture the mechanisms of resistance selection in treated participants (Figure 5). PK and PK-PD models were fitted sequentially. Model evaluation was performed using standard diagnostic plots and visual predictive checks. Simulations were performed to predict the PK and kinetics of viral rebound during ATI after washout periods of varying lengths following TAB / ZAB administration. Modeling was performed using Phoenix® NLME. Simulations and plots were performed using R software.

[0234] result PK modeling. The PK data of 3BNC117, 10-1074, TAB, and ZAB were well described by a linear two-compartment PK model (Figure 6). For 3BNC117 and 10-1074, the estimated half-life was the longest in people without HIV, followed by suppressed people with HIV, and the shortest in viremic people with HIV (Figure 7). For TAB and ZAB, the estimated half-life was longer than those of 3BNC117 and 10-1074, similar between people without HIV and suppressed people with HIV (62 days and 79 days for TAB and ZAB, respectively), and shorter in viremic people with HIV (46 days and 55 days for TAB and ZAB, respectively) (Figure 7).

[0235] PK-PD modeling. The PK-PD model appropriately described the dynamics of virus suppression in viremic people with HIV after treatment with different doses of 3BNC117, 10-1074 alone and in combination, and after combination treatment with TAB and ZAB (Figure 8). This model described the time to viral rebound during ATI after treatment with bNAb alone or in combination with 10-1074 (Figure 9). The estimated mean serum concentrations corresponding to 50% of the maximum drug effect (EC 50 ) for 3BNC117 / TAB and 10-1074 / ZAB were 25.4 and 32.2 μg / mL, which corresponded to EC 20 of 6.35 and 8.06 μg / mL, respectively (Table 5).

Table 5

[0236] PK-PD stimulation. PK-PD simulations predicted that, after a washout period of 48 weeks or more following single-dose intravenous administration of TAB and ZAB, the viral neutralizing effect of these bNAbs would have minimal impact on the time to viral rebound during ATI (Figure 10). After intravenous administration of 30 mg / kg / kg TAB and 10 mg / kg ZAB, both bNAb concentrations were predicted to decrease to below their in vivo EC50 in approximately the same time and maintain similar levels compared to subsequent EC50, thus minimizing the risk of resistance development from functional monotherapy with either bNAb. At week 48, both bNAb concentrations were predicted to be below EC50 in over 90% of participants (Figure 11).

[0237] Example 4 Phase 2 trial of telopavimab (GS-5423) and dinriluvimab (GS-2872) in combination with the capsid inhibitor lenacapavir (LEN) in virologically suppressed adults with HIV-1 infection. Study Design: GS-US-539-5939 (NCT05729568 on ClinicalTrials.gov) is a phase 2 randomized, open-label, active-controlled, multicenter study to evaluate the safety and efficacy of a long-acting combination regimen of the capsid inhibitors lenacapavir (LEN), telopavimab (GS-5423), and dinrilvimab (GS-2872). The study includes approximately 125 participants who are susceptible to both bNAbs according to the protocol definition criteria and meet the eligibility criteria, and who are randomized unstratified in a 2:2:1 ratio to treatment groups 1, 2, and 3. A schematic diagram of the clinical trial study is shown in Figure 12.

[0238] Participants will take their final dose of baseline oral antiretroviral therapy (ART) on day 1. Participants randomized to treatment groups 1 and 2 will discontinue their baseline ART regimen after administering the complete study regimen (subcutaneously injectable LEN, oral LEN 600 mg, and intravenous (IV) infusions of GS-5423 and GS-2872) on day 1, and self-administer oral LEN 600 mg on day 2. Participants in treatment group 3 will continue their baseline oral ARV regimen until prescribed until week 52. Participants randomized to treatment groups 1 and 2 will receive the study drug (injectable LEN and IV infusions of GS-5423 and GS-2872) at week 26. All participants in all treatment groups will return to the study center for hospital visits at weeks 4, 12, 24, 26, 38, 50, and 52.

[0239] At week 52, participants in treatment groups 1 and 2 who received the LEN, GS 5423, and GS-2872 study regimens and completed study follow-up to week 52 with plasma HIV RNA levels less than 50 copies / mL will be enrolled in the study extension phase. Participants who choose not to participate in the extension phase, or who are not eligible to participate in the extension phase, will resume their baseline ART regimen (or an appropriate regimen selected by the principal investigator) and return for study follow-up visits at 30, 90, and 180 days after week 52. Participants randomized to treatment group 3 who had plasma HIV-1 RNA levels <50 copies / mL throughout the randomization phase and completed study follow-up to week 52 will receive the LEN, GS-5423, and GS-2872 study regimens every 26 weeks. The doses of GS-5423 and GS-2872 will be determined at the time of the primary analysis. Participants in treatment group 3 who reached week 52 before the primary analysis will remain in treatment group 2 until after the completion of the primary analysis and dose selection (unless treatment group 2 is modified in response to the data monitoring committee (DMC)). Participants in treatment group 3 who have not received the trial regimen at 52 weeks will return for a 30-day follow-up visit.

[0240] An independent DMC will be convened to review safety and efficacy data after two planned interim analyses: after approximately 50% of enrolled participants have completed their visits at weeks 12 and 26, or after premature discontinuation of the study drug. In addition, if four or more participants in any LEN+bNAb treatment group in any cohort experience a virologic rebound (VR) before all participants reach week 26, an ad hoc DMC meeting may be held to evaluate the data.

[0241] Virological Failure (VF): Participants who experience a virological rebound (VR) as defined below are considered to be in a state of virological failure and may be included in resistance analysis.

[0242] Virological rebound: Participants who meet the following criteria are considered to have VR. • At any visit from day 1 onward, the HIV-1 RNA rebound is ≥ 50 copies / mL, which is subsequently confirmed at the next scheduled or unscheduled visit, or Any participant with HIV-1 RNA ≥ 50 copies / mL at the time of discontinuation of the investigational drug.

[0243] If, before all participants reach week 26, the above-mentioned scheduled or ad-hoc provisional DMC analysis of efficacy (based on virological failure (VF), i.e., plasma levels of HIV-1 RNA ≥ 50 copies / mL at weeks 12 and 26, or virological rebound) exceeds the futility threshold (i.e., in the proportion of VF > 0, the lower limit of the 95% confidence interval (CI) of the treatment difference (Treatment Group 1 or Group 2 - Stay on Baseline Regimen, SBR)), then the DMC will be considered a lower dose age. It may be recommended to drop the arm. The decision to discontinue the administration arm will be made by the sponsor.

[0244] Target population: Adults with HIV-1 receiving ART who have demonstrated virological suppression for at least 12 months prior to meeting protocol criteria for screening and susceptibility to bNAb (plasma levels of HIV-1 RNA <50 copies / mL).

[0245] Intervention period: up to 52 weeks during the randomization phase and 104 weeks during the extension phase. [Table 6] * PO = Per Os, oral administration; SC = subcutaneous administration; IV = intravenous administration.

[0246] Statistical Methods: The primary efficacy endpoint is the proportion of participants with HIV-1 RNA ≥ 50 copies / mL at week 26, as defined by the FDA-defined snapshot algorithm. 95% confidence intervals (CIs) are constructed using the unconditional exact test. Efficacy endpoints are compared between treatment groups by Fisher's exact test. The proportion of participants with HIV-1 RNA ≥ 50 copies / mL at week 52, and the proportion of participants with HIV-1 RNA < 50 copies / mL at weeks 26 and 52, as determined by the US FDA-defined snapshot algorithm, are analyzed using the same methodology as the primary efficacy endpoint.

[0247] The change in CD4+ T cell count from baseline is summarized for each treatment using descriptive statistics. The difference in the change in CD4+ T cell count from baseline between the two treatment groups is compared.

[0248] Adverse events (AEs), serious adverse events (SAEs), and adverse events leading to permanent discontinuation of the investigational drug that occur under treatment are classified by treatment group and organ. It is preferable to use the current version of the System Organ Class (SOC) and the Medical Dictionary for Regulatory Activities (MedDRA). The data is summarized using appropriate terminology. Clinical test results and changes from baseline for selected clinical tests are summarized for each treatment group and visit. The incidence of abnormal test results during treatment is summarized for each treatment group. Vital signs and electrocardiogram data are summarized for each treatment group.

[0249] List the serum or plasma concentrations and PK parameters for GS-5423, GS-2872, and LEN (and metabolites, if applicable), and summarize for each analyte using descriptive statistics by treatment group, as necessary. [Table 7]

[0250] The examples and embodiments described herein are for illustrative purposes only, and it will be understood that various modifications or changes will be suggested in light of them and should be included in the spirit and scope of this application and the appended claims. All publications, patents and patent applications referenced herein are incorporated herein by reference in their entirety for all purposes. The present invention provides, for example, the following items: (Item 1) A method for treating or preventing HIV in human subjects who require such treatment, a) Co-administration of (i) an effective amount of a first antibody that competes with or contains the VH and VL regions that bind to the epitopes of gp120 in a high-mannose patch containing a third variable loop (V3) and / or N332 oligomannose glycan, and (ii) an effective amount of a second antibody that competes with or contains the VH and VL regions that bind to the epitopes of gp120 containing a CD4 binding site (CD4bs), wherein both the first antibody and the second antibody contain Fc amino acid substitutions to extend the serum half-life, b) A method comprising co-administering an effective amount of the first antibody and an effective amount of the second antibody at a second time point at least about 24 weeks after the first time point, for example, at least about 25 weeks, for example, at least about 26 weeks. (Item 2) The first antibody and the second antibody, at the indicated position (EU index numbering), contain the following amino acids, (i) Tyrosine at position 252, threonine at position 254, and glutamic acid (YTE) at position 256, (ii) Leucine at position 428 and serine at position 434 (LS), (iii) Lysine at position 433 and phenylalanine at position 434, (iv) Glutamine at position 250 and leucine at position 428 (QL), (v) Glutamine at 307th place, valine at 311th place, and valine at 378th place (DF215 ), (vi) Aspartic acid at position 256, aspartic acid at position 286, arginine at position 307, valine at position 311, and valine at position 378 (DF228), or (vii) The method according to item 1, comprising an Fc region containing aspartic acid at position 309, histidine at position 311, and serine (DHS) at position 434. (Item 3) The first antibody is 10-1074-LS (GS-2872, dinrilbimab), 10-1074, 10-1074-J, GS-9722, GS-9721, PGT-121, PGT-121.66, PGT-121.414, PGT-122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-128, PGT-130, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-138, PGT-139, VRC24, 2G12, BG18, 354BG8, 354BG18, 354BG42, The second antibody competes with or contains the VH and VL regions of antibodies selected from 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1, and VRC29.03, wherein the second antibody is 3BNC117-LS (GS-5423, telopavimab), 3BNC117, GS-9723, 3BNC60, b12, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b01 The method according to item 1 or 2, wherein the VH and VL regions of antibodies selected from VRC08, VRC0801, NIH45-46, PGV04 (VRC-PG04), CH103, 44-VRC13.01, 1NC9, 12A12, N6, 1-18, N49-P7, NC-Cow1, IOMA, CH235, and CH235.12, N49P6, N49P7, N49P11, N49P9, and N60P25 compete with or include the VH and VL regions. (Item 4) The method according to any one of items 1 to 3, wherein the first antibody competes with or includes the VH and VL regions of 10-1074, and the second antibody competes with or includes the VH and VL regions of 3BNC117. (Item 5) The method according to any one of items 1 to 4, wherein the first antibody comprises 10-1074-LS (also known as dinrilvimab, GS-2872) and the second antibody comprises 3BNC117-LS (also known as telopavimab, GS-5423). (Item 6) The method according to any one of items 1 to 5, wherein the first antibody and the second antibody are co-administered every six months (Q6M). (Item 7) The method according to any one of items 1 to 5, wherein the first antibody and the second antibody are co-administered every 24 weeks (Q24W). (Item 8) The method according to any one of items 1 to 5, wherein the first antibody and the second antibody are co-administered every 25 weeks (Q25W). (Item 9) The method according to any one of items 1 to 5, wherein the first antibody and the second antibody are co-administered every 26 weeks (Q26W). (Item 10) The method according to any one of items 1 to 9, wherein the first antibody and the second antibody are administered intravenously in doses ranging from about 500 mg to about 3000 mg, for example, about 550 mg to about 2900 mg, for example, about 600 mg to about 2800 mg, for example, about 650 mg to about 2700 mg, for example, about 700 mg to about 2600 mg, for example, about 850 mg to about 2550 mg. (Item 11) The method according to any one of items 1 to 10, wherein the first antibody is administered intravenously at a dose of 2550 mg, and the second antibody is administered intravenously at a dose of 2550 mg. (Item 12) The method according to any one of items 1 to 10, wherein the first antibody is administered intravenously at a dose of 850 mg, and the second antibody is administered intravenously at a dose of 1275 mg. (Item 13) The method according to any one of items 1 to 10, wherein the first antibody is administered intravenously at a dose of 850 mg, and the second antibody is administered intravenously at a dose of 1700 mg. (Item 14) The method according to any one of items 1 to 10, wherein the first antibody is administered intravenously at a dose of 850 mg, and the second antibody is administered intravenously at a dose of 2550 mg. (Item 15) The method according to any one of items 1 to 14, further comprising co-administering one or more long-acting HIV drugs. (Item 16) The method according to item 15, wherein the one or more long-acting HIV drugs are selected from long-acting capsid inhibitors, long-acting integrase chain transfer inhibitors (INSTIs), long-acting non-nucleoside reverse transcriptase inhibitors (NNRTIs), long-acting nucleoside reverse transcriptase inhibitors (NRTIs), and long-acting protease inhibitors (PIs). (Item 17) The method according to item 16, wherein the one or more long-acting HIV drugs include a long-acting capsid inhibitor. (Item 18) The method according to item 16 or 17, wherein the long-acting capsid inhibitor is selected from lenacapavir, VH4004280, and VH4011499. (Item 19) The method according to any one of items 16 to 18, wherein the long-acting capsid inhibitor comprises lenacapavir. (Item 20) The method according to item 18, wherein the lenacapavir is administered in a dose ranging from 300 mg to 1000 mg. (Item 21) The method according to any one of items 18 to 20, wherein the lenacapavir is administered orally or subcutaneously. (Item 22) The method according to any one of items 16 to 21, wherein the long-acting INSTI is selected from bictegravir, raltegravir, elvitegravir, dolutegravir, cabotegravir, GS-1720, GS-6212, GS-1219, GS-3242, and VH4524184. (Item 23) The method according to any one of items 16 to 22, wherein the long-acting NNRTI is selected from rilpivirine, elsulfavirine, doravirine, and GS-5894. (Item 24) The method according to any one of items 16 to 23, wherein the long-acting NRTI is selected from islatravir and its prodrugs, tenofovir alafenamide (TAF) and tenofovir prodrugs, lovajovir etalafenamide, and GS-1614. (Item 25) The aforementioned long-acting protease inhibitor is selected from atazanavir, ritonavir, darunavir, GS-1156, and GS-1156 prodrugs, as well as combinations thereof. The method described in any one of items 16 to 24. (Item 26) The method according to any one of items 1 to 25, further comprising determining the susceptibility of the subject to HIV to one or both of the first antibody and the second antibody. (Item 27) The method described in any one of items 1 to 26, wherein the subject is a person with severe treatment experience (HTE). (Item 28) The method according to any one of items 1 to 27, wherein the subject is resistant to or unresponsive to one or more of the integrase chain transfer inhibitors (INSTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), and protease inhibitors (PIs). (Item 29) The method according to any one of items 1 to 28, wherein the subject is viremia. (Item 30) The method described in any one of items 1 to 28, wherein the subject is virologically suppressed. (Item 31) The method described in any one of items 1 to 30, wherein the subject is receiving antiretroviral therapy (ART). (Item 32) The method according to any one of items 1 to 30, wherein antiretroviral therapy (ART) is discontinued before administration of the first and second antibodies. (Item 33) The method described in any one of items 1 to 32, wherein the subject is acutely infected with HIV. (Item 34) The method described in item 33, wherein the subject has Fiebig stage IV or earlier HIV infection. (Item 35) The method described in item 34, wherein the subject has not undergone seroconversion. (Item 36) The method described in any one of items 1 to 35, wherein the subject has recently been infected with HIV. (Item 37) The method according to item 36, wherein the antibody is administered to a subject having HIV infection of Fiebig stage V or Fiebig stage VI. (Item 38) The method described in any one of items 1 to 26, wherein the subject is chronically infected with HIV. (Item 39) The method described in any one of items 1 to 38, wherein the subject is infected with HIV clade B virus. (Item 40) A method for treating or preventing HIV in human subjects who require such treatment, a) At the first time point, (i) an effective dose of 10-1074-LS (dinrilvimab, GS-2872) and (ii) an effective dose of 3BNC117-LS (telopavimab, (GS-5423)) shall be administered together. b) A method comprising co-administering an effective dose of 10-1074-LS and an effective dose of 3BNC117-LS at a second time point at least about 24 weeks after the first time point, for example, at least about 25 weeks after, for example, at least about 26 weeks after. (Item 41) The aforementioned 10-1074-LS and 3BNC117-LS are used together every six months (Q6M). The method described in item 40, which is administered. (Item 42) The method according to item 40, wherein the aforementioned 10-1074-LS and the aforementioned 3BNC117-LS are co-administered every 24 weeks (Q24W). (Item 43) The method according to item 40, wherein the 10-1074-LS and the 3BNC117-LS are co-administered every 25 weeks (Q25W). (Item 44) The method according to item 40, wherein 10-1074-LS and 3BNC117-LS are co-administered every 26 weeks (Q26W). (Item 45) The method according to any one of items 40 to 44, wherein the 10-1074-LS and the 3BNC117-LS are administered together twice over a period of one year. (Item 46) The method according to any one of items 40 to 44, wherein the 10-1074-LS and the 3BNC117-LS are administered together four times over a period of two years. (Item 47) The method according to any one of items 40 to 44, wherein the 10-1074-LS and the 3BNC117-LS are administered together six times over a period of three years. (Item 48) The method according to any one of items 40 to 44, wherein the 10-1074-LS and the 3BNC117-LS are administered together eight times over a period of four years. (Item 49) The method according to any one of items 40 to 48, wherein 10-1074-LS is administered intravenously at a dose of 30 mg / kg and 3BNC117-LS is administered intravenously at a dose of 30 mg / kg. (Item 50) The method according to any one of items 40 to 48, wherein 10-1074-LS is administered intravenously at a dose of 10 mg / kg and 3BNC117-LS is administered intravenously at a dose of 30 mg / kg. (Item 51) The method according to any one of items 40 to 50, wherein 10-1074-LS and 3BNC117 are administered intravenously independently in doses ranging from about 500 mg to about 3000 mg, for example, about 550 mg to about 2900 mg, for example, about 600 mg to about 2800 mg, for example, about 650 mg to about 2700 mg, for example, about 700 mg to about 2600 mg, for example, about 850 mg to about 2550 mg. (Item 52) The method according to item 51, wherein 10-1074-LS is administered intravenously at a dose of 2550 mg, and 3BNC117-LS is administered intravenously at a dose of 2550 mg. (Item 53) The method according to item 51, wherein 10-1074-LS is administered intravenously at a dose of 850 mg, and 3BNC117-LS is administered intravenously at a dose of 1275 mg. (Item 54) The method according to item 51, wherein 10-1074-LS is administered intravenously at a dose of 850 mg, and 3BNC117-LS is administered intravenously at a dose of 1700 mg. (Item 55) The method according to item 51, wherein 10-1074-LS is administered intravenously at a dose of 850 mg, and 3BNC117-LS is administered intravenously at a dose of 2550 mg. (Item 56) When the serum concentrations of 10-1074-LS and 3BNC117-LS are as described above, The method according to any one of items 40-55, wherein the concentration is at least 10 μg / mL after 26 weeks of administration. (Item 57) The method according to any one of items 40 to 56, wherein the plasma or serum concentration of HIV RNA is less than 50 copies / mL 26 weeks after the first time point. (Item 58) The method according to any one of items 40 to 57, further comprising co-administering one or more long-acting HIV drugs. (Item 59) The method according to item 58, wherein the one or more long-acting HIV drugs are selected from long-acting capsid inhibitors, long-acting integrase chain transfer inhibitors (INSTIs), long-acting non-nucleoside reverse transcriptase inhibitors (NNRTIs), long-acting nucleoside reverse transcriptase inhibitors (NRTIs), and long-acting protease inhibitors (PIs). (Item 60) The method according to item 59, wherein the long-acting capsid inhibitor is selected from lenacapavir, VH4004280, and VH4011499. (Item 61) The method according to item 59 or 60, wherein the long-acting capsid inhibitor comprises lenacapavir. (Item 62) The method according to item 61, wherein the lenacapavir is administered in a dose ranging from 300 mg to 1000 mg. (Item 63) The method according to any one of items 60 to 62, wherein the lenacapavir is administered orally or subcutaneously. (Item 64) The method according to any one of items 59 to 63, wherein the long-acting INSTI is selected from bictegravir, raltegravir, elvitegravir, dolutegravir, cabotegravir, GS-1720, GS-6212, GS-1219, GS-3242, and VH4524184. (Item 65) The method according to any one of items 59 to 64, wherein the long-acting NNRTI is selected from rilpivirine, elsulfavirine, doravirine, and GS-5894. (Item 66) The method according to any one of items 59 to 65, wherein the long-acting NRTI is selected from islatravir and its prodrugs, tenofovir alafenamide (TAF) and tenofovir prodrugs, lovajovir etalafenamide, and GS-1614. (Item 67) The method according to any one of items 59 to 66, wherein the long-acting protease inhibitor is selected from atazanavir, ritonavir, darunavir, GS-1156, and GS-1156 prodrugs, and combinations thereof. (Item 68) The method according to any one of items 40 to 67, further comprising determining the susceptibility of the subject to HIV to one or both of 10-1074-LS and 3BNC117-LS. (Item 69) The method described in any one of items 40 to 68, wherein the subject is a person with severe treatment experience (HTE). (Item 70) The aforementioned targets are integrase chain transfer inhibitors (INSTIs) and non-nucleoside reverse transcriptases. The method according to any one of items 40 to 69, wherein the patient is resistant to or unresponsive to one or more of the following: an inhibitor (NNRTI), a nucleoside reverse transcriptase inhibitor (NRTI), and a protease inhibitor (PI). (Item 71) The method according to any one of items 40 to 70, wherein the subject is viremia. (Item 72) The method described in any one of items 40 to 70, wherein the subject is virologically suppressed. (Item 73) The method described in any one of items 40 to 72, wherein the subject is receiving antiretroviral therapy (ART). (Item 74) The method according to any one of items 40 to 72, wherein antiretroviral therapy (ART) has been discontinued before administration of 10-1074-LS and 3BNC117-LS. (Item 75) The method described in any one of items 40 to 74, wherein the subject is acutely infected with HIV. (Item 76) The method described in item 75, wherein the subject has Fiebig stage IV or earlier HIV infection. (Item 77) The method described in item 76, wherein the subject has not undergone seroconversion. (Item 78) The method described in any one of items 40 to 77, wherein the subject has recently been infected with HIV. (Item 79) The method according to item 78, wherein the antibody is administered to a subject having HIV infection of Fiebig stage V or Fiebig stage VI. (Item 80) The method described in any one of items 40 to 68, wherein the subject is chronically infected with HIV. (Item 81) The method described in any one of items 40 to 80, wherein the subject is infected with HIV clade B virus. (Item 82) A kit comprising one or more unit doses of a first antibody that binds to HIV gp120 V3 glycan and a second antibody that binds to HIV gp120 CD4bs, wherein the first antibody and the second antibody have serum half-life-extending amino acid substitutions, and the first antibody and the second antibody are formulated for administration twice a year (for example, every 6 months (Q6M), every 26 weeks (Q26W), every 25 weeks (Q25W), or every 24 weeks (Q24W)). (Item 83) The kit according to item 82, wherein the unit doses of the first antibody and the second antibody are independently in the range of about 500 mg to about 3000 mg, for example, about 550 mg to about 2900 mg, for example, about 600 mg to about 2800 mg, for example, about 650 mg to about 2700 mg, for example, about 700 mg to about 2600 mg, for example, about 850 mg to about 2550 mg. (Item 84) A kit comprising one or more unit doses of 3BNC117-LS (telopavimab) and 10-1074-LS (dinriluvimab), wherein the 3BNC117-LS (telopavimab) and 10-1074-LS (dinriluvimab) are administered twice a year (for example, every 6 months). A kit formulated for administration every 26 weeks (Q6M), every 25 weeks (Q25W), or every 24 weeks (Q24W). (Item 85) The kit described in item 84, wherein the unit doses of 10-1074-LS and 3BNC117-LS are independently in the range of approximately 500 mg to approximately 3000 mg, for example, approximately 550 mg to approximately 2900 mg, for example, approximately 600 mg to approximately 2800 mg, for example, approximately 650 mg to approximately 2700 mg, for example, approximately 700 mg to approximately 2600 mg, for example, approximately 850 mg to approximately 2550 mg. (Item 86) The kit according to item 85, wherein one or more unit doses of 10-1074-LS are 2550 mg, and one or more unit doses of 3BNC117-LS are 2550 mg. (Item 87) The kit according to item 85, wherein one or more unit doses of 10-1074-LS are 850 mg, and one or more unit doses of 3BNC117-LS are 1275 mg. (Item 88) The kit according to item 85, wherein one or more unit doses of 10-1074-LS are 850 mg, and one or more unit doses of 3BNC117-LS are 1700 mg. (Item 89) The kit according to item 85, wherein one or more unit doses of 10-1074-LS are 850 mg, and one or more unit doses of 3BNC117-LS are 2550 mg. (Item 90) The kit according to any one of items 84 to 89, wherein the 10-1074-LS and the 3BNC117-LS are formulated for intravenous administration. (Item 91) A kit according to any one of items 82 to 90, wherein the one or more unit doses are contained in one or more containers. (Item 92) The kit according to item 91, wherein one or more of the containers are selected from vials, ampoules, and pre-filled syringes. (Item 93) A kit as described in any one of items 82 to 92, further comprising one or more long-acting HIV drugs in one or more unit doses. (Item 94) The kit according to item 93, wherein one or more long-acting HIV drugs in one or more unit doses are selected from long-acting capsid inhibitors, long-acting integrase chain transfer inhibitors (INSTIs), long-acting non-nucleoside reverse transcriptase inhibitors (NNRTIs), long-acting nucleoside reverse transcriptase inhibitors (NRTIs), and long-acting protease inhibitors (PIs). (Item 95) The kit according to item 94, wherein the long-acting capsid inhibitor is selected from lenacapavir, VH4004280, and VH4011499. (Item 96) The method according to item 94 or 95, wherein the long-acting capsid inhibitor comprises lenacapavir. (Item 97) A kit as described in item 96, in which the unit dose of lenacapavir is in the range of 300 mg to 1000 mg. (Item 98) The aforementioned lenacapvir is formulated for oral or subcutaneous administration, as described in item 96 or 97. A kit containing [something]. (Item 99) The kit according to any one of items 94 to 98, wherein the long-acting INSTI is selected from bictegravir, raltegravir, elvitegravir, dolutegravir, cabotegravir, GS-1720, GS-6212, GS-1219, GS-3242, and VH4524184. (Item 100) The kit according to any one of items 94 to 99, wherein the long-acting NNRTI is selected from rilpivirine, elsulfavirine, doravirine, and GS-5894. (Item 101) The kit according to any one of items 94 to 100, wherein the long-acting NRTI is selected from islatravir and its prodrugs, tenofovir alafenamide (TAF) and tenofovir prodrugs, lovajovir etalafenamide, and GS-1614. (Item 102) The kit according to any one of items 94 to 101, wherein the long-acting protease inhibitor is selected from atazanavir, ritonavir, darunavir, GS-1156, and GS-1156 prodrugs, and combinations thereof.

Claims

[Claim 1] The invention described in the specification.

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