Dosing and Scheduling Regimens for Broadly Neutralizing Antibodies

Abstract

Methods are provided for administering a long-acting, broadly neutralizing anti-HIV antibody, e.g., Q6M, Q24W, Q25W, or Q26W, twice a year. In another aspect, methods of treating or preventing HIV are provided in a human subject in need thereof. In some embodiments, the methods include: (a) at a first time point, co-administering (i) an effective amount of 10-1074-LS (ginriluvimab, GS-2872) and (ii) an effective amount of 3BNC117-LS (telopavimab, GS-5423); and (b) at a second time point at least about 24 weeks, e.g., at least about 25 weeks, e.g., at least about 26 weeks, after the first time point, co-administering an effective amount of 10-1074-LS and an effective amount of 3BNC117-LS.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 373,597, filed August 26, 2022, and U.S. Provisional Application No. 63 / 514,711, filed July 20, 2023, which are incorporated by reference herein in their entireties for all purposes.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML format and is incorporated herein by reference in its entirety. The XML copy created on July 20, 2023 is titled 1445-WO-PCT_sequencelisting.XML and is 512,134 bytes in size. [Background technology]

[0003] Human immunodeficiency virus type 1 (HIV-1) infection causes severe, life-threatening disease and remains one of the leading causes of morbidity and mortality worldwide. Approximately 1 million people in the United States (US) are infected with HIV (people with HIV, PWH), and more than 38 million people worldwide (UNAIDS. Fact Sheet - Global HIV Statistics 2021). Advances in antiretroviral (ARV) therapy (ART) for HIV have led to significant improvements in morbidity and mortality by suppressing viral replication, preserving immunological function, and avoiding disease progression to AIDS. However, current treatment strategies have failed 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, among patients prescribed chronic or lifelong treatment, "treatment fatigue," defined as "a decreased desire and motivation to maintain vigilance in adhering to a treatment regimen," can occur (Claborn, et al., Psychol Health Med (2015) 20(3):255-65), which can lead to nonadherence 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-stage selective inhibitor of HIV-1 capsid function targeted for the treatment of HIV-1 infection. Lenacapavir has potent antiviral activity and does not share overlapping resistance with any licensed product. Lenacapavir has low human clearance and is being developed as a long-acting antiretroviral drug (ARV) for the treatment and prevention of HIV-1. Lenacapavir has the potential to fulfill a high unmet medical need in PWH who could benefit from long-acting treatment or a novel mechanism of action. Monoclonal antibodies (mAbs) with neutralizing activity against HIV-1 envelope glycoproteins have been identified (Burton and Mascola, Nat Immunol (2015) 16(6):571-6), and parenteral administration of broadly neutralizing mAbs resulted in significant reductions in plasma viremia in treatment-naive PWH, and virologic suppression was maintained in virologically suppressed PWH who received broadly neutralizing antibodies (bNAbs) before undergoing analytical treatment interruption (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 a long time, potentially mitigating the challenges of daily therapy or lifelong adherence. Antibodies can also engage the immune system, potentially contributing to beneficial HIV-specific immune responses (Niessl et al., Nat Med (2020) 26(2):222-7), including the potential clearance of latently infected cells (Gaebler, et al., Nature (2022) 606(7913):368-374), which cannot be achieved with ARV drugs. As biologics, bNAbs can rescue patients from the adverse effects associated with chronic ARV therapy. However, HIV-1 is a diverse virus, and its variants have varying levels of sensitivity to any given bNAb. Therefore, bNAbs identified to date have incomplete breadth when measured by their ability to neutralize a variety 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 bNAbs can occur after antibody titers fade (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 USA (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 problem]

[0007] In one aspect, a method of treating or preventing HIV in a human subject in need thereof is provided. In some embodiments, the method comprises: (a) at a first time point, co-administering (i) an effective amount of a first antibody that competes with or comprises VH and VL regions that bind to an epitope of gp120 within the third variable loop (V3) and / or the high mannose patch comprising the N332 oligomannose glycan, and (ii) an effective amount of a second antibody that competes with or comprises VH and VL regions that bind to an epitope of gp120 comprising the CD4 binding site (CD4bs), wherein both the first and second antibodies comprise Fc amino acid substitutions to extend serum half-life; and (b) at a second time point at least about 24 weeks, e.g., at least about 25 weeks, e.g., at least about 26 weeks, after the first time point, co-administering an effective amount of the first antibody and an effective amount of the second antibody. In some embodiments, the first antibody and the second antibody contain the following amino acids at the 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; (iii) lysine at position 433 and phenylalanine at position 434; (iv) glutamine at position 250 and 428 (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 selected from the group consisting of GS-2872 (also known as ginlilvimab), 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 and the second antigen-binding molecule competes with or comprises the VH and VL regions of an antibody selected from GS-5423, 3BNC117, GS-9723, 3BNC60, b12, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, and VRC06b01. In some embodiments, the first antibody competes with or comprises the VH and VL regions of an antibody selected from VRC08, VRC0801, NIH45-46, PGV04 (VRC-PG04), CH103, 44-VRC13.01, 1NC9, 12A12, N6, 1-18, N49-P7, NC-Cowl, IOMA, CH235, and CH235.12, N49P6, N49P7, N49P11, N49P9, and N60P25. In some embodiments, the first antibody competes with or comprises the VH and VL regions of 10-1074, and the second antibody competes with or comprises the VH and VL regions of 3BNC117. In some embodiments, the first antibody comprises 10-1074-LS (also known as ginlilvimab, GS-2872) and the second antibody comprises 3BNC117-LS (also known as teropavimab, GS-5423). In some embodiments, the first antibody and the second antibody are co-administered every 6 months (Q6M). In some embodiments, the first antibody and the second antibody are co-administered every 24 weeks (Q24W). In some embodiments, the first antibody and the second antibody 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 independently administered intravenously at a dose ranging from about 500 mg to about 3000 mg, e.g., about 550 mg to about 2900 mg, e.g., about 600 mg to about 2800 mg, e.g., about 650 mg to about 2700 mg, e.g., about 700 mg to about 2600 mg, e.g., 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-administering one or more long-acting HIV drugs. In some embodiments, the one or more long-acting HIV drugs are selected from a long-acting capsid inhibitor, a long-acting integrase strand transfer inhibitor (INSTI), a long-acting non-nucleoside reverse transcriptase inhibitor (NNRTI), a long-acting nucleoside reverse transcriptase inhibitor (NRTI), and a long-acting protease inhibitor (PI). In some embodiments, the one or more long-acting HIV drugs comprise a long-acting capsid inhibitor. In some embodiments, the long-acting capsid inhibitor is selected from lenacapavir, VH4004280, and VH4011499. In some embodiments, the long-acting capsid inhibitor comprises lenacapavir. In some embodiments, the lenacapavir is administered at a dose 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 prodrugs of tenofovir, lobafovir etalafenamid, and GS-1614. In some embodiments, the long-acting protease inhibitor is selected from atazanavir, ritonavir, darunavir, GS-1156, and prodrugs of GS-1156, and combinations thereof. In some embodiments, the method further comprises determining the susceptibility of HIV in the subject to one or both of the first antibody and the second antibody. In some embodiments, the subject is viremic (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 prior to administration of the first and second antibodies, e.g., prior to 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 has not seroconverted. 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 an HIV clade B virus.

[0008] In another aspect, methods of treating or preventing HIV in a human subject in need thereof are provided. In some embodiments, the methods include: (a) at a first time point, co-administering (i) an effective amount of 10-1074-LS (ginriluvimab, GS-2872) and (ii) an effective amount of 3BNC117-LS (telopavimab, GS-5423); and (b) at a second time point at least about 24 weeks, e.g., at least about 25 weeks, e.g., at least about 26 weeks, after the first time point, co-administering an effective amount of 10-1074-LS and an effective amount of 3BNC117-LS. 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 one year. In some embodiments, 10-1074-LS and 3BNC117-LS are co-administered four times over two years. In some embodiments, 10-1074-LS and 3BNC117-LS are co-administered six times over three years. In some embodiments, 10-1074-LS and 3BNC117-LS are co-administered eight times over four years. 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 independently administered intravenously at a dose ranging from about 500 mg to about 3000 mg, e.g., from about 550 mg to about 2900 mg, e.g., from about 600 mg to about 2800 mg, e.g., from about 650 mg to about 2700 mg, e.g., from about 700 mg to about 2600 mg, e.g., from 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 26 weeks after the first time point. In some embodiments, the method further comprises co-administering one or more long-acting HIV medications. In some embodiments, the one or more long-acting HIV medications are selected from a long-acting capsid inhibitor, a long-acting integrase strand transfer inhibitor (INSTI), a long-acting non-nucleoside reverse transcriptase inhibitor (NNRTI), a long-acting nucleoside reverse transcriptase inhibitor (NRTI), and a long-acting protease inhibitor (PI). In some embodiments, the long-acting capsid inhibitor is selected from lenacapavir, VH4004280, and VH4011499. In some embodiments, the long-acting capsid inhibitor comprises lenacapavir. In some embodiments, the lenacapavir is administered at a dose ranging from 300 mg to 1000 mg. In some embodiments, the 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 prodrugs of tenofovir, lobafovir etalafenamid, and GS-1614. In some embodiments, the long-acting protease inhibitor is selected from atazanavir, ritonavir, darunavir, GS-1156 and prodrugs of GS-1156, and combinations thereof. In some embodiments, the method further comprises determining the susceptibility of HIV in the subject to one or both of 10-1074-LS and 3BNC117-LS. In some embodiments, the subject is viremic. 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 prior to administration of 10-1074-LS and 3BNC117-LS. 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 has not seroconverted. 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 an HIV clade B virus.

[0009] In a further aspect, kits are provided. In some embodiments, the kits include one or more unit doses of a first antibody that binds to HIV gp120 V3 glycans 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)). 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, e.g., about 550 mg to about 2900 mg, e.g., about 600 mg to about 2800 mg, e.g., about 650 mg to about 2700 mg, e.g., about 700 mg to about 2600 mg, e.g., about 850 mg to about 2550 mg. If desired, the unit doses may be the same or different. In some embodiments, the kit comprises one or more unit doses of 3BNC117-LS (telopavimab, GS-5423) and 10-1074-LS (ginriluvimab, GS-2872), wherein 3BNC117-LS (telopavimab) and 10-1074-LS (ginriluvimab) 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, e.g., about 550 mg to about 2900 mg, e.g., about 600 mg to about 2800 mg, e.g., about 650 mg to about 2700 mg, e.g., about 700 mg to about 2600 mg, e.g., 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 is 850 mg and one or more unit doses of 3BNC117-LS is 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, the one or more unit doses are contained in one or more containers. In some embodiments, the one or more containers are selected from vials, ampoules, and pre-filled syringes. In some embodiments, the kit further comprises one or more unit doses of one or more long-acting HIV medications. In some embodiments, the one or more unit doses of one or more long-acting HIV medications are selected from a long-acting capsid inhibitor, a long-acting integrase strand transfer inhibitor (INSTI), a long-acting non-nucleoside reverse transcriptase inhibitor (NNRTI), a long-acting nucleoside reverse transcriptase inhibitor (NRTI), and a long-acting protease inhibitor (PI). In some embodiments, the long-acting capsid inhibitor is selected from lenacapavir, VH4004280, and VH4011499. In some embodiments, the long-acting capsid inhibitor comprises lenacapavir. In some embodiments, the unit dose of lenacapavir ranges from 300 mg to 1000 mg. In some embodiments, the 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 prodrugs of tenofovir, lobafovir etalafenamid, and GS- 1614. In some embodiments, the long-acting protease inhibitor is selected from atazanavir, ritonavir, darunavir, GS-1156 and prodrugs of GS-1156, and combinations thereof. [Brief explanation of the drawings]

[0010] [Figure 1A] Figure 1A shows the study scheme for the Phase 1b study GS-US-536-5816 (NCT04811040 at 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 lenalidomide, SC lenalidomide, and bNAb) were included in the efficacy analysis (N = 20). Figure 1C shows the virologic efficacy outcomes at week 26 of the Phase 1b study according to the FDA Snapshot algorithm. Eighteen of 20 participants maintained viral suppression on the study regimen through week 26. One participant withdrew at week 12 with HIV-1 RNA <50 copies / mL. One participant had confirmed virologic rebound at week 16 and was re-suppressed on baseline oral ART. [Figure 1B] Figure 1A shows the study scheme for the Phase 1b study GS-US-536-5816 (NCT04811040 at 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 lenalidomide, SC lenalidomide, and bNAb) were included in the efficacy analysis (N = 20). Figure 1C shows the virologic efficacy outcomes at week 26 of the Phase 1b study according to the FDA Snapshot algorithm. Eighteen of 20 participants maintained viral suppression on the study regimen through week 26. One participant withdrew at week 12 with HIV-1 RNA <50 copies / mL. One participant had confirmed virologic rebound at week 16 and was re-suppressed on baseline oral ART. [Figure 1C]Figure 1A shows the study scheme for the Phase 1b study GS-US-536-5816 (NCT04811040 at 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 lenalidomide, SC lenalidomide, and bNAb) were included in the efficacy analysis (N = 20). Figure 1C shows the virologic efficacy outcomes at week 26 of the Phase 1b study according to the FDA Snapshot algorithm. Eighteen of 20 participants maintained viral suppression on the study regimen through week 26. One participant withdrew at week 12 with HIV-1 RNA <50 copies / mL. One participant had confirmed virologic rebound at week 16 and was re-suppressed on baseline oral ART.

[0011] [Figure 2] Pharmacokinetics of teropavimab (TAB), zinlirvimab (ZAB), and lenacapavir (LEN) in a Phase 1b study.

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

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

[0014] [Figure 5]A schematic diagram of the PK-PD viral dynamics model for evaluating the prediction of GS-5423 (3BNC117-LS, telopavimab, TAB) and GS-2872 (10-1074-LS, ginriluvimab, ZAB) concentrations and washout periods is shown. C1 and C2 are the serum concentrations of 3BNC117 / TAB and 10-1074 / ZAB, respectively; EC50, drug 1; and EC50, drug 2, the concentrations that produce 50% of the maximum effect of 3BNC117 / TAB and 10-1074 / ZAB, respectively; fi, the initial fraction of the i-th viral compartment; kg, the maximum viral replication rate constant; kdel,drug1 and kdel,drug2, the viral elimination rate constants for 3BNC117 / TAB and 10-1074 / ZAB, respectively; rd,i, the viral elimination rate for the i-th viral compartment; rg,i, the replication rate for the i-th viral compartment. Grade; TAB, telopavimab; VL1, 3 copies of virus sensitive to both BNC117 / TAB and 10-1074 / ZAB; VL2, 3 copies of virus sensitive to BNC117 / TAB and resistant to 10-1074 / ZAB; VL3, 10-1074 / ZAB sensitive and 3 copies of virus resistant to BNC117 / TAB; VL4, 3 copies of virus resistant to both BNC117 / TAB and 10-1074 / ZAB (assumed to be 0); VL total, total viral load; VLss, steady-state viral load; ZAB, zinriluvimab.

[0015] [Figure 6] Figure 1 shows observed vs. predicted bNAb serum concentrations from the PK model. bNAb, broadly neutralizing antibody; PK, pharmacokinetics; TAB, telopavimab; ZAB, ginliluvimab. Circles represent individual data points. Solid lines represent LOESS (locally estimated scatterplot smoothing) fits. Dashed lines represent lines of identity.

[0016] [Figure 7]Figure 1 shows model-predicted PK profiles after a single 30 mg / kg IV infusion dose. IV = intravenous; PWH = people with HIV. 1,000 hypothetical subjects were simulated using the population PK models for 3BNC117, 10-1074, TAB, and ZAB. The solid and dashed lines represent the model-predicted median values ​​for monotherapy and combination therapy, respectively, and the shaded areas represent the 90% prediction intervals for the population.

[0017] [Figure 8] Model-predicted versus observed viral kinetics following bNAb treatment in viremic people with HIV. Q5, 5th percentile; Q50, 50th percentile; Q95, 95th percentile. One hundred trial simulations were performed with the same number of subjects as the original dataset used to model the fit. Predicted quantiles were calculated from the median quantiles across all study replicates. Arrows represent bNAb administration.

[0018] [Figure 9] Model-predicted time to viral rebound during ATI after bNAb treatment versus observation time is shown. ATI, analytical treatment interruption; bNAb, broadly neutralizing antibody; CI, confidence interval. Doses in ATI studies: NCT02446847, 3BNC117 at 30 mg / kg for two doses every three weeks or 3BNC117 at 30 mg / kg every two weeks for up to four doses; NCT02825797, 3BNC117 at 30 mg / kg and 10-1074 at 30 mg / kg every three weeks for up to three doses; NCT03526848, 3BNC117 at 30 mg / kg and 10-1074 at 30 mg / kg every two weeks for three doses, followed by up to four doses every four weeks (Group 1, ATI started on day 2; Group 2, ATI started at week 26 [one participant started at week 21]). One hundred trial simulations were performed with the same number of subjects as the original dataset used for model fitting. The solid blue line (shaded area) represents the median (2.5-97.5 percentile) across all test replicates. The arrow indicates bNAb administration. The dotted red line indicates the onset of ATI.

[0019] [Figure 10] Figure 1 shows model-predicted viral rebound kinetics after single-dose TAB / ZAB combination treatment with different ATI onset times. PD, pharmacodynamics. The horizontal dotted line indicates the threshold for viral rebound (200 cp / mL). 1000 virtual subjects were simulated using the population PK-PD model. The solid line represents the model-predicted median value, and the shaded area represents the 90% prediction interval for the population. The arrows represent bNAb administration. The red dashed line indicates the onset of ATI.

[0020] [Figure 11] Figure 1 shows simulated bNAb serum concentrations over time and their ratios to in vivo EC50 after single IV doses of TAB 30 mg / kg and ZAB 10 mg / kg. EC50, the concentration resulting in 50% of the maximum drug effect. 1000 hypothetical subjects were simulated using a population PK model. The solid line represents the median model prediction, and the shaded area represents the 90% prediction interval for the population. The ratios were calculated based on the EC50 values ​​estimated from the PK-PD model (25.4 μg / mL for TAB and 32.2 μg / mL for ZAB). The dashed black line indicates the proposed earliest onset time of ATI.

[0021] [Figure 12] The study scheme for the Phase 2 study GS-US-539-5939 is shown. DETAILED DESCRIPTION OF THE INVENTION

[0022] 1. Introduction Thus, the present method is based in part on the discovery that co-administration of a first anti-HIV broadly neutralizing antibody (bNAb) that binds to an epitope of gp120 within the third variable loop (V3) and / or the high-mannose patch, including the N332 oligomannose glycan, with a second bNAb that binds to an epitope of gp120 comprising the CD4 binding site (CD4bs) with an Fc amino acid substitution that extends serum half-life, can be administered twice a year (e.g., Q6M, Q24W, Q25W, Q26W) and achieve therapeutic efficacy. To date, bNAbs, even those with serum half-life-extending Fc amino acid substitutions, have been administered every three months or more frequently.

[0023] Generally, the method involves co-administering, at a first time point, (i) an effective amount of a first antibody that competes with or comprises a VH and VL region that binds to an epitope of gp120 within the third variable loop (V3) and / or the high mannose patch comprising the N332 oligomannose glycan, and (ii) an effective amount of a second antibody that competes with or comprises a VH and VL region that binds to an epitope of gp120 comprising the CD4 binding site (CD4bs), where both the first and second antibodies comprise Fc amino acid substitutions to extend serum half-life; and then 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, e.g., at least about 25 weeks, e.g., at least about 26 weeks, from the first time point.

[0024] 3BNC117 and 10-1074 have been modified to increase their half-life, resulting in GS 5423 (telopavimab, 3BNC117-LS) and GS-2872 (ginlilvimab, 10-1074-LS), which allow for the maintenance of high bNAb concentrations over extended periods. Combination therapy consisting of long-acting bNAbs and antiretroviral drugs may overcome the limitations of bNAbs alone and enable a safe, long-acting treatment option for PWH. The modified LS version contains two amino acid substitutions in the 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) and extend the half-life of the bNAbs in vivo. Affinity binding to other Fc receptors remains unchanged. These modifications do not alter the fragment antigen-binding domain (Fab) of the bNAbs and therefore do not alter their interaction with antigen or safety profile.

[0025] 2. Co-administered broadly neutralizing antibodies a.General broadly neutralizing antibodies HIV-1 is the predominant family of HIV and accounts for 95% of all infections worldwide, while HIV-2 is found primarily 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 is responsible for the majority of HIV / AIDS cases worldwide. Based on their genetic sequences, M groups are further subdivided into subtypes (also called clades) according to their prevalence in different geographic 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 subtypes are known to be more virulent or resistant to different drugs. There are also "circulating recombinants" or CRFs resulting from recombinations between viruses of different subtypes, each of which is given a number. CRF12_BF, for example, is a recombination between subtypes B and F. Subtype A is common in West Africa. Subtype B is the predominant form in Europe, America, Japan, Thailand, and Australia. Subtype C is the predominant 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 recombined with subtype A as CRF01_AE. Subtype F has been found in Central Africa, South America, and Eastern Europe. Subtype G (and CRF02_AG) has been found in Africa and Central Europe. Subtype H is restricted 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 primarily in North, Central, and West Africa, and Caribbean subtype K is restricted to the Democratic Republic of the Congo and Cameroon. These subtypes may be further divided into subsubtypes such as A1 and A2, or F1 and F2. In 2015, the CRF19 strain, a recombinant of subtypes A, D, and G with a subtype D protease, was found to be strongly associated with rapid progression to AIDS in Cuba.

[0028] The present disclosure provides methods involving the administration of human anti-HIV neutralizing antibodies (e.g., broadly neutralizing Abs) that target the gp120 polypeptide on the surface of HIV-infected cells, among other things. Neutralizing antibodies against viral envelope proteins provide adaptive immune defense against HIV-1 exposure by blocking infection of susceptible cells. Broad neutralization indicates that the antibody can neutralize HIV-1 isolates from different clades. Thus, 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) that targets HIV-1. A "neutralizing antibody" is one that can neutralize the ability of HIV to initiate and / or sustain infection in host and / or target cells in vitro. The present disclosure provides neutralizing monoclonal human antibodies, which recognize an antigen from HIV, e.g., the gp120 polypeptide. In certain embodiments, a "neutralizing antibody" can inhibit entry of 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 et al., J. Virol., 70(1):445-458 (1996)).

[0030] In some embodiments, the administered antibody is or is derived from a human broadly neutralizing antibody (e.g., monoclonal) that targets HIV-1. A "broadly neutralizing antibody" refers to 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 broadly neutralizing antibody may neutralize at least 2, 3, 4, 5, 6, 7, 8, 9, or more different strains of HIV-1, where the strains belong to the same or different clades. In certain embodiments, a broadly neutralizing antibody can neutralize multiple HIV-1 species belonging to at least 2, 3, 4, 5, or 6 different clades. In certain embodiments, the inhibitory concentration of an anti-HIV gp120 V3-glycan-binding antibody or antigen-binding fragment can be less than about 0.0001 μg / ml, less than about 0.001 μg / ml, less than about 0.01 μg / ml, less than about 0.1 μg / ml, less than about 0.5 μg / ml, less than about 1.0 μg / ml, less than about 5 μg / ml, less than about 10 μg / ml, less than about 25 μg / ml, less than about 50 μg / ml, or less than about 100 μg / ml to neutralize about 50% of input virus in a neutralization assay.

[0031] gp120 The envelope glycoprotein gp120 (or gp120) 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 bound together and anchored to the membrane by the gp41 protein. Gp120 is essential for viral infection because it facilitates HIV entry into host cells through interactions with cell surface receptors. These receptors include DC-SIGN, heparan sulfate proteoglycans, and the CD4 receptor. Binding to CD4 on helper T cells induces the initiation of a cascade of conformational changes in gp120 and gp41, which leads to fusion of the virus with the host cell membrane.

[0032] Gp120 is encoded by the HIV env gene, which 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 protease furin into gp120 (approximately 480 amino acids) and gp41 (approximately 345 amino acids).

[0033] Broadly neutralizing antibodies are described, for example, in 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 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 by reference in their entireties for all purposes.

[0034] b.Antibodies directed against 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 camouflaging glycans (the so-called "high-mannose patch") (Sok, et al., Immunity (2016) 45, 31-45). Broadly neutralizing antibodies (bnAbs) against the V3 glycan site are the most common of all Abs 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 (SEQ ID NO: 1).

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

[0036] The amino acid sequence of an exemplary gp160 polypeptide of an HIV clone identified in NCBI Ref Seq No. NP_057856.1 is provided below (the V3 hypervariable loop is shown in bold, and the potential N-linked glycosylation site at N332 is shown in bold and underlined): [ka]

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

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

[0039] The amino acid sequence of another exemplary gp120 polypeptide (see bioafrica.net / proteomics / ENV-GP120prot.html) is 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 (SEQ ID NO: 6)

[0040] Genomic diversity among independent human immunodeficiency virus type 1 (HIV-1) isolates, and to a lesser extent between successive isolates from the same patient, and even within a single patient isolate, is a well-known feature of HIV-1. This sequence heterogeneity is distributed throughout the genome, but the majority of the heterogeneity is located in the env gene. Comparison of deduced amino acid sequences from several different isolates showed that sequence heterogeneity is clustered in five variable regions (designated V1 to V5) of the surface glycoprotein gp120. The V3 region, although only 35 amino acids long, exhibits considerable sequence variability. Interestingly, despite this variability, the V3 region is the only region that encodes the CD4 +These include determinants that mediate interactions with cells. Increased gp120 variability leads to higher levels of viral replication, suggesting increased viral fitness in individuals infected with diverse HIV-1 variants. Variability in potential N-linked glycosylation sites (PNGS) also leads to increased viral fitness. PNGS allow the attachment of long-chain carbohydrates to the highly variable region of gp120. Thus, the number of PNGS in env may affect viral fitness by rendering it more or less susceptible to neutralizing antibodies.

[0041] Exemplary broadly neutralizing antibodies that bind to gp120 in the third variable loop (V3) and / or in the high mannose patch containing the 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-134, PGT-135, PGT-136, PGT-137, PGT-138, PGT-139, PGT-140, PGT-141, PGT-142, PGT-143, PGT-144, PGT-145, PGT-146, PGT-147, PGT-148, PGT-149 ... These include GT-135, PGT-136, PGT-137, PGT-138, PGT-139, 10-1074, 10-1074-LS (ginrilvimab, 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. Additional broadly neutralizing antibodies that bind to gp120 in the third variable loop (V3) and / or high mannose patch, including the N332 oligomannose glycan, and that can be used in the methods described herein are described, for example, in WO 2012 / 030904; WO 2014 / 063059; WO 2016 / 149698; WO 2017 / 106346; WO 2018 / 075564; WO 2018 / 125813; WO 2018 / 237148; WO 2019 / 226829; WO 2020 / 023827; WO 2020 / 056145; and Kerwin, et al., J Pharm Sci. 2020 Jan;109(1):233-246, which are incorporated herein by reference in their entirety for all purposes.

[0042] Exemplary sequences of complementarity determining regions (CDRs) of antibodies targeting the HIV gp120 V3 glycan region are provided in Tables A1-A4. Exemplary sequences of VH and VL of antibodies targeting the HIV gp120 V3 glycan region are provided in Table B.

Table A1-1

Table A1-2

Table A1-3

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 B-1

Table B-2

Table B-3

Table B-4

Table B-5

[0043] In some embodiments, the anti-HIV gp120 V3 glycan-binding antibody comprises a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3, and a VL comprising a VL-CDR1, a VL-CDR2, and a second VH-CDR3, wherein VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 comprise the sequences set forth 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. , SEQ ID NOs: 14, 19, 20, 17, 11 and 18, SEQ ID NOs: 21, 22, 23, 24, 25 and 26, SEQ ID NOs: 21, 22, 27, 24, 25 and 26, SEQ ID NOs: 28, 29, 30, 31, 32 and 33, SEQ ID NOs: 34, 35, 36, 37, 25 and 38, SEQ ID NOs: 39, 40, 41, 42, 43 and 44, SEQ ID NOs: 45, 46, 47, 48, 49 and 50, SEQ ID NOs: 45, 51, 52, 53, 49 and 54, SEQ ID NOs: 55, 56, 57, 58, 59 and 44, SEQ ID NOs: 56, 57, 58, 59 and 44, SEQ ID NOs: 57, 58, 59 and 44, SEQ ID NOs: 59, 60, 59 and 61, SEQ ID NOs: 59, 61, 62, 59 and 62, SEQ ID NOs: 63, 64, 65, 66, 67, 68, 68 and 69, SEQ ID NOs: 64, 65, 66, 67, 68, 69 and 70, SEQ ID NOs: 65, 66, 67, 68, 69 and 71, SEQ ID NOs: 67, 68, 69 and 72, SEQ ID NOs: 68, 69 and 73, S Nos. 60, 46, 61, 58, 49 and 44, SEQ ID NOs. 62, 63, 64, 65, 66 and 67, SEQ ID NOs. 68, 69, 70, 71, 72 and 73, SEQ ID NOs. 74, 75, 76, 77, 78 and 73, SEQ ID NOs. 79, 80, 81, 82, 83 and 73, SEQ ID NOs. 84, 85, 86, 87, 88 and 89, SEQ ID NOs. 84, 90, 91, 92, 93 and 89, SEQ ID NOs. 84, 85, 86, 95, 96 and 89, SEQ ID NOs. 84, 97, 98, 99, 100, and 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 (CDRs according to Kabat).

[0044] In some embodiments, the anti-HIV gp120 V3 glycan-binding antibody comprises a VH comprising VH-CDR1, VH-CDR2, and VH-CDR3, and a VL comprising VL-CDR1, VL-CDR2, and a second VH-CDR3, wherein VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 comprise the sequences set forth 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 89 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 (CDRs according to Chothia).

[0045] In some embodiments, the anti-HIV gp120 V3 glycan-binding antibody comprises a VH comprising VH-CDR1, VH-CDR2, and VH-CDR3, and a VL comprising VL-CDR1, VL-CDR2, and a second VH-CDR3, wherein VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 comprise the sequences set forth 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, 168, 169, 170, 171, and 172; 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, 201 1, and 44, SEQ ID NOs: 202, 203, 204, 200, 193, and 44, SEQ ID NOs: 205, 206, 207, 208, 209, and 67, SEQ ID NOs: 210, 211, 212, 213, 214, and 73, SEQ ID NOs: 215, 216, 217, 218, 219, and 73, SEQ ID NOs: 220, 216, 221, 222, 223, and 73, SEQ ID NOs: 224, 225, 86, 226, 227, and 89, SEQ ID NOs: 228, 225, 86, 226, 227, and 89, SEQ ID NOs: 229, 230, 91, 231, 232, and 89, SEQ ID NO: 229, 233, 91, 231, 232 and 89, SEQ ID NOs: 228, 225, 86, 234, 235 and 89, SEQ ID NOs: 229, 236, 98, 231, 232 and 101, SEQ ID NOs: 229, 236, 98, 231, 232 and 102, SEQ ID NOs: 229, 236, 98, 237, 232 and 89, SEQ ID NOs: 229, 238, 91, 231, 232 and 89, SEQ ID NOs: 229, 236, 98, 231, 232 and 105, SEQ ID NOs: 239, 240, 108, 241, 242 and 111, SEQ ID NOs: 243, 244, 113, 241, 245,and 115, or SEQ ID NOs: 243, 246, 117, 241, 242, and 119 (CDRs according to IMGT).

[0046] In some embodiments, the anti-HIV gp120 V3 glycan-binding antibody comprises a VH comprising VH-CDR1, VH-CDR2, and VH-CDR3, and a VL comprising VL-CDR1, VL-CDR2, and a second VH-CDR3, wherein VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 comprise the sequences set forth 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 NO: 259; 260, 261, 257, 251, and 258, SEQ ID NOs: 262, 263, 264, 265, 266, and 267, SEQ ID NOs: 262, 263, 268, 265, 266, and 267, SEQ ID NOs: 269, 270, 271, 272, 273, and 274, SEQ ID NOs: 275, 276, 277, 278, 279, and 280, SEQ ID NOs: 281, 282, 283, 284, 285, and 286, SEQ ID NOs: 287, 288, 289, 290, 291, and 286, SEQ ID NOs: 287, 292, 293, 294, 291, and 295, SEQ ID NOs: 296, 297, 298, 299, 291, 292, 293, 294, 295, 296, 297, 298, 299, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 98, 299, 300, and 286, SEQ ID NOs: 301, 288, 302, 299, 291, and 286, SEQ ID NOs: 303, 304, 305, 306, 307, and 308, SEQ ID NOs: 309, 310, 311, 312, 313, and 314, SEQ ID NOs: 315, 316, 317, 318, 319, and 314, SEQ ID NOs: 320, 321, 322, 323, 324, and 314, SEQ ID NOs: 325, 326, 327, 328, 329, and 330, SEQ ID NOs: 331, 326, 327, 328, 329, and 330, SEQ ID NOs: 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, and 350, SEQ ID NOs: 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, and 370, SEQ ID NOs: 371, 372, 373, 3 35, 336, and 330, SEQ ID NOs: 332, 337, 334, 335, 336, and 330, SEQ ID NOs: 331, 326, 327, 338, 339, and 330, SEQ ID NOs: 340, 341, 342, 335, 343, and 344, SEQ ID NOs: 340, 341, 342, 335, 345, 346, SEQ ID NOs: 340, 341, 342, 347, 348, and 330, SEQ ID NOs: 332, 349, 334, 335, 336, and 330, SEQ ID NOs: 340, 341, 342, 335, 345, and 350, SEQ ID NOs: 351, 352, 353, 354, 355,and 356, and SEQ ID NOs: 357, 358, 359, 354, 360, and 361, or SEQ ID NOs: 357, 362, 363, 354, 364, and 356 (CDRs according to Honegger).

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

[0048] In some embodiments, the anti-HIV gp120 V3 glycan-binding antibody comprises a VH and a VL comprising 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, respectively, to a set amino acid sequence, such as selected from the following SEQ ID NOs: SEQ ID NOs: 365 and 366, SEQ ID NOs: 367 and 368, SEQ ID NOs: 369 and 370, SEQ ID NOs: 371 and 372, SEQ ID NOs: 373 and 374, SEQ ID NOs: 375 and 376, SEQ ID NOs: 377 and 378, SEQ ID NOs: 379 and 380, SEQ ID NOs: 381 and 382, ​​SEQ ID NOs: 383 and 384, SEQ ID NOs: 385 and 386, SEQ ID NOs: 387 and 388, SEQ ID NOs: 389 and 390, SEQ ID NOs: 391 and 392, SEQ ID NOs: 393 and 394, SEQ ID NOs: 395 and 396, SEQ ID NOs: 397 and 398, Column 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 (SEQ ID NO: 433) Light chain SYVRPLSVALGETARISCGRQALGSRAVQWYQHRPGQAPILLIYNNQDRPSGIPERFSGTPDINFGTRATLTISGVEAGDEADYYCHMWDSRSGFSWSFGGATRLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 434)

[0050] c.Antibodies directed against the CD4bs region of HIV gp120 The CD4-binding site (CD4bs) of gp120 contains structurally conserved regions located within β1-α1, loop D, β20-β21 (bridging sheet), and β24-α5, which determine CD4 binding and contribute to the epitope of CD4bs-binding antibodies (Qiao, et al., Antiviral Res. 2016 Aug;132:252-61). The CD4bs of gp120 forms a conformational epitope recognized by anti-CD4bs antibodies involving one or more amino acid residues selected from Thr278, Asp279, Ala281, Thr283, Asp368, Trp427, Glu460, Ser461, Glu462, Leu452, Leu453, and Arg476. Amino acid residue and position numbering is based on the HXB2 subtype B HIV-1 isolate, which corresponds to residues 1-511 of the NCBI reference sequence NP_057856.1 provided below. Residues that may contribute to the 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 that contribute to the gp120 CD4bs are described, 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; Chen, et al., Science. 2009 Nov 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 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 bind to an epitope that overlaps with or is identical to the epitope bound by 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 HIV env gene, which 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 protease furin into gp120 (approximately 480 amino acids) and gp41 (approximately 345 amino acids).

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

[0054] The amino acid sequence of an exemplary gp120 polypeptide of an HXB2 subtype B HIV-1 isolate (GenBank accession number K0345; corresponding to residues 1-511 of 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 exemplary gp120 polypeptide is provided below: [ka]

[0056] The amino acid sequence of another exemplary gp120 polypeptide (see bioafrica.net / proteomics / ENV-GP120prot.html) is provided below. [ka]

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

[0058] Exemplary broadly neutralizing antibodies that bind to gp120 in the CD4bs and can be used in the methods described herein include, but are not limited to, antibodies derived from 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] Exemplary sequences of complementarity determining regions (CDRs) of antibodies targeting the HIV gp120 CD4bs region useful in the methods described herein are provided in Tables C1-C4. Exemplary sequences of VH and VL of antibodies targeting the HIV gp120 CD4bs region useful in the methods described herein are provided in Table D. [Table C1] [Table C2] [Table C3] [Table C4] [Table D-1] [Table D-2]

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

[0061] In some embodiments, the anti-HIV gp120 CD4bs binding antibody comprises a VH comprising VH-CDR1, VH-CDR2, and VH-CDR3, and a VL comprising VL-CDR1, VL-CDR2, and a second VH-CDR3, wherein VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 comprise the sequences set forth below: SEQ ID NOs: 478, 479, 480, 481, 482, and 483; SEQ ID NOs: 484, 479, 485, 481, 486, and 487; 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 (CDRs according to Chothia).

[0062] In some embodiments, the anti-HIV gp120 CD4bs binding antibody comprises a VH comprising VH-CDR1, VH-CDR2, and VH-CDR3, and a VL comprising VL-CDR1, VL-CDR2, and a second VH-CDR3, wherein VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 comprise the sequences set forth in SEQ ID NOs: 512, 513, 514, 481, 482, and 447, SEQ ID NOs: 515, 513, 516, 481, 482, and 447. 2 and 447, SEQ ID NOs: 517, 518, 519, 520, 490 and 455, SEQ ID NOs: 517, 522, 519, 520, 521 and 455, SEQ ID NOs: 522, 523, 524, 520, 490 and 455, SEQ ID NOs: 525, 526, 527, 528, 498 and 465, SEQ ID NOs: 529, 530, 531, 532, 504 and 471, or SEQ ID NOs: 533, 534, 535, 536, 510 and 477 (CDRs according to IMGT).

[0063] In some embodiments, the anti-HIV gp120 CD4bs binding antibody comprises a VH comprising VH-CDR1, VH-CDR2, and VH-CDR3, and a VL comprising VL-CDR1, VL-CDR2, and a second VH-CDR3, wherein VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 comprise the sequences set forth below: SEQ ID NOs: 538, 539, 540, 541, 542, and 483, SEQ ID NO: 543, 539, 544, 541, 545 and 483, SEQ ID NOs: 546, 547, 548, 549, 550 and 483, SEQ ID NOs: 546, 551, 548, 549, 550 and 483, SEQ ID NOs: 555, 556, 557, 558, 559 and 499, SEQ ID NOs: 560, 561, 562, 563, 564 and 505, SEQ ID NOs: 566, 567, 568, 569, 569 and 511 (CDRs according to Honegger).

[0064] In some embodiments, an anti-HIV gp120 CD4bs binding antibody comprises a VH and a VL comprising 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, respectively, to a set amino acid sequence, such as selected from the following SEQ ID NOs: 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, and SEQ ID NOs: 587 and 588.

[0065] In some embodiments, the anti-HIV gp120 CD4bs binding 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 (SEQ ID NO: 589) Light chain DIQMTQSPSSLSASVGDTVTITCQANGYLNWYQQRRGKAPKLLIYDGSKLERGVPSRFSGRRWGQEYNLTINNLQPEDIATYFCQVYEFVVPGTRLDLKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 590)

[0066] d. Fc amino acid substitutions that increase serum half-life In some embodiments, the Fc region or Fc domain of an anti-HIV gp120 bNAb comprises an amino acid modification that promotes an increase in the serum half-life of the anti-binding molecule. Amino acid substitutions that increase antibody half-life have been described. In one embodiment, the Fc region or Fc domain of one or both heavy chains comprises 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, e.g., U.S. Patent No. 7,658,921. This type of variant, designated "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 comprises an IgG constant domain containing one, two, three or more amino acid substitutions among amino acid residues at positions 251-257, 285-290, 308-314, 385-389, and 428-436 (EU numbering). Alternatively, the M428L and N434S ("LS") amino acid substitutions can increase the pharmacokinetic half-life of the multispecific antigen-binding molecule. In another embodiment, the Fc region or Fc domain of one or both heavy chains comprises M428L and N434S substitutions (EU numbering). In another embodiment, the Fc region or Fc domain of one or both heavy chains comprises T250Q and M428L (EU numbering) amino acid substitutions, e.g., as described in U.S. Patent Nos. 7,217,797 and 7,217,798. In another embodiment, the Fc region or Fc domain of one or both heavy chains comprises H433K and N434F (EU numbering) amino acid substitutions, e.g., as described in U.S. Patent No. 8,163,881.In other embodiments, the Fc region or Fc domain of one or both heavy chains comprises T307Q / Q311V / A378V (DF215) or T256D / N286D / T307R / Q311V / A378V (DF228) (EU numbering) amino acid substitutions, e.g., 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 comprises an aspartic acid at position 309, a histidine at position 311, and a serine at position 434 (DHS), as described in U.S. Patent Publication No. 11,059,892.

[0067] 3. Scheduling Regimen Generally, the method involves treating or preventing HIV in a human subject in need thereof by co-administering twice a year an effective amount of a bNAb that binds to an epitope of gp120 within the third variable loop (V3) and / or a high mannose patch comprising the N332 oligomannose glycan, and an effective amount of a bNAb that binds to an epitope of gp120 comprising the CD4 binding site (CD4bs), where both bNAbs have Fc amino acid substitutions to extend serum half-life. In various embodiments, the frequency of co-administration can 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] A "subject," "individual," or "patient" refers to any mammal, including humans and non-human primates. In some embodiments, the mammal is a human.

[0069] An "effective amount" or "therapeutically effective amount" refers to the amount of an antibody sufficient to effect treatment or a beneficial result in a subject when administered to a cell, tissue, or subject, alone or in combination with another therapeutic agent. What constitutes an "effective amount" varies depending on the antibody and its specific use, as well as the condition and its severity, mode of administration, and age of the subject potentially being treated, but can be routinely determined by one of ordinary skill in the art in light of their own knowledge and this disclosure. A therapeutically effective dose also refers to an amount of antibody sufficient to treat, prevent, or ameliorate an infectious or disease state, or the progression of an infectious or disease state, and an amount sufficient to increase the rate of treatment, cure, prevention, or amelioration of such a condition. When applied to an individual antibody administered alone, a therapeutically effective dose refers to that active ingredient alone. When applied to a combination, a therapeutically effective dose refers to the combined amounts of the active ingredients that result in a therapeutic effect, whether administered in combination, sequentially, or simultaneously. In some embodiments, a therapeutically effective dose allows for effective blood or serum concentrations of antibody upon a second or subsequent administration (e.g., 6 months, 24 weeks, 25 weeks, or 26 weeks after a first or previous administration).

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

[0071] As used herein, "treat," "treating," or "treatment" encompasses treatment of a disease, injury, or condition of interest (e.g., an 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., halting its development; (ii) reducing or alleviating the disease, injury, or condition, i.e., causing regression of the disease or condition; or (iii) alleviating symptoms resulting from the disease, injury, or condition. As used herein, the terms "disease," "disorder," and "condition" can be used interchangeably. As used herein, "inhibition," "treatment," "treating," and "ameliorating" are used interchangeably and refer to, for example, stasis of symptoms, prolongation of survival, partial or complete improvement of symptoms, and partial or complete eradication of a condition, disease, or disorder.

[0072] As used herein, "preventing" or "prevention" includes (i) preventing or inhibiting a disease, disorder, or condition from occurring in a subject, especially if such subject is predisposed to the condition but has not yet been diagnosed as having the condition; or (ii) reducing the likelihood of a disease, disorder, or condition occurring in a subject.

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

[0074] In certain embodiments, the anti-HIV gp120 V3 glycan-binding antibodies and anti-HIV gp120 CD4bs-binding antibodies described herein are combined in a unit dosage form for simultaneous administration to a patient, either separately or as an admixture, e.g., as a liquid or suspension dosage form for intravenous, intramuscular, or subcutaneous administration.

[0075] In certain embodiments, the anti-HIV gp120 V3 glycan-binding agent and the anti-HIV gp120 CD4bs-binding agent are formulated separately or in admixture as a liquid solution or suspension that may optionally contain one or more other agents useful for treating HIV (e.g., an HIV capsid inhibitor, e.g., lenacapavir). In certain embodiments, the liquid solution or suspension may include another active ingredient for treating HIV, such as 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 site (or allosteric) integrase inhibitor, a pharmacokinetic enhancer, and combinations thereof.

[0076] In certain embodiments, such liquid solutions or suspensions are suitable for administration twice a year, for example, 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).

[0077] In some embodiments, after one or more co-administrations of 10-1074-LS and 3BNC117-LS, the serum concentration of 10-1074-LS and 3BNC117-LS is 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, the serum concentration of HIV RNA is 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 infection In various embodiments, the human subject is an adult, adolescent, or infant. The subject may be symptomatic (e.g., viraemic) or asymptomatic (e.g., acutely infected or ART suppressed). In some embodiments, the human subject is acutely or recently infected with HIV. In certain embodiments, the subject has not seroconverted. In some embodiments, the human subject is chronically infected with HIV. The subject may or may not be receiving an antiretroviral therapy (ART) regimen.

[0080] Patients can be classified into Fiebig stages I through VI based on the sequential acquisition of positive HIV-1 clinical diagnostic assays (viral RNA measured by PCR, p24 and p31 viral antigens measured by enzyme-linked immunosorbent assay (ELISA)). p24 antigen is a viral core protein that appears transiently in the blood during the rising phase after HIV-1 RNA levels rise above 10,000 copies / mL and before the development of detectable HIV antibodies. In Fiebig stage I, only HIV-1 RNA can be detected in the blood during rising viremia. Fiebig stage II begins approximately 7 days after a positive test result detecting p24 antigen. In Fiebig stage III, IgM anti-HIV-1 antibodies can be detected using a sufficiently sensitive enzyme immunoassay (EIA) (e.g., a third-generation EIA) within approximately 5 days after a positive p24 antigen test result. Stage III typically occurs 1 to 2 weeks after the onset of acute retroviral symptoms. Fiebig stage IV occurs approximately three days after the Western blot test indicates indeterminate progression and the EIA test shows a positive result. Conversion to a clearly positive Western blot test, Fiebig stage V, generally occurs an additional seven days or about one month after 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 entireties for all purposes. In some embodiments, the biological sample being evaluated is from a human subject with HIV infection at or before Fiebig stage IV, 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 at Fiebig stage V or Fiebig stage VI HIV infection.

[0081] Susceptibility of HIV in subjects to one or both bNAbs In some embodiments, the method further comprises obtaining a biological sample (e.g., blood, serum, plasma, semen, lymph node) from the subject. In some embodiments, the method involves receiving a report of HIV gp120 amino acid residues present at designated positions of interest, e.g., one or more amino acid positions from the group consisting of 332 and 325, and 63, 179, 320, and 330, wherein the amino acid positions are referenced to SEQ ID NO:4.

[0082] In various embodiments, the method further includes identifying patients most likely to benefit from therapy with one or both of an antibody targeting the V3 glycan region of HIV gp120 and an antibody targeting the CD4bs of HIV gp120. In some embodiments, the sensitivity of a subject to one or both of an antibody targeting the V3 glycan region of HIV gp120 and an antibody targeting the CD4bs of HIV gp120 is determined as an IC90 of the bNAb of 2 μg / mL or less in the PhenoSense mAb Assay (Monogram).

[0083] HIV susceptible to anti-HIV gp120 V3-glycan antibodies In some embodiments, the patient is identified by receiving a report of the HIV strain infecting the patient that specifies HIV gp120 amino acid residues present at designated amino acid positions of interest, e.g., one or more amino acid positions from the group consisting of 332 and 325, and 63, 179, 320, and 330, where the amino acid positions are referenced in SEQ ID NO: 4 (supra, corresponding to residues 1-511 of the HXB2 subtype B HIV-1 isolate (GenBank Accession No. K0345, NCBI Ref Seq No. NP_057856.1)). Assays useful for determining whether a subject is likely to be susceptible to anti-HIV gp120 V3-glycan antibodies, including 10-1074-LS, are described, for example, in WO 2020 / 236753, which is incorporated 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 residues present at designated amino acid positions of interest in the amino acid sequence of gp120 or the gp120 protein of the HIV strain 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 polypeptide level. In some embodiments, the amino acid present at the gp120 residue position of interest is determined at the polypeptide level.

[0085] In various embodiments, the methods involve identifying subjects infected with HIV or a population of HIV that express a gp120 comprising the N332 glycan, D325, and T63, the amino acid positions refer to SEQ ID NO:4.

[0086] In various embodiments, the methods involve identifying subjects infected with HIV or a population of HIV that express a gp120 comprising the N332 glycan, D325, and L179, the amino acid positions refer to SEQ ID NO:4.

[0087] In various embodiments, the methods involve identifying subjects infected with HIV or a population of HIV that express a gp120 comprising the N332 glycan, D325, and T320, the amino acid positions refer to SEQ ID NO:4.

[0088] In various embodiments, the methods involve identifying subjects infected with HIV or a population of HIV that express a gp120 comprising the N332 glycan, D325, and H330, the amino acid positions refer to SEQ ID NO:4.

[0089] In various embodiments, the methods involve identifying subjects infected with HIV or a population of HIV that express a gp120 comprising the N332 glycan, D325, T63, and L179, where the amino acid positions refer to SEQ ID NO:4.

[0090] In various embodiments, the methods involve identifying subjects infected with HIV or a population of HIV that express a gp120 comprising the N332 glycan, D325, T63, and T320, where the amino acid positions refer to SEQ ID NO:4.

[0091] In some embodiments, the subject is infected with an HIV Clade B virus. In various embodiments, the method involves identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising the N332 glycan, D325, T63, and H330, where the amino acid positions refer to SEQ ID NO: 4. In various embodiments, the method involves identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising the N332 glycan, D325, T63, L179, T320, and H330, where the amino acid positions refer to SEQ ID NO: 4.

[0092] In various embodiments, the methods involve identifying subjects infected with HIV or a population of HIV that express a gp120 comprising the N332 glycan, D325, T320, and H330, where the amino acid positions refer to SEQ ID NO:4.

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

[0094] In various embodiments, the methods involve identifying subjects infected with HIV or a population of HIV that express a gp120 comprising the N332 glycan, D325, T63, L179, and T320, where the amino acid positions refer to SEQ ID NO:4.

[0095] In various embodiments, the methods involve identifying subjects infected with HIV or a population of HIV that express a gp120 comprising the N332 glycan, D325, T63, L179, and H330, where the amino acid positions refer to SEQ ID NO:4.

[0096] HIV susceptible to anti-HIV gp120 CD4bs antibodies In some embodiments, the patient is identified by receiving a report of the HIV strain infecting the patient that identifies an HIV gpl20 amino acid residue present at a designated amino acid position of interest, e.g., position 201, and one or more amino acid positions from the group consisting of positions 102, 108, 281, 318, and 353, where the amino acid position is referenced to SEQ ID NO: 439. 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 gpl20 or the amino acid residue present at the designated amino acid position of interest in the gpl20 protein of the HIV strain infecting the patient. Identification of the full-length or partial sequence of the gpl20 protein obtained from the subject can be determined at the polynucleotide level or polypeptide level. In some embodiments, the amino acid present at the gpl20 residue position of interest is determined at the polypeptide level. Assays useful for determining whether a subject is likely to be susceptible to anti-HIV gp120 CD4 binding site antibodies, including 3BNC117-LS, are described, for example, in WO 2022 / 103758, which is incorporated by reference in its entirety for all purposes.

[0097] In various embodiments, the methods involve identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising I201 and F353, the amino acid positions refer to SEQ ID NO:439.

[0098] In various embodiments, the methods involve identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising I201, I108, and F353, the amino acid positions refer to SEQ ID NO:439.

[0099] In various embodiments, the methods involve identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising I201, I108, A281, and F353, the amino acid positions of which refer to SEQ ID NO:439.

[0100] In various embodiments, the methods involve identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising I201, E102, I108, A281, and F353, the amino acid positions of which refer to SEQ ID NO:439.

[0101] In various embodiments, the methods involve identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising I201, E102, I108, A281, Y318, and F353, the amino acid positions of which refer to SEQ ID NO: 439.

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

[0103] Determining the gp120 amino acid of interest Determining the amino acid residues in a subject's HIV gp120 sequence at a specified position of interest, e.g., one or more amino acid positions from the group consisting of 332 and 325, and 63, 179, 320, and 330 (amino acid positions refer to SEQ ID NO: 3), 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 from a subject is 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] Optionally, primers that anneal to and amplify HIV env coding sequences, particularly the CD4bs region of gp120, can be used. In some embodiments, a nested set of primers can be used. In various embodiments, RNA can be sequenced directly 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 at an early Fiebig stage of disease, e.g., before Fiebig stage III, e.g., Fiebig stage I or II. In various embodiments, single genome amplification (SGA) and sequencing is performed. Methods for single genome 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 U S A. (2008) 105(21):7552-7. The application of SGA to determine amino acid sequence variations in HIV gp120 sequences, which can be used in the methods described herein, is described, for example, in Bar, et al., N Engl J 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 technologies are used to sequence gp120, including at least the CD4bs region, from a population of HIV strains 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 strains in one or more biological samples from a patient 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, including at least the CD4bs region, from a patient, which can be applied in the present 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 the nucleic acid sequence can be assembled into longer sequences that include at least the CD4bs region of gp120. Methods for assembling contigs 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 certain embodiments, methods are provided for treating or preventing HIV infection in a human having or at risk of having an infection, the methods comprising administering to the human a therapeutically effective amount of an anti-HIV gp120 V3 glycan and an anti-HIV gp120 CD4bs binding antibody disclosed herein in combination with a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents. In one embodiment, methods are provided for treating HIV infection in a human having or at risk of having an infection, the methods comprising administering to the human a therapeutically effective amount of an anti-HIV gp120 V3 glycan and an anti-HIV gp120 CD4bs binding antibody disclosed herein in combination with a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents.

[0106] In one embodiment, a pharmaceutical composition is provided that includes an anti-HIV gp120 V3 glycan and an anti-HIV gp120 CD4bs binding antibody as disclosed herein in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents and a pharmaceutically acceptable carrier, diluent, or excipient.

[0107] In certain embodiments, methods are provided for treating HIV infection, comprising administering to a patient in need of treatment a therapeutically effective amount of an anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibody or antigen-binding fragment thereof described herein, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating HIV infection.

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

[0109] Administration of HIV combination therapy In certain embodiments, the anti-HIV gp120 V3 glycans and anti-HIV gp120 CD4bs binding antibodies or antigen-binding fragments thereof described herein are co-administered with one or more additional therapeutic agents. Co-administration of the anti-HIV gp120 CD4bs binding antibodies described herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of the anti-HIV gp120 CD4bs binding antibodies described herein and one or more additional therapeutic agents such that therapeutically effective amounts of the anti-HIV gp120 V3 glycans and anti-HIV gp120 CD4bs binding antibodies described herein and one or more additional therapeutic agents are both present in the patient's body. When administered sequentially, the combination may be administered in two or more doses.

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

[0111] In certain embodiments, the anti-HIV gp120 V3 glycan-binding antibodies and anti-HIV gp120 CD4bs-binding antibodies disclosed herein are combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, e.g., a solid, liquid, or suspension dosage form for oral, intravenous, intramuscular, or subcutaneous administration.

[0112] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-binding 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 include another active ingredient for treating HIV, such as 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 site (or allosteric) integrase inhibitor, a pharmacokinetic enhancer, and combinations thereof.

[0113] In certain embodiments, such liquid solutions or suspensions are suitable for administration twice a year, e.g., every 6 months (Q6M), every 26 weeks (Q26W), every 25 weeks (Q25W), or every 24 weeks (Q24W).

[0114] HIV combination therapy In the above embodiments, the additional therapeutic agent may be an anti-HIV agent. 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 site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an HIV capsid inhibitor, a nucleocapsid protein 7 (NCp7) inhibitor, an HIV Tat or Rev inhibitors, inhibitors of Tat-TAR-P-TEFb immune modulators (e.g., immune stimulators), immunotherapeutics, antibody-drug conjugates, gene modifiers, gene editors (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), cell therapy (chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy, engineered B cells, NK cells, etc.), latent infection reactivators, immune-based therapies, 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 modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, HIV-1 Nef modulators, TNF alpha ligand inhibitors, HIV Nef inhibitors, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing agent modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, IFN antagonists, retrocyclin modulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, cytochrome P4503 inhibitors, CXCR4 modulators, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement agent H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, HPK1 (MAP4K1) inhibitors, proprotein convertase PC9 stimulators, 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 therapy, HIV vaccines, anti-HIV peptides, and combinations thereof.

[0115] In some embodiments, the additional therapeutic agent is selected from the group consisting of combination medications for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversers, HIV capsid inhibitors, HIV Tat or Rev inhibitors, immunomodulators (e.g., immune stimulators), immunotherapeutics, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0116] In some embodiments, the additional therapeutic agent or 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, agonists of TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, bispecific antibodies that recruit T cells and NK cells, chimeric T cell receptors that target HIV antigens, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.

[0117] In some embodiments, the additional therapeutic agent or additional 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-binding antibodies and anti-HIV gp120 CD4bs-binding antibodies disclosed herein are further combined with one or more additional anti-HIV antibodies, in some embodiments, the 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 Env trimer tip, (ii) the gp120 / gp41 interface, or (iii) the silent face of gp120. The aforementioned epitopes or regions of gp120 bound by broadly 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 by reference in their entirety for all purposes.

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

[0120] In some embodiments, the combination therapy comprises an antibody that binds to an epitope or region of gp120 in the second variable loop (V2) and / or Env trimer tip and competes with or comprises CDRs and / or VH and VL regions 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 comprises an antibody that binds to an epitope or region of gp120 at the gp120 / gp41 interface and competes with or comprises CDRs 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 comprises an antibody that binds to an epitope or region of the gp120 silent face and competes with or comprises a second VH and VL region from 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 includes 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 ("KLIC" disclosed as SEQ ID NO: 496), an invariant site of the transmembrane protein gp41, and competes with or includes a second VH and VL region from the clone 3 human monoclonal antibody (Cl3hmAb) (Protheragen). See, e.g., Vanini, et al., AIDS. (1993) 7(2):167-74.

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

[0125] In some embodiments, the combination therapy includes a multispecific antibody, e.g., a bispecific or trispecific antibody, that binds to an HIV antigen. 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 can be modified to have enhanced drug-like properties, reduced immunogenicity, enhanced ADCC, and favorable pharmacokinetic properties. Such antibodies have been shown to bind to HIV envelope glycoproteins expressed on the surface of virions or infected cells and mediate both direct virus neutralization and potent NK, monocyte, and PBMC killing of these cells. This property allows the antibodies to treat HIV infection by neutralizing the virus and also to kill and eliminate latent HIV-infected cells in infected individuals, potentially resulting in a sterile cure for HIV.

[0127] In various embodiments, all antibodies administered in a combination 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, the anti-HIV gp120 CD4bs-binding antibodies or antigen-binding fragments, and any combination of bNAbs, can be delivered in vivo, e.g., expressed in vivo, from administered mRNA or engineered B cells. Examples of in vivo delivered bNAbs include AAV8-VRC07; mRNA encoding the anti-HIV antibody VRC01; and engineered 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-binding antibodies 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® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA® (da 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 alafenamide enamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; tenofovir analogs; 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® (bicregravir + 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® (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 + zidovudine lamivudine, 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 These 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, lenacapavir + islatravir (oral, injectable), and dual-targeted HIV-1 reverse transcriptase / nucleocapsid protein 7 inhibitors.

[0130] Other HIV drugs Examples of other drugs for treating HIV include, but are not limited to, aspernigrin C, Gamimune, metenkephalin, 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, ABBV-382, obefagimod (ABX-464), AG-1105, APH-0812, APH0202, bryostatin-1, bryostatin-23, bryostatin analogs, SUW-133, BIT-225, BRII-732, BRII-778, Kodivir CYT-107, CS-TATI-1, fluoro-beta-D-ala Binose nucleic acid (FANA)-modified antisense oligonucleotides, FX-101, Griffithin, 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-002H, ODE-Bn-TFV, PA-105 0040 (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-CLIPS peptide, HRF-4467, thrombospondin analog, TBL-1004HI, VG-1177, xl-081, AVI-CO-004, rfh SP-D, [18F]-MC-225, URMC-099-C, RES-529, Verdinexor, IMC-M113V, IML-106, antiviral fc conjugates (AVC), WP-1096, WP-1097, Gammora, ISR-CO48, ISR-48, ISR-49, MK-8527, cannabinoids, ENOB-HV-32, T-1144, VIR-576, Nipamobil, Covimuro, 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 binding antibodies described herein are combined with an HIV protease inhibitor. Examples of HIV protease inhibitors include, but are not limited to, amprenavir, atazanavir, brecanavir, 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. Additional examples of HIV protease inhibitors are described, for example, in U.S. Pat. No. 10,294,234 and U.S. Patent Application Publication Nos. 2020030327 and 2019210978.

[0132] HIV ribonuclease H inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with an HIV RNase H inhibitor. Examples of HIV RNase 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 binding antibodies 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 binding antibodies described herein are combined with a non-nucleoside or non-nucleotide inhibitor. Examples of HIV non-nucleoside or non-nucleoside inhibitors of reverse transcriptase include, but are not limited to, dapivirine, delavirdine, delavirdine 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 (extended-release oral), doravirine plus israelavir (fixed-dose combination / oral tablet formulation), elsulfavirine (long-acting injectable nanosuspension), and elsulfavirine (VM-1500).

[0135] In certain 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. Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase 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 amibufenamid fumarate (HS-10234), tenofovir disoproxil hemifumarate, VIDEX®, and VIDEX®. EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fozalvudinetidoxine, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fodivudine tidoxil, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, lobafovir etalafenamid (GS-9131), GS-9148, GS-1614, GSK-4023991, MK-8504, islatravir, MK-8583, VM-2500, and KP-1461.

[0136] Additional examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include, but are not limited to, those described in U.S. Patent Application Publication Nos. 2007049754, 2016250215, 2016237062, 2016251347, 2002119443, 2013065856, 2013090473, 2014221356, and WO04096286.

[0137] HIV integrase inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-binding antibodies described herein are combined with an HIV integrase inhibitor, examples of which include, but are not limited to, elvitegravir, elvitegravir (sustained-release microcapsules), curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicamenoylquinic acid, derivatives of 3,5-dicamenoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, PEGylated raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, Carbotegravir (long-acting injectable), diketoquinoline-4-one 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, stilbene disulfonic 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 binding antibodies described herein are combined with an HIV non-catalytic or allosteric integrase inhibitor (NCINI). Examples of HIV non-catalytic or allosteric integrase inhibitors (NCINI) 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 binding antibodies described herein are combined with a capsid inhibitor. Examples of capsid inhibitors that can be combined with the agents of the present disclosure include capsid polymerization inhibitors or capsid-disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, 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, and compounds described in WO 2019 / 087016, U.S. Patent Application Publication Nos. 2014 / 0221356, 2016 / 0016973, 2018 / 0051005, and 2016 / 0108030.

[0140] HIV viral infectivity factor inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with HIV viral infectivity inhibitors, such as 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 binding antibodies described herein are combined with an HIV entry inhibitor. Examples of HIV entry (fusion) inhibitors include AAR-501, LBT-5001, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, gp160 inhibitors, and CXCR4 inhibitors.

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

[0143] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with a CXCR4 inhibitor, examples of which include plerixafor, ALT-1188, N15 peptide, varishafortide, and vMIP (Haimipu).

[0144] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-binding antibodies described herein are combined with a gp41 inhibitor. Examples of gp41 inhibitors include albuvirtide, enfuvirtide, griffithin (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 sifuvirtide.

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

[0146] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-binding antibodies described herein are combined with a gp120 inhibitor, including anti-HIV microbicides, Radha-108 (receptor) 3B3-PE38, BMS818251, BanLec, bentonite-based nanomedicines, fostemsavir tromethamine, IQP-0831, VVX-004, and BMS-663068.

[0147] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with a gp160 inhibitor. Examples of gp160 inhibitors that can be combined include fungiquinolin.

[0148] HIV maturation inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with an HIV maturation inhibitor, examples of which 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 binding antibodies described herein are combined with an HIV latency reversing agent. Examples of latent infection reactivating agents 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 proteins (e.g., XmAb24306), recombinant interleukin-15 (e.g., AM0015, NIZ-985), pegylated IL-15 (e.g., NKTR-255)), toll-like receptor (TLR) agonists (including TLR7 agonists, e.g., vesatormod (GS-9620); TLR8 agonists, e.g., sergantolimod (GS-9688); TLR9 agonists, e.g., lefitolimod (MGN-1703), histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as velcade, protein kinase C (PKC) inhibitors, and the like. C, PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors (e.g., ZL-0580, apabetalone, etc.), ionomycin, IAP antagonists (inhibitors of apoptotic proteins such as APG-1387, LBW-242), SMAC mimetics (including TL32711, LCL161, GDC-0917, HGS1029, and xebinapant (AT-406)), Debio-1143, PMA, SAHA (suberoylanilide hydroxamic acid or suberoyl, anilides, and hydroxamic acids), NIZ-985, IL-15 modulating antibodies (including IL-15, IL-15 fusion proteins, and IL-15 receptor agonists, e.g., ALT-803), JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors such as largazole analogs, APH-0812, and GSK-343. Examples of PKC activators include indolactams, prostratin, ingenol B, and DAG-lactone.

[0150] Toll-like receptor (TLR) agonists In certain embodiments, the anti-HIV gp120 V3 glycans and anti-HIV gp120 CD4bs binding antibodies described herein are combined with an agonist of a toll-like receptor (TLR), such as an agonist of 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 (vesatolimod), vesatolimod analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, 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 the compounds described in U.S. Patent Application Publication No. 20100143301 (Gilead). Sciences), U.S. Patent Application Publication No. 20110098248 (Gilead Sciences), and U.S. Patent Application Publication No. 20090047249 (Gilead Sciences), 2010143301, U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 20140073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 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 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 of compounds include, but are not limited to, compounds disclosed in U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics).

[0152] TLR7 / TLR8 agonists that may be co-administered are NKTR-262, telluritolimod, 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, motolimod, resiquimod, sergantolimod (GS-9688), VTX-1463, VTX-763, 3M-051, 3M-052, and the compounds described in 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), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 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 No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics).

[0154] Exemplary TLR9 agonists that may be co-administered include, but are not limited to, AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod, and PUL-042. Examples of TLR3 agonists include lintatolimod, 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 binding antibodies described herein are administered in conjunction with an inhibitor of histone deacetylase, e.g., an inhibitor of histone deacetylase 1, 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, belinostat, CKD-581, CS-055 (HBI-8000), CT-101, CUDC-907 (fimepinostat), entinostat, gibinostat, mocetinostat, panobinostat, pracinostat, xinostat (JNJ-26481585), resminostat, licorinostat, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.

[0156] Cytochrome P450 3 inhibitors In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies 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 modulators In certain embodiments, the anti-HIV gp120 V3 glycans and anti-HIV gp120 CD4bs-binding antibodies described herein are combined with an RNA polymerase modulator, examples of which include, but are not limited to, those described in U.S. Patent Nos. 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 binding antibodies described herein are combined with an inhibitor or antagonist of a cyclin-dependent kinase (CDK), such as cyclin-dependent kinase 4 (CDK4; NCBI Gene ID: 1019), cyclin-dependent kinase 6 (CDK6; NCBI Gene ID: 1021), or 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] Stimulator of Interferon Genes (STING) agonist In some embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-binding antibodies described herein are combined with a stimulator of interferon genes (STING) receptor agonist or activator. 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 di-AMP.

[0160] RIG-I agonists In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-binding antibodies 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, as 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 binding antibodies described herein are combined or co-administered with anti-TIM-3 (also known as Hepatitis A Virus Cellular Receptor 2 antibody (HAVCR2; NCBI Gene ID: 84868), e.g., TSR-022, LY-3321367, MBG-453, INCAGN-2390. In some embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with anti-LAG-3 (lymphocyte-activating) (NCBI Gene ID: 3902) antibodies, e.g., liratolimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385.

[0162] immune system therapy In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-binding antibodies described herein are combined with immune system therapies, such as toll-like receptor (TLR) modulators, including TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Programmed cell death protein 1 (PD-1) modulators, programmed death-ligand 1 (PD-L1) modulators, IL-15 modulators (e.g., IL-15 receptor agonists such as ALT-803; interleukin-15 / Fc fusion proteins (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 polyethyleneimine (PEI), gepon, IL-12, WF-10, VGV-1, MOR-22, BMS-936559, CYT-107, normferon, pegylated interferon alpha-2a, pegylated interferon alpha-2b, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103.

[0163] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-binding antibodies described herein are combined with a TLR agonist, including, but not limited to, vesatolimod (GS-9620), lefitolimod, tilsotolimod, lintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, sergantolimod (GS-9688), LHC-165, BDB-001, RG-7854, and teratolimod.

[0164] Immune checkpoint receptor protein modulators In various embodiments, the anti-HIV gp120 V3 glycans and anti-HIV gp120 CD4bs-binding antibodies described herein are combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and / or one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can effectively regulate T cell or NK cell activation and prevent immune leakage of infected cells. Activating or stimulating stimulatory immune checkpoints can enhance the effectiveness of immune checkpoint inhibitors in treating infections. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., as reviewed in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, immune checkpoint proteins or receptors regulate NK cell responses (reviewed, e.g., in 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 glycans and anti-HIV gp120 CD4bs-binding antibodies described herein include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane 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 immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H Long-Term Receptor-Associated 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) 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-associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112);CD226 (DNAM-1); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); PVR-related immunoglobulin domain-containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain-containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activation 3 (LAG3, CD223); signaling lymphocyte activation molecule family member 1 (SLAMF1, SL Lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16-binding protein 1 (ULBP1); UL16-binding protein 2 (ULBP2); UL16-binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript 1L (RAET1L; ULBP6) ; lymphocyte activation 3 (CD223); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 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 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 kinase 1 (HPK1, MAP4K1).

[0166] In various embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Exemplary T cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (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 inhibitor of T-cell activation 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated immunoglobulin domain-containing (PVRIG, CD112R); T cell immunoreceptor with 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, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); 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); and killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1). In various embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors.Exemplary T cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; 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); 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). See, e.g., 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 binding antibodies described herein are combined with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); 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 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-binding antibodies described herein are combined with one or more agonists or activators of one or more NK cell-stimulating immune checkpoint proteins or receptors. Exemplary NK cell-stimulating 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). See, e.g., 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, the one or more immune checkpoint inhibitors comprise a proteinaceous inhibitor (e.g., an antibody or fragment thereof, or an antibody mimetic) of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the one or more immune checkpoint inhibitors comprise a small organic molecule inhibitor 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 -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 inhibitors of programmed cell death 1 (PDCD1; NCBI Gene ID: 5133, CD279, PD-1, PD1) that may be combined or co-administered include zimberelimab (AB122, GLS-010, WBP-3055), pembrolizumab (KEYTRUDA®, MK-3475, SCH900475), nivolumab (OPDIVO®, BMS-93 6558, MDX-1106), cemiplimab (LIBTAYO®; cemiplimab-rwlc, REGN-2810), pidilizumab (CT-011), AMG-404, MEDI0680 (AMP-514), spartalizumab (PDR001), tislelizumab (BGB-A317), toripalimab (JS-001), genolimuzumab (CBT-501, APL-501, GB 226), SHR-1201, camrelizumab (SHR-1210), sintilimab (TYVYT®, IBI-308), dostallimab (TSR-042, WBP-285), lambrolizumab (MK-3475); sasanlimab (PF-06801591), cetrelimab (JNJ-63723283), serplulimab (HLX-10), retifanlimab (MGA-012), balstilimab (AGEN2034), prorugolimab (BCD 100), budigalimab (ABBV-181), bopratelimab (JTX-4014), AK-103 (HX-008), AK-105, CS-1003, BI-754091, LZM-009, Sym-021, BAT-1306, PD1-PIK, tebotelimab (MGD013; PD-1 / LAG-3), RO-7247669 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), RO- These 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 domain comprises the extracellular domain of human programmed cell death 1 ligand 2 (PD-L2) and binds to PD1 (e.g., AMP-224).

[0171] Examples of inhibitors of the CD274 molecule (NCBI Gene ID: Gene ID: 29126; B7-H, B7H1, PD-L1) that may be combined or co-administered include atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®; MSB0010718C), embafolimab (ASC22), durvalumab (IMFINZI®; MEDI-4736), BMS-936559 (MDX1105), cosibelimab (CK-301), lodapolimab (LY 3300054), valivlimab (BGB A333), embafolimab (KN035), opcolimab (HLX20), manelimab (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- These 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), as well as human-derived allogeneic natural killer cells engineered to express a chimeric antigen receptor (CAR) that targets PD-L1, such as PD-L1 t-haNK.

[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 MAX 10181. In some embodiments, the small molecule inhibitor of CTLA4 comprises BPI-002.

[0173] In various embodiments, the antibodies described herein are combined with an anti-TIGIT antibody, such as domvanalimab, ralzapastotug, vibostolimab, osipellimab, tiragolumab, rilbegostomig, berrestug, etigilimab, 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 binding antibodies described herein are agonists of one or more TNF receptor superfamily (TNFRSF) members, such as 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; NCBI Gene ID: 356), TNFRSF8 (OX40, CD134; NCBI Gene ID: 356), TNFRSF9 (OX40, CD134; NCBI Gene ID: 356), TNFRSF10 (OX40, CD134; NCBI Gene ID: 356), TNFRSF11 (OX40, CD134; NCBI Gene ID: 356), TNFRSF12 (OX40, CD134; NCBI Gene ID: 356), TNFRSF13 (OX40, CD134; NCBI Gene ID: 356), TNFRSF14 (OX40, CD134; NCBI Gene ID: 356), TNFRSF15 (OX40, CD134; NCBI Gene ID: 356), TNFRSF16 (OX40, CD134; NCBI Gene ID: 356), TNFRSF17 (OX40, CD134; NCBI Gene ID: 356), TNFRSF18 (OX40, CD134; NCBI Gene ID: 356), TNFRSF19 (OX40, CD134; NCBI Gene ID: 356), TNFRSF20 (OX , NCBI Gene ID; 939), 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 TNFRSF16 (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 (tabolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and antibodies described in WO 2016179517, WO 2017096179, WO 2017096182, WO 2017096281, and WO 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 varlilumab (CDX-1127) is co-administered.

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

[0179] Exemplary anti-TNFRSF18 (GITR) antibodies that may be co-administered 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 binding antibodies described herein are combined with an interleukin receptor agonist, e.g., an IL-2, IL-7, IL-15, IL-10, IL-12 agonist. 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), bempegaldesleukin, AIC-284, ALKS-423. 0, 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-15Synthorin (PEGylated IL-15), P-22339, and IL-15-PD-1 fusion protein N-809; examples of IL-7 include CYT-107.

[0181] Examples of interferon receptor agonists that can be combined with the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-binding antibodies 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 binding antibodies described herein are combined with an Flt3 agonist, such as GS-3583 or CDX-301.

[0183] Bispecific and trispecific natural killer (NK) cell engagers In various embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are used in combination with bi-specific NK-cell engagers (BiKE) or tri-specific NK cell engagers (TKI) directed against NK cell activating receptors, such as CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), natural cytotoxicity receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptors FcγR (which mediate antibody-dependent cellular cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (4-1BB). The anti-CD16 binding bispecific molecule may be combined with an NK-cell engager (TriKE) (e.g., without an Fc) or a bispecific antibody (e.g., with an Fc). Exemplary anti-CD16 bispecific antibodies, BiKE, or TriKE that can be co-administered include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). Optionally, the anti-CD16 binding bispecific molecule may or may not have an Fc. Exemplary bispecific NK cell engagers that can be co-administered target CD16 and one or more HIV-related antigens, as described herein. BiKE and TriKE are described, for example, in Felices, et al., Methods Mol Biol. (2016) 1441:333-346; Fang, et al., Semin Immunol. (2017) 31:37-54. Examples of trispecific NK cell inducers (TRiKEs) 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-binding antibodies 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 derivatives (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 binding antibodies described herein are combined with a PI3K inhibitor. Examples of PI3K inhibitors include idelalisib, alpelisib, bupalisib, CAI orotate, copanlisib, duvelisib, gedatricib, neratinib, panulisib, perifosine, pictilisib, pilalalisib, pukitinib mesylate, rigosertib, rigosertib sodium, sonoliside, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, 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 antagonists In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with an alpha-4 / beta-7 antagonist, examples of which 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-binding antibodies 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 glycans and anti-HIV gp120 CD4bs binding antibodies described herein are combined with a pharmacokinetic enhancer. Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

[0189] Additional therapeutic agents Examples of additional therapeutic agents include those described 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), U.S. Patent Application Publication No. 2013 / 0165489 (University of and compounds disclosed in U.S. Patent Application Publication No. 2014 / 0221378 (Japan Tobacco), U.S. Patent Application Publication No. 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), U.S. Patent Application Publication No. 20140221356 (Gilead Sciences), U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), and U.S. Patent Application Publication No. 2013 / 091096 (Boehringer Ingelheim).

[0190] HIV combination therapy In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are selected from the group consisting of ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine), BIKTARVY® (bicregravir + emtricitabine + tenofovir alafenamide), COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir Disoproxil; Tenofovir disoproxil fumarate; Tenofovir alafenamide; Tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; Raltegravir; Raltegravir and lamivudine; Maraviroc; Enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (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;in combination with one, two, three, or four additional therapeutic agents selected from: prolastin; fosamprenavir; fosamprenavir calcium efavirenz; 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 (Receptor); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate;

[0191] Those skilled in the art will appreciate that the additional therapeutic agents listed above may fall into more than one of the classes listed above. The particular classes are not intended to limit the functionality of the compounds listed in those classes.

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

[0193] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies 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 binding antibodies 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 binding antibodies described herein are combined or co-administered 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 binding antibodies 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, wherein the second additional therapeutic agent is emtricitabine.

[0197] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with one or more additional therapeutic agents in a therapeutically effective dosage, e.g., in the range of 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 binding antibody or antigen-binding fragment thereof. In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with one or more additional therapeutic agents in a therapeutically effective dosage, e.g., within the range of 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 binding antibody or antigen-binding fragment thereof. In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with one or more additional therapeutic agents in a therapeutically effective dosage, e.g., within the range of 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 binding antibody or antigen-binding fragment thereof.

[0198] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-binding antibody described herein is combined with 5-30 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-binding antibody described herein is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 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-binding antibody described herein is 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-binding antibody described herein is 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-binding antibodies 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-binding 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-binding 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 binding antibody described herein may be combined with agents provided herein in any dosage amount (e.g., 1 mg to 500 mg of anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibody), as if each combination of dosage amounts were specifically and individually recited.

[0200] Long-acting HIV inhibitors In some embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs-binding antibodies 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, e.g., every 6 months (Q6M), every 24 weeks (Q24W), every 25 weeks (Q25W), or every 26 weeks (Q26W). Examples of long-acting HIV inhibitors that can be combined 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, cabotegravir long-acting (LA), long-acting raltegravir (RAL); long-acting NRTIs, such as EFdA / MK-8591 (4-ethynyl-2-fluoro-2-deoxyadenosine; islatravir) implant, tenofovir alafenamide fumarate, fumarate (TAF) implant, injectable lobafovir etalafenamid (GS-9131); long-acting NNRTIs, such as GS-5894, long-acting dapivirine (DPV), long-acting rilpivirine (RPV), and elsulfavirine; and VM-1500 LAI, maraviroc (LAI), and long-acting dolutegravir (RPV). Long-acting anti-HIV drugs are reviewed in Singh, et al., Pharmaceuticals (2019) 12:62.

[0201] HIV vaccine In certain embodiments, the anti-HIV gp120 V3 glycans and anti-HIV gp120 CD4bs binding antibodies described herein are combined with an HIV vaccine. Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, HIV MAG vaccines, and the like. DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, adenovirus vector vaccines (e.g., Ad5, Ad26, or Ad35), simian adenovirus (chimpanzee, gorilla, rhesus macaque, 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-based vaccines, enteric virus-based vaccines, gorilla adenovirus vaccines, lentivirus-vectored vaccines, bipartite or tripartite arenavirus-based vaccines (e.g., LCMV, Pichinde), trimeric HIV-1 vaccines, measles virus-based vaccines, flavivirus-vectored vaccines, tobacco mosaic virus-vectored vaccines, varicella-zoster virus-based vaccines, human parainfluenza virus 3 (PIV) These vaccines include poxvirus-based vaccines (such as modified vaccinia virus Ankara (MVA), orthopoxvirus-derived NYVAC, and avipoxvirus-derived ALVAC (canarypox virus) strains); fowlpox virus-based vaccines; rhabdovirus-based vaccines, such as vesicular stomatitis virus (VSV) and Maraba virus; recombinant human CMV (rhCMV)-based vaccines; alphavirus-based vaccines, such as Semliki Forest virus, Venezuelan equine encephalitis virus, and Sindbis virus (see, for example, Lauer, et al., Clin Vaccine Immunol (2017) 24(1):e00298-16); LNP-formulated mRNA-based 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-HIV gp140, AE-298p, anti-CD40.Env-gp140 vaccine, Ad4-EnvC150, BG505 SOSIP.664 gp140 adjuvanted vaccine, BG505 SOSIP.GT1.1 gp140 adjuvanted vaccine, ChAdOx 1.tHIV consv1 vaccine, CMV-MVA triplex vaccine, ChAdOx 1.HTI, Chimigen HIV vaccine, ConM SOSIP.v7 gp140, rgp120(AIDSVAX), ALVAC HIV(vCP1521) / AIDSVAX B / E(gp120)(RV 144), monomeric gp120 HIV-1 subtype C vaccine, MPER-656 liposomal 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-based HIV vaccine, 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.Virus-like particle vaccines such as 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 pseudovirion vaccines, CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccine, conjugate polypeptide vaccine, dendritic cell vaccine (DermaVir, etc.), gag-based 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-mer 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 immunostimulation), HIV p24gag basal-enhanced plasmid DNA vaccine, HIV-1 iglb12 neutralizing VRC-01 antibody-stimulating anti-CD4 vaccine, arenavirus vector-based vaccine (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimen, mRNA-based prophylactic vaccine, VPI-211, HIV ANTI-CD40.ENV GP140, HIV ANTI-CD40.HIV5PEP, multimeric HIV gp120 vaccine TBL-1203HI, CH505 Examples of such vaccines include TF chTrimer, CD40.HIVRI.Env vaccine, VRC-HIVRGP096-00-VP, Drep-HIV-PT-1, BG505 MD39.3 mRNA, BG505 MD39.3 gp151 CD4KO mRNA, BG505 MD39.3 gp151 mRNA, mRNA-1644, mRNA-1547, mRNA-1574, and the anti-HIV vaccines described in WO2021011544 and WO2022155258.

[0203] Combined birth control (contraceptive) therapy In certain embodiments, the anti-HIV gp120 V3 glycans and anti-HIV gp120 CD4bs-binding antibodies described herein are combined with a birth control or contraceptive regimen. Therapeutic agents used for birth control (contraception) include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethynodiol, etonogestrel, levomefolate, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norregestromin, norethindrone, nortinodrel, norgestimate, ormeloxifene, segestrel acetate, ulipristal acetate, and any combination thereof.

[0204] Gene Therapy and Cell Therapy In certain embodiments, the anti-HIV gp120 V3 glycans and anti-HIV gp120 CD4bs-binding antibodies described herein are combined with gene or cell therapy regimens. Gene and cell therapies include, but are not limited to, genetic modifications to silence genes; genetic approaches to directly kill infected cells; infusions 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 find and kill infected cells; and genetic approaches to modify cell activity to further alter endogenous immune responsiveness 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. Examples of dendritic cell therapies include AGS-004. CCR5 gene editing agents include, but are not limited to, SB-728T and SB-728-HSPC. 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 antibodies 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-binding antibody described herein are combined with a gene editing agent, e.g., an HIV-targeting gene editing agent. In various embodiments, the genome editing system can be selected from the group consisting of a CRISPR / Cas9 complex, a zinc finger nuclease complex, a TALEN complex, a homing endonuclease complex, and a meganuclease complex. Exemplary HIV targets for 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-binding antibody described herein can be co-administered with a population of immune effector cells genetically engineered to express a chimeric antigen receptor (CAR), where the CAR comprises an HIV antigen-binding domain. The HIV antigen includes an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4-binding site on gp120, a CD4-inducible binding site on gp120, an N-glycan on gp120, V2 of gp120, or a membrane-proximal region on gp41. The immune effector 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-T 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 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 a 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 that bind to HIV-derived peptides present on the surface of virally infected cells, e.g., HLA-binding proteins present on the surface of HIV-infected cells. * It is engineered to target IMC-M113V, a TCR bispecific with a TCR binding domain that targets a peptide derived from the Gag protein presented by A02 and a second antigen-binding domain that targets CD3.

[0208] 6. Kit Further provided is a kit comprising one or more unit doses of a first antibody that binds to HIV gp120 V3 glycans 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)).

[0209] In certain embodiments, kits comprising an anti-HIV gp120 V3 glycan-binding antibody and an anti-HIV gp120 CD4bs-binding antibody described herein are combined in a unit dosage form for simultaneous administration to a patient, either separately or as an admixture, e.g., as a liquid or suspension dosage form for intravenous, intramuscular, or subcutaneous administration.

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

[0211] In some embodiments, the kit further comprises one or more unit doses of a long-acting anti-HIV drug. In some embodiments, the one or more long-acting HIV drugs are selected from a long-acting capsid inhibitor, a long-acting integrase strand transfer inhibitor (INSTI), a long-acting non-nucleoside reverse transcriptase inhibitor (NNRTI), a long-acting nucleoside reverse transcriptase inhibitor (NRTI), and a long-acting protease inhibitor (PI). In some embodiments, the long-acting capsid inhibitor comprises lenacapavir. In some embodiments, the unit dose of lenacapavir is in the range of 300 mg to 1000 mg, e.g., 300 mg, 600 mg, 900 mg, or 927 mg. If desired, 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, elsulfavirine, doravirine, and GS-5894. In some embodiments, the long-acting NRTI is selected from islatravir and its prodrugs, tenofovir alafenamide (TAF) and prodrugs of tenofovir, lobafovir etalafenamid, and GS-1614. In some embodiments, the long-acting protease inhibitor is selected from atazanavir, ritonavir, darunavir, GS-1156 and prodrugs of GS-1156, 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 of the components of the pharmaceutical compositions described herein, such as the anti-HIV gp120 V3 glycan-binding antibodies and anti-HIV gp120 CD4bs-binding antibodies described herein. In some examples, the kit comprises a pharmaceutical composition described herein. In one embodiment, a kit is provided that comprises the anti-HIV gp120 V3 glycan-binding antibodies and anti-HIV gp120 CD4bs-binding antibodies described herein or pharmaceutical compositions thereof in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents (such as those disclosed above).

[0213] Optionally, associated with such container may be a notice in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceutical or biological products, which notice reflects approval by the agency of the manufacture, use, or sale for human administration. [Example]

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

[0215] Example 1 Phase 1b study: 26W primary outcomes of a long-acting broadly neutralizing antibody in combination with lenacapavir GS-US-536-5816 (NCT04811040 on ClinicalTrials.gov) is a randomized, blinded, phase 1b, proof-of-concept study evaluating the safety and efficacy of a single dose of a long-acting regimen of lenacapvir, telopavimab (GS5423, 3BNC117-LS, TAB), and ginliruvimab (GS2872, 10-1074-LS, ZAB) in HIV-1-infected adults who were virologically suppressed (HIV-1 RNA <50 copies / mL) on oral ART.

[0216] Administration Participants were adults with HIV virological suppression on ART for ≥2 years (HIV-1 RNA <50 copies / mL), HIV proviral phenotype (PhenoSense mAb IC90 ≤2 μg / mL, Monogram Biosciences) sensitive to both bNAbs, and a CD4 nadir ≥350 and CD4 count ≥500 at study entry. Participants who provided written consent and met all eligibility criteria were randomized 1:1 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 injectable lenacapavir 927 mg subcutaneously on day 1. Participants were clinically monitored for plasma HIV-1 RNA every 4 weeks until the primary endpoint at week 26. The primary endpoint was safety, and secondary endpoints included virologic outcomes by FDA snapshot analysis.

[0217] In a first-in-human study 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. Five of the 43 enrolled participants reported five solicited adverse events (AEs) within 4 weeks of administration, all of Grade 1 severity: injection site tenderness (2%), headache (2%), fatigue / fatigue (2%), and nausea (4%). In addition, 48 non-application-specific AEs were reported by 28 of the 43 enrolled participants, with 29 (58%) of the reported events occurring within 4 weeks of intraperitoneal administration of the study drug. Of the reported events, nine were grade 2 in severity (17%), two were grade 3 in severity (4%) (proteinuria and cellulitis requiring hospitalization for IV antibodies), and one was grade 4 in severity (hypokalemia). One participant was hospitalized with a transient ischemic attack secondary to a right carotid artery thrombosis. Further evaluation revealed a vascular anatomic abnormality likely leading to a thrombotic event. This serious AE was not considered related to IP. The most commonly reported AEs were those related to upper respiratory tract infection (14%), nausea (4%), and dizziness (4%).

[0218] In a first-in-human study 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 (every 12 weeks) of the antibody cocktail. 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 placebo. As of July 2020, 20 solicited AEs were reported by 15 of the 77 enrolled participants, all of grade 1 severity: erythema / skin discoloration at the administration site (8%), pain (4%), and induration (2%), headache (4%), fever (4%), malaise / fatigue (3%), and myalgia (1%). In addition, 86 unsolicited AEs were reported by 46 participants. Of these, 29 (33.7%) of the 86 AEs occurred within 4 weeks of IP administration. Of the reported unsolicited AEs, 10 were grade 2 in severity (11.6%), and 8 reported events were grade 3 in severity (9.3%): kidney stones (1%), increased 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 medical history of hypertension. The most common AEs were those related to upper respiratory tract infection (25%), localized musculoskeletal pain (8%), and gastroenteritis symptoms (8%).

[0219] NCT04811040 Phase 1b Study Overview Participants discontinued their background oral ART regimen one day before receiving study medication on Day 1. Of 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% Asian, and 33% 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 an adapted regimen selected by the investigator) and returned to the clinic for visits at weeks 38 and 52.

[0221] Approximately 20 participants were in the primary cohort: adults with HIV-1 who had no history of virologic failure (VF) or antiretroviral drug resistance, a CD4 nadir ≥ 350 cells / µL, demonstrated virologic suppression (HIV-1 RNA < 50 copies / mL) for at least 18 months prior to screening, had been on first-line ART for at least 2 years, and were willing to change their ART regimen for the investigational strategy. A schematic diagram of the study is provided in Figure 1.

[0222] Twenty-one participants were enrolled and randomized in the primary cohort; 20 received the full study regimen (10 in each treatment group); 1 participant received oral lenacapavir and withdrew consent before completing the administration procedure. The median age of participants was 44 years (range, 25-61 years); 18 (86%) were male at birth; all had HIV-1 RNA <50 copies / mL and CD4 count >500 cells / µL. Demographic and baseline characteristics of enrolled participants are summarized in Table 1.

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

[0224] Efficacy was assessed 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 (155 copies / mL, confirmed at 524 copies / mL) and was resuppressed upon resumption of baseline ART. One participant in group 2 withdrew consent at week 12 (HIV-1 RNA < 50 copies / mL). 18 / 20 (90%) participants had HIV-1 RNA < 50 copies / mL at week 26. Primary efficacy results are summarized in Table 2 and Figure 1C. [Table 2] ^Resistance testing pending * Withdrew from the study after 12 weeks $AE / reason other than death or lack of efficacy

[0225] There were no treatment-emergent serious adverse events, no treatment-emergent adverse events leading to discontinuation of the study drug or study, and no deaths. The most common treatment-emergent adverse event was an injection site reaction associated with administration of subcutaneous lenacapavir (LEN) (17 of 20 patients, or 85%). Two participants had grade 3 AEs: one had injection site cellulitis and one had injection site erythema at the LEN injection site. The combination of LEN + GS-5423 (telopavimab) + GS-2872 (ginriluvimab) 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 combination of LEN + GS-5423 (telopavimab) + GS-2872 (ginriluvimab) provides long-acting treatment for HIV with twice-yearly administration.

[0226] Example 2 Modeling to determine a uniform annual schedule that allows for two doses per year In this example, we performed population PK (popPK) modeling and simulation to predict the PK profiles of GS-5423 (telopavimab) and GS-2872 (ginriluvimab) with weight-based dosing and flat dosing at different doses, and compared them with target efficacy levels to determine the optimal dose ranges of GS-5423 and GS-2872 with dosing every 6 months in adults with HIV.

[0227] method PK data for GS-5423 (telopavimab; 3BNC117-LS, TAB) and GS-2872 (dinlilvimab; 10-1074-LS, ZAB) were obtained from four clinical studies in viremic or virologically suppressed patients (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 lenalidomide, or without lenalidomide. The studies included YCO-0946 (NCT03254277) and YCO-0971 (NCT03554408). Serum concentrations of TAB and ZAB were measured using the validated Mesa Scale Discovery electrochemiluminescence immunoassay. A two-compartment population PK model was developed to describe the PK data for 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). Population PK models for TAB and ZAB were developed using nonlinear mixed-effects modeling. Covariate analysis was performed to identify significant covariates, including the effects of body weight, demographics, baseline characteristics, concomitant use regimens, and disease status, on the PK parameters of GS-5423 and GS-2872. Population PK models were simulated to predict the PK profiles of GS-5423 and GS-2872 after IV administration of a normalized dose of 30 or 10 mg / kg body weight or an equivalent flat dose every 6 months. Model simulations were performed to predict the concentrations of TAB and ZAB after flat versus weight-based dosing. The weight distribution is assumed to be consistent with previous studies in adults with HIV who are virologically suppressed on antiretroviral therapy (mean 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 are expected to produce similar exposures as 30 mg / kg or 10 mg / kg body weight-based doses, respectively, without a significant increase in PK variability (Figures 3A-3D). Therefore, given that doses of GS-5423 and GS-2872 alone or in combination up to 30 mg / kg were well tolerated in the ongoing studies GS-US-536-5816 and previous studies in HIV+ participants, doses up to 2550 mg 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 adequately 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 who were viremic had significantly increased clearance of TAB and ZAB compared with those suppressed at baseline. Model simulations suggest that a fixed dose of 2550 mg would result in similar exposures to 30 mg / kg for both TAB and ZAB, based on the weight distribution in a recent phase 3 HIV study of adult PWH, whose mean body weight was approximately 85 kg.

[0230] Previous studies of the non-LS forms of each antibody in HIV+ participants who underwent treatment interruption (Mendoza, et al., Nature. (2018) 561(7724):479-484 and Gaebler, et al., Nature (2022) 606(7913):368-374) showed that virologic 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 are expected to maintain concentrations above 10 μg / mL in 99%-100% of subjects for 6 months (26 weeks) after dosing (Figures 4A-4B, Table 3). Therefore, a dose range of 1700 to 2550 mg GS-5423 and 850 to 2550 mg GS-2872 administered IV every 6 months is expected to be an effective and safe dose range for the two bNAbs. [Table 3]

[0231] Example 3 Assessment of therapeutic concentrations of anti-HIV antibodies 3BNC117 / telopavimab and 10-1074 / dinliruvimab by PK-PD modeling and washout period prediction in HIV cure trials 3BNC117 and 10-1074 have been shown to induce a rapid decline in viremia in people with HIV and delay the time to viral rebound in suppressed people with HIV during analytical treatment interruption (ATI) (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, have been investigated for their potential to eliminate HIV reservoirs and induce long-term remission in people with HIV. However, due to their potent viral neutralizing effects, insufficient washout periods before antiretroviral therapy (ATI) can confound efficacy assessments of time to virologic rebound in HIV cure studies. The objectives of this study were to characterize the pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) relationships of these bNAbs through PK-PD viral dynamic modeling and to predict the required length of washout of TAB / ZAB in HIV cure studies to assess post-treatment viral control during antiretroviral therapy (ATI).

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

[0233] bNAb concentrations were measured by ELISA assay, except for 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). PK data for bNAbs were modeled using a two-compartment linear PK model. Covariates (demographics, disease status, concomitant treatments) were tested using stepwise forward addition (α = 0.01) and backward elimination (α = 0.001) methods. The PK-PD model accounts for viral replication using a logistic growth function and viral clearance using first-order kinetics, with a nonlinear saturable (Emax) model to describe the relationship between bNAb concentration and viral clearance rate. Different viral populations sensitive or resistant to each bNAb were modeled to capture the mechanism 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 different washout periods 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 for 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-lives were longest in people without HIV, followed by suppressed people with HIV, and shortest in viremic people with HIV (Figure 7). For TAB and ZAB, the estimated half-lives were longer than those of 3BNC117 and 10-1074, similar between people without HIV and suppressed people with HIV (62 and 79 days for TAB and ZAB, respectively), and shorter in viremic people with HIV (46 and 55 days for TAB and ZAB, respectively) (Figure 7).

[0235] PK-PD Modeling. The PK-PD model adequately described the kinetics of viral suppression in viremic people with HIV after bNAb treatment with different doses of 3BNC117, 10-1074 alone and in combination, and after combined treatment with TAB and ZAB (Figure 8). The model described the time to viral rebound during ATI after bNAb treatment with 3BNC117 alone or in combination with 10-1074 (Figure 9). The median maximal drug effect (EC) of 3BNC117 / TAB and 10-1074 / ZAB was 1.25. 50 ) were estimated mean serum concentrations of 25.4 and 32.2 μg / mL, which corresponded to EC s of 6.35 and 8.06 μg / mL, respectively. 20 corresponds to (Table 5). [Table 5] CI, confidence interval; CV, coefficient of variation; EC 20 , the concentration that produces 20% of the maximum drug effect; EC 50 , concentration producing 50% of maximum drug effect; PD, pharmacodynamics; PK = pharmacokinetics; TAB, telopavimab; ZAB, zinliruvimab. a Mean (95% CI) EC was 6.35 (4.90–8.22) μg / mL 20 Corresponds to the value. bCorresponding to a mean (95% CI) EC20 value of 8.06 (2.53-25.7) μg / mL.

[0236] PK-PD Simulation. PK-PD simulations predicted that the viral neutralizing effects of these bNAbs would have minimal impact on the time to viral rebound during ATI after a washout period of 48 weeks or more following single-dose intravenous administration of TAB and ZAB (Figure 10). Following intravenous administration of 30 mg / kg / kg TAB and 10 mg / kg ZAB, concentrations of both bNAbs were predicted to fall below their in vivo EC50s at approximately similar times and to remain at similar levels compared to their EC50s thereafter, thus minimizing the risk of resistance development from functional monotherapy of either bNAb. At week 48, concentrations of both bNAbs were predicted to be below the EC50 in more than 90% of participants (Figure 11).

[0237] Example 4 A Phase 2 Study of Telopavimab (GS-5423) and Dinliruvimab (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 at 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 ginlilvimab (GS-2872). The study will include approximately 125 participants who are sensitive to both bNAbs by protocol-defined criteria and meet eligibility criteria, and will be randomized without stratification in a 2:2:1 ratio to treatment arms 1, 2, and 3. A schematic diagram of the clinical trial study is shown in Figure 12.

[0238] Participants will take their last dose of baseline oral antiretroviral therapy (ART) on Day 1, and participants randomized to treatment arms 1 and 2 will discontinue their baseline ART regimen after administration of the full study regimen (subcutaneous injectable LEN, oral LEN 600 mg, and intravenous (IV) infusion of GS-5423 and GS-2872) on Day 1 and self-administer oral LEN 600 mg on Day 2. Participants in treatment arm 3 will continue their baseline oral ARV regimen as prescribed through Week 52. Participants randomized to treatment arms 1 and 2 will receive study medication (injectable LEN and IV infusion of GS-5423 and GS-2872) at Week 26. All participants in all treatment arms will return to the study center for visits at Weeks 4, 12, 24, 26, 38, 50, and 52.

[0239] At week 52, participants in treatment arms 1 and 2 who receive the study regimen of LEN, GS 5423, and GS-2872 and complete study follow-up through week 52 with HIV RNA plasma levels <50 copies / mL will be enrolled in the study extension phase. Participants who choose not to participate in the extension phase or who are ineligible to participate in the extension phase will resume their baseline ART regimen (or an appropriate regimen selected by the investigator) and return for study follow-up visits 30, 90, and 180 days after week 52. Participants randomized to treatment arm 3 who have HIV-1 RNA plasma levels <50 copies / mL throughout the randomization phase and complete study follow-up through week 52 will receive the study regimen of LEN, GS-5423, and GS-2872 every 26 weeks. The doses of GS-5423 and GS-2872 will be determined at the time of the primary analysis. Participants in Arm 3 who reach Week 52 before the primary analysis will receive the study regimen at the dose specified for Arm 2 until after completion of the primary analysis and dose selection (unless Arm 2 is amended in response to the data monitoring committee (DMC)). Participants in Arm 3 who are not receiving the study regimen after Week 52 will return for a 30-day follow-up visit.

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

[0241] Virologic Failure (VF): Participants who experience virologic rebound (VR), as defined below, are considered to be in the context of virologic failure and may be eligible for resistance analysis.

[0242] Virologic Rebound: Participants who meet the following criteria are considered to have VR: HIV-1 RNA rebound ≥ 50 copies / mL at any visit after Day 1, 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 study drug discontinuation.

[0243] If the above scheduled or ad hoc interim DMC analysis of efficacy (based on virologic failure (VF) i.e., HIV-1 RNA plasma levels ≥ 50 copies / mL at Week 12, Week 26, or virologic rebound) exceeds the futility boundary (i.e., rate of VF > 0, and the lower limit of the 95% confidence interval (CI) of the treatment difference (Treatment Arm 1 or Arm 2 - Stay on Baseline Regimen (SBR))) before all participants reach Week 26, the DMC may recommend dropping the lower dose arm. The decision to discontinue a dosing arm is made by the Sponsor.

[0244] Target population: Adults with HIV-1 receiving ART who have demonstrated virologic suppression (plasma level of HIV-1 RNA <50 copies / mL) for at least 12 months prior to screening and who meet protocol criteria for sensitivity to bNAbs.

[0245] Intervention duration: up to 52 weeks during the randomized phase and 104 weeks during the extension phase. [Table 6] * PO = Per Os, given orally; SC = subcutaneous; IV = intravenous

[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% CIs will be constructed using the unconditional exact method. Efficacy endpoints will be 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, will be analyzed using the same methods as the primary efficacy endpoint.

[0247] Change from baseline in CD4+ T cell counts will be summarized by treatment using descriptive statistics. Differences in change from baseline in CD4+ T cell counts between the two treatment groups will be compared.

[0248] Treatment-emergent adverse events (AEs), serious adverse events (SAEs), and adverse events leading to permanent study drug discontinuation will be summarized by treatment group, system organ class (SOC), and preferred terminology using the current version of the Medical Dictionary for Regulatory Activities (MedDRA). Laboratory test results and changes from baseline for selected laboratory tests will be summarized by treatment group and visit. The incidence of treatment-emergent laboratory abnormalities will be summarized by treatment group. Vital signs and electrocardiogram data will be summarized by treatment group.

[0249] Serum or plasma concentrations and PK parameters for GS-5423, GS-2872, and LEN (and metabolites, if applicable) will be listed and summarized for each analyte using descriptive statistics by treatment group, as appropriate. [Table 7]

[0250] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and are to be included within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. 1. A method of treating or preventing HIV in a human subject in need thereof, comprising: a) at a first time point, co-administering (i) an effective amount of a first antibody that competes with or comprises VH and VL regions that bind to an epitope of gp120 within the third variable loop (V3) and / or the high mannose patch comprising the N332 oligomannose glycan, and (ii) an effective amount of a second antibody that competes with or comprises VH and VL regions that bind to an epitope of gp120 comprising the CD4 binding site (CD4bs), wherein both the first antibody and the second antibody comprise Fc amino acid substitutions to extend serum half-life; b) co-administering an effective amount of the first antibody and an effective amount of the second antibody at a second time point that is at least about 24 weeks, e.g., at least about 25 weeks, e.g., at least about 26 weeks, after the first time point.

2. the first antibody and the second antibody contain, at the indicated positions (EU index numbering), the following amino acids: (i) tyrosine at position 252, threonine at position 254, and glutamic acid at position 256 (YTE); (ii) a leucine at position 428 and a 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 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) the Fc region comprises aspartic acid at position 309, histidine at position 311, and serine at position 434 (DHS), according to claim 1.

3. The first antibody is 10-1074-LS (GS-2872, ginrilvimab), 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 comprises the VH and VL regions of an antibody selected from 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1, and VRC29.03, and the second antibody is selected from the group consisting of 3BNC117-LS (GS-5423, telopavimab), 3BNC117, GS-9723, 3BNC60, b12, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, and VRC06b01; 3. The method of claim 1 or 2, wherein the antibody competes with or comprises the VH and VL regions of an antibody 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.

4. 4. The method of any one of claims 1 to 3, wherein the first antibody competes with or comprises the VH and VL regions of 10-1074, and the second antibody competes with or comprises the VH and VL regions of 3BNC117.

5. The method of any one of claims 1 to 4, wherein the first antibody comprises 10-1074-LS (also known as ginlilvimab, GS-2872) and the second antibody comprises 3BNC117-LS (also known as telopavimab, GS-5423).

6. 6. The method of any one of claims 1 to 5, wherein the first antibody and the second antibody are co-administered every six months (Q6M).

7. 6. The method of any one of claims 1 to 5, wherein the first antibody and the second antibody are co-administered every 24 weeks (Q24W).

8. 6. The method of any one of claims 1 to 5, wherein the first antibody and the second antibody are co-administered every 25 weeks (Q25W).

9. 6. The method of any one of claims 1 to 5, wherein the first antibody and the second antibody are co-administered every 26 weeks (Q26W).

10. 10. The method of any one of claims 1 to 9, wherein the first antibody and the second antibody are independently administered intravenously at a dose ranging from about 500 mg to about 3000 mg, such as from about 550 mg to about 2900 mg, for example, from about 600 mg to about 2800 mg, such as from about 650 mg to about 2700 mg, for example, from about 700 mg to about 2600 mg, for example, from about 850 mg to about 2550 mg.

11. 11. The method of any one of claims 1-10, 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.

12. 11. The method of any one of claims 1-10, 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.

13. 11. The method of any one of claims 1-10, 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.

14. 11. The method of any one of claims 1-10, 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.

15. 15. The method of any one of claims 1 to 14, further comprising co-administering one or more long-acting HIV drugs.

16. 16. The method of claim 15, wherein the one or more long-acting HIV drugs are selected from long-acting capsid inhibitors, long-acting integrase strand transfer inhibitors (INSTIs), long-acting non-nucleoside reverse transcriptase inhibitors (NNRTIs), long-acting nucleoside reverse transcriptase inhibitors (NRTIs), and long-acting protease inhibitors (PIs).

17. 17. The method of claim 16, wherein the one or more long-acting HIV drugs comprises a long-acting capsid inhibitor.

18. 18. The method of claim 16 or 17, wherein the long-acting capsid inhibitor is selected from lenacapavir, VH4004280, and VH4011499.

19. 19. The method of any one of claims 16 to 18, wherein the long-acting capsid inhibitor comprises lenacapavir.

20. 19. The method of claim 18, wherein the lenacapavir is administered at a dose ranging from 300 mg to 1000 mg.

21. 21. The method of any one of claims 18 to 20, wherein the lenacapavir is administered orally or subcutaneously.

22. 22. The method of any one of claims 16-21, wherein the long-acting INSTI is selected from bictegravir, raltegravir, elvitegravir, dolutegravir, cabotegravir, GS-1720, GS-6212, GS-1219, GS-3242, and VH4524184.

23. 23. The method of any one of claims 16 to 22, wherein the long-acting NNRTI is selected from rilpivirine, elsulfavirine, doravirine, and GS-5894.

24. 24. The method of any one of claims 16 to 23, wherein the long-acting NRTI is selected from islatravir and its prodrugs, tenofovir alafenamide (TAF) and prodrugs of tenofovir, lobafovir etalafenamid, and GS-1614.

25. 25. The method of any one of claims 16 to 24, wherein the long-acting protease inhibitor is selected from atazanavir, ritonavir, darunavir, GS-1156 and prodrugs of GS-1156, and combinations thereof.

26. The method of any one of claims 1 to 25, further comprising determining the susceptibility of the HIV in the subject to one or both of the first antibody and the second antibody.

27. 27. The method of any one of claims 1 to 26, wherein the subject is a heavily treatment-experienced individual (HTE).

28. 28. The method of any one of claims 1-27, wherein the subject is resistant or non-responsive to one or more of an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), a nucleoside reverse transcriptase inhibitor (NRTI), and a protease inhibitor (PI).

29. The method of any one of claims 1 to 28, wherein the subject is viremic.

30. The method of any one of claims 1 to 28, wherein the subject is virologically suppressed.

31. 31. The method of any one of claims 1 to 30, wherein the subject is receiving antiretroviral therapy (ART).

32. 31. The method of any one of claims 1 to 30, wherein antiretroviral therapy (ART) is discontinued prior to administration of the first and second antibodies.

33. The method of any one of claims 1 to 32, wherein the subject is acutely infected with HIV.

34. 34. The method of claim 33, wherein the subject has HIV infection at or before Fiebig stage IV.

35. 35. The method of claim 34, wherein the subject has not seroconverted.

36. The method of any one of claims 1 to 35, wherein the subject is recently infected with HIV.

37. 37. The method of claim 36, wherein the antibody is administered to a subject with Fiebig stage V or Fiebig stage VI HIV infection.

38. The method of any one of claims 1 to 26, wherein the subject is chronically infected with HIV.

39. 39. The method of any one of claims 1 to 38, wherein the subject is infected with an HIV clade B virus.

40. 1. A method of treating or preventing HIV in a human subject in need thereof, comprising: a) at a first time point, co-administering (i) an effective amount of 10-1074-LS (ginriluvimab, GS-2872) and (ii) an effective amount of 3BNC117-LS (telopavimab, (GS-5423)); b) co-administering an effective amount of 10-1074-LS and an effective amount of 3BNC117-LS at a second time point that is at least about 24 weeks, e.g., at least about 25 weeks, e.g., at least about 26 weeks, after said first time point.

41. 41. The method of claim 40, wherein the 10-1074-LS and the 3BNC117-LS are co-administered every six months (Q6M).

42. 41. The method of claim 40, wherein the 10-1074-LS and the 3BNC117-LS are co-administered every 24 weeks (Q24W).

43. 41. The method of claim 40, wherein the 10-1074-LS and the 3BNC117-LS are co-administered every 25 weeks (Q25W).

44. 41. The method of claim 40, wherein the 10-1074-LS and the 3BNC117-LS are co-administered every 26 weeks (Q26W).

45. 45. The method of any one of claims 40 to 44, wherein the 10-1074-LS and the 3BNC117-LS are co-administered twice over the course of one year.

46. 45. The method of any one of claims 40-44, wherein the 10-1074-LS and the 3BNC117-LS are co-administered four times over a two-year period.

47. 45. The method of any one of claims 40-44, wherein the 10-1074-LS and the 3BNC117-LS are co-administered six times over a three-year period.

48. 45. The method of any one of claims 40-44, wherein the 10-1074-LS and the 3BNC117-LS are co-administered eight times over a four year period.

49. 49. The method of any one of claims 40 to 48, wherein the 10-1074-LS is administered intravenously at a dose of 30 mg / kg and the 3BNC117-LS is administered intravenously at a dose of 30 mg / kg.

50. The method of any one of claims 40 to 48, wherein the 10-1074-LS is administered intravenously at a dose of 10 mg / kg and the 3BNC117-LS is administered intravenously at a dose of 30 mg / kg.

51. 51. The method of any one of claims 40 to 50, wherein the 10-1074-LS and the 3BNC117 are independently administered intravenously at a dose ranging from about 500 mg to about 3000 mg, such as from about 550 mg to about 2900 mg, for example, from about 600 mg to about 2800 mg, for example, from about 650 mg to about 2700 mg, for example, from about 700 mg to about 2600 mg, for example, from about 850 mg to about 2550 mg.

52. 52. The method of claim 51, wherein the 10-1074-LS is administered intravenously at a dose of 2550 mg and the 3BNC117-LS is administered intravenously at a dose of 2550 mg.

53. 52. The method of claim 51, wherein the 10-1074-LS is administered intravenously at a dose of 850 mg and the 3BNC117-LS is administered intravenously at a dose of 1275 mg.

54. 52. The method of claim 51, wherein the 10-1074-LS is administered intravenously at a dose of 850 mg and the 3BNC117-LS is administered intravenously at a dose of 1700 mg.

55. 52. The method of claim 51, wherein the 10-1074-LS is administered intravenously at a dose of 850 mg and the 3BNC117-LS is administered intravenously at a dose of 2550 mg.

56. 56. The method of any one of claims 40-55, wherein the serum concentration of the 10-1074-LS and the 3BNC117-LS is at least 10 μg / mL 26 weeks after the first time point.

57. 57. The method of any one of claims 40-56, wherein the plasma or serum concentration of HIV RNA is less than 50 copies / mL 26 weeks after said first time point.

58. 58. The method of any one of claims 40-57, further comprising co-administering one or more long-acting HIV drugs.

59. 59. The method of claim 58, wherein the one or more long-acting HIV drugs are selected from long-acting capsid inhibitors, long-acting integrase strand transfer inhibitors (INSTIs), long-acting non-nucleoside reverse transcriptase inhibitors (NNRTIs), long-acting nucleoside reverse transcriptase inhibitors (NRTIs), and long-acting protease inhibitors (PIs).

60. 60. The method of claim 59, wherein the long-acting capsid inhibitor is selected from lenacapavir, VH4004280, and VH4011499.

61. 61. The method of claim 59 or 60, wherein the long-acting capsid inhibitor comprises lenacapavir.

62. 62. The method of claim 61, wherein the lenacapavir is administered at a dose ranging from 300 mg to 1000 mg.

63. 63. The method of any one of claims 60-62, wherein the lenacapavir is administered orally or subcutaneously.

64. 64. The method of any one of claims 59-63, wherein the long-acting INSTI is selected from bictegravir, raltegravir, elvitegravir, dolutegravir, cabotegravir, GS-1720, GS-6212, GS-1219, GS-3242, and VH4524184.

65. 65. The method of any one of claims 59 to 64, wherein the long-acting NNRTI is selected from rilpivirine, elsulfavirine, doravirine, and GS-5894.

66. 66. The method of any one of claims 59 to 65, wherein the long-acting NRTI is selected from islatravir and its prodrugs, tenofovir alafenamide (TAF) and prodrugs of tenofovir, lobafovir etalafenamid, and GS-1614.

67. 67. The method of any one of claims 59 to 66, wherein the long-acting protease inhibitor is selected from atazanavir, ritonavir, darunavir, GS-1156 and prodrugs of GS-1156, and combinations thereof.

68. 68. The method of any one of claims 40 to 67, further comprising determining the susceptibility of said HIV in said subject to one or both of 10-1074-LS and 3BNC117-LS.

69. 69. The method of any one of claims 40 to 68, wherein the subject is a heavily treatment-experienced individual (HTE).

70. 70. The method of any one of claims 40-69, wherein the subject is resistant or non-responsive to one or more of an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), a nucleoside reverse transcriptase inhibitor (NRTI), and a protease inhibitor (PI).

71. 71. The method of any one of claims 40 to 70, wherein the subject is viremic.

72. 71. The method of any one of claims 40 to 70, wherein the subject is virologically suppressed.

73. 73. The method of any one of claims 40 to 72, wherein the subject is receiving antiretroviral therapy (ART).

74. 73. The method of any one of claims 40 to 72, wherein antiretroviral therapy (ART) has been discontinued prior to administration of 10-1074-LS and 3BNC117-LS.

75. 75. The method of any one of claims 40 to 74, wherein the subject is acutely infected with HIV.

76. 76. The method of claim 75, wherein the subject has HIV infection at or before Fiebig stage IV.

77. 77. The method of claim 76, wherein the subject has not seroconverted.

78. 78. The method of any one of claims 40 to 77, wherein the subject is recently infected with HIV.

79. 79. The method of claim 78, wherein the antibody is administered to a subject with Fiebig stage V or Fiebig stage VI HIV infection.

80. 69. The method of any one of claims 40 to 68, wherein the subject is chronically infected with HIV.

81. 81. The method of any one of claims 40 to 80, wherein the subject is infected with an HIV clade B virus.

82. 1. 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)).

83. 83. The kit of claim 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, such as 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.

84. 1. A kit comprising one or more unit doses of 3BNC117-LS (telopavimab) and 10-1074-LS (ginriluvimab), wherein the 3BNC117-LS (telopavimab) and the 10-1074-LS (ginriluvimab) 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)).

85. 85. The kit of claim 84, wherein the unit doses of 10-1074-LS and 3BNC117-LS are independently in the range of about 500 mg to about 3000 mg, such as 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.

86. 86. The kit of claim 85, wherein the one or more unit doses of 10-1074-LS are 2550 mg and the one or more unit doses of 3BNC117-LS are 2550 mg.

87. 86. The kit of claim 85, wherein the one or more unit doses of 10-1074-LS are 850 mg and the one or more unit doses of 3BNC117-LS are 1275 mg.

88. 86. The kit of claim 85, wherein the one or more unit doses of 10-1074-LS are 850 mg and the one or more unit doses of 3BNC117-LS are 1700 mg.

89. 86. The kit of claim 85, wherein the one or more unit doses of 10-1074-LS are 850 mg and the one or more unit doses of 3BNC117-LS are 2550 mg.

90. The kit of any one of claims 84 to 89, wherein the 10-1074-LS and the 3BNC117-LS are formulated for intravenous administration.

91. 91. The kit of any one of claims 82 to 90, wherein the one or more unit doses are contained in one or more containers.

92. 92. The kit of claim 91, wherein the one or more containers are selected from vials, ampoules, and pre-filled syringes.

93. 93. The kit of any one of claims 82 to 92, further comprising one or more unit doses of one or more long-acting HIV drugs.

94. 94. The kit of claim 93, wherein the one or more unit doses of one or more long-acting HIV drugs are selected from long-acting capsid inhibitors, long-acting integrase strand transfer inhibitors (INSTIs), long-acting non-nucleoside reverse transcriptase inhibitors (NNRTIs), long-acting nucleoside reverse transcriptase inhibitors (NRTIs), and long-acting protease inhibitors (PIs).

95. 95. The kit of claim 94, wherein the long-acting capsid inhibitor is selected from lenacapavir, VH4004280, and VH4011499.

96. 96. The method of claim 94 or 95, wherein the long-acting capsid inhibitor comprises lenacapavir.

97. 97. The kit of claim 96, wherein the unit dose of lenacapavir ranges from 300 mg to 1000 mg.

98. The kit of claim 96 or 97, wherein the lenacapavir is formulated for oral or subcutaneous administration.

99. 99. The kit of any one of claims 94-98, wherein the long-acting INSTI is selected from bictegravir, raltegravir, elvitegravir, dolutegravir, cabotegravir, GS-1720, GS-6212, GS-1219, GS-3242, and VH4524184.

100. The kit of any one of claims 94 to 99, wherein the long-acting NNRTI is selected from rilpivirine, elsulfavirine, doravirine, and GS-5894.

101. 101. The kit of any one of claims 94 to 100, wherein the long-acting NRTI is selected from islatravir and its prodrugs, tenofovir alafenamide (TAF) and prodrugs of tenofovir, lobafovir etalafenamid, and GS-1614.

102. 102. The kit of any one of claims 94 to 101, wherein the long-acting protease inhibitor is selected from atazanavir, ritonavir, darunavir, GS-1156 and prodrugs of GS-1156, and combinations thereof.

Images