Dosing and scheduling regimens for broadly neutralizing antibodies

Abstract

Provided are methods for administering a long-acting, anti-HIV, extensively neutralizing antibody twice every year, such as Q6M, Q24W, Q25W, or Q26W.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 373,597, filed on August 26, 2022, and U.S. Provisional Application No. 63 / 514,711, filed on July 20, 2023, under 35 U.S.C. §119(e), which are hereby incorporated by reference in their entirety for all purposes.

[0003] Sequence Listing

[0004] This application contains a sequence listing, which is electronically submitted in XML format and is hereby incorporated by reference in its entirety. The XML copy was created on July 20, 2023, is named 1445-WO-PCT_sequencelisting.XML, and is 512,134 bytes in size. Background Art

[0005] 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. In the United States (US), there are approximately 1 million people infected 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, maintaining immune function, and avoiding disease progression to AIDS. However, current treatment strategies cannot eliminate the virus and cure HIV-1 infection.

[0006] Although the combination ART currently used to treat HIV-1 infection is effective and well tolerated, these agents need to be taken daily and require near-perfect compliance to minimize the appearance of drug-resistant variants. Therefore, "treatment fatigue" can occur in patients who prescribe long-term or lifelong treatment, defined as "reduced desire and motivation to remain vigilant when adhering to the treatment regimen" (Claborn et al., Psychol Health Med (2015) 20 (3): 255-65), which can lead to non-compliance and treatment failure. Therefore, there is still a significant medical need for ARVs (i.e., long-acting drug products) that can be applied less frequently, thereby providing alternative treatment options for HIV-1 infected individuals.

[0007] Lenacapasvir is a new, first-in-class, multi-stage, selective inhibitor of HIV-1 capsid function for the targeted treatment of HIV-1 infection. Lenacapasvir has potent antiviral activity with no overlapping resistance with any approved products. It has a low human clearance rate and is being developed as a long-acting ARV for the treatment and prevention of HIV-1. Lenacapasvir has the potential to meet a high unmet medical need in PWH who could benefit from a long-acting treatment or a novel mechanism of action.

[0008] Monoclonal antibodies (mAbs) with increased potency and breadth of 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 produced a significant reduction in plasma viremia in untreated PWH and maintained virological suppression in PWH who had received virological suppression with broadly neutralizing antibodies (bNAbs) prior to undergoing analytic 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 be long-acting and have the potential to alleviate the challenge of daily therapy or lifelong compliance. Antibodies also engage the immune system, which may contribute to beneficial HIV-specific immune responses (Niessl et al., Nat Med (2020) 26(2):222-7), including potential clearance of latently infected cells (Gaebler et al., Nature (2022) 606(7913):368-374), which is not possible with ARV drugs. As biologics, bNAbs can protect patients from the adverse effects associated with chronic ARV treatment. However, HIV-1 is a diverse virus, and its variants have different levels of sensitivity to any bNAb. Therefore, when measuring the ability of bNAbs to neutralize multiple HIV-1 isolates, the bNAbs identified to date have incomplete breadth (Nishimura et al., Nature (2017) 543(7646):559-63). 3BNC117 and 10-1074 are two of the most potent bNAbs that have been 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 wane (Bar-On et al., Nat Med (2018) 24:1701-7). Summary of the invention

[0009] In one aspect, a method for treating or preventing HIV in a human subject in need thereof is provided. In some embodiments, the method comprises: (a) co-administering (i) an effective amount of a first antibody and (ii) an effective amount of a second antibody at a first time point, the first antibody competing with or comprising a VH region and a VL region that bind to a gp120 epitope within the third variable loop (V3) comprising N332 mannooligosaccharide glycan and / or a high mannose membrane patch, the second antibody competing with or comprising a VH region and a VL region that bind to a gp120 epitope that comprises a CD4 binding site (CD4bs), wherein both the first antibody and the second antibody comprise an Fc amino acid substitution to extend serum half-life; and (b) 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) after the first time point. In some embodiments, the first antibody and the second antibody comprise an Fc region comprising the following amino acids at the specified positions (EU index number): (i) tyrosine at position 252, threonine at position 254, and glutamic acid at position 256 (YTE); (ii) leucine at position 428 and serine at position 434 (LS); (iii) lysine at position 433 and phenylalanine at position 434; (iv) glutamine at position 250 and leucine at position 428 (QL); (v) glutamine at 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 competes with or comprises the VH region and VL region of an antibody selected from the group consisting of GS-2872 (also known as zinlirvimab), 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-13 9. VRC24, 2G12, BG18, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG4 26, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1 and VRC29.03; and the second antibody competes with or comprises the VH region and VL region of an antibody selected from the group consisting of GS-5423, 3BNC117, GS-9723, 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. In some embodiments, the first antibody competes with or includes the VH and VL regions of 10-1074, and the second antibody competes with or includes the VH and VL regions of 3BNC117. In some embodiments, the first antibody comprises 10-1074-LS (also known as Jinliweimab; 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 administered intravenously independently at a dosage ranging from about 500 mg to about 3000 mg (e.g., about 550 mg to about 2900 mg, for example, about 600 mg to about 2800 mg, for example, about 650 mg to about 2700 mg, for example, about 700 mg to about 2600 mg, for example, about 850 mg to about 2550 mg). In some embodiments, the first antibody is administered intravenously at a dosage of 2550 mg, and the second antibody is administered intravenously at a dosage of 2550 mg. In some embodiments, the first antibody is administered intravenously at a dosage of 850 mg, and the second antibody is administered intravenously at a dosage of 1275 mg. In some embodiments, the first antibody is administered intravenously at a dosage of 850 mg, and the second antibody is administered intravenously at a dosage of 1700 mg. In some embodiments, the first antibody is administered intravenously at a dosage of 850 mg, and the second antibody is administered intravenously at a dosage of 2550 mg. In some embodiments, the method further comprises co-administering one or more long-acting HIV drugs. In some embodiments, one or more long-acting HIV drugs are selected from long-acting capsid inhibitors, long-acting integrase strand transfer inhibitors (INSTI), long-acting non-nucleoside reverse transcriptase inhibitors (NNRTI), long-acting nucleoside reverse transcriptase inhibitors (NRTI) and long-acting protease inhibitors (PI). In some embodiments, one or more long-acting HIV drugs include long-acting capsid inhibitors. In some embodiments, long-acting capsid inhibitors are selected from lenacapasvir, VH4004280 and VH4011499. In some embodiments, long-acting capsid inhibitors include lenacapasvir. In some embodiments, lenacapasvir is administered at a dose ranging from 300 mg to 1000 mg. In some embodiments, lenacapasvir is administered orally or subcutaneously. In some embodiments, long-acting INSTIs are selected from bicagevir, 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, essavirine, doravirine and GS-5894. In some embodiments, the long-acting NRTI is selected from isclatravir and its prodrugs, tenofovir alafenamide (TAF) and prodrugs of tenofovir, etanervir and GS-1614. In some embodiments, the long-acting protease inhibitor is selected from atazanavir, ritonavir, darunavir, GS-1156 and the prodrugs of GS-1156, and combinations thereof. In some embodiments, the method further comprises determining the sensitivity of HIV in the subject to one or both of the first antibody and the second antibody. In some embodiments, the subject has viremia (ie, HIV-1 RNA>50 copies / mL).In some embodiments, the subject is virologically suppressed (ie, HIV-1RNA <50 copies / mL). In some embodiments, the subject is receiving antiretroviral therapy (ART). In some embodiments, antiretroviral therapy (ART) is interrupted before the administration of the first antibody and the second antibody (e.g., before the first time point). In some embodiments, the subject 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 has recently been infected with HIV. In some embodiments, antibodies are administered to subjects with HIV infection in Fiebig stage V or Fiebig stage VI. In some embodiments, the subject is chronically infected with HIV. In some embodiments, the subject is infected with HIV clade B virus.

[0010] In another aspect, a method for treating or preventing HIV in a human subject in need thereof is provided. In some embodiments, the method includes: (a) co-administering (i) an effective amount of 10-1074-LS (Zinliweimab; GS-2872) and (ii) an effective amount of 3BNC117-LS (Telopavir monoclonal antibody; GS-5423) at a first time point; and (b) co-administering an effective amount of 10-1074-LS and an effective amount of 3BNC117-LS at a second time point of at least about 24 weeks (e.g., at least about 25 weeks, e.g., at least about 26 weeks) after the first time point. 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 2 times within 1 year. In some embodiments, 10-1074-LS and 3BNC117-LS are co-administered 4 times within 2 years. In some embodiments, 10-1074-LS and 3BNC117-LS are co-administered 6 times within 3 years. In some embodiments, 10-1074-LS and 3BNC117-LS are co-administered 8 times within 4 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 dosage of 10 mg / kg, and 3BNC117-LS is administered intravenously at a dosage of 30 mg / kg. In some embodiments, 10-1074-LS and 3BNC117-LS are administered intravenously independently at a dosage 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, 10-1074-LS is administered intravenously at a dosage of 2550 mg, and 3BNC117-LS is administered intravenously at a dosage 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, 26 weeks after the first time point, the serum concentration of 10-1074-LS and 3BNC117-LS is at least 10 μg / mL. In some embodiments, 26 weeks after the first time point, the plasma or serum concentration of HIV RNA is less than 50 copies / mL. In some embodiments, the method also includes co-administering one or more long-acting HIV drugs. In some embodiments, one or more long-acting HIV drugs are selected from long-acting capsid inhibitors, long-acting integrase strand transfer inhibitors (INSTI), long-acting non-nucleoside reverse transcriptase inhibitors (NNRTI), long-acting nucleoside reverse transcriptase inhibitors (NRTI) and long-acting protease inhibitors (PI). In some embodiments, the long-acting capsid inhibitor is selected from lenacapasvir, VH4004280 and VH4011499. In some embodiments, the long-acting capsid inhibitor includes lenacapasvir. In some embodiments, lenacapasvir is administered at a dose ranging from 300 mg to 1000 mg. In some embodiments, lenacapasvir is administered orally or subcutaneously. In some embodiments, the long-acting INSTI is selected from bicagevir, 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, essavirine, 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, etafovir and GS-1614. In some embodiments, the long-acting protease inhibitor is selected from atazanavir, ritonavir, darunavir, GS-1156 and GS-1156 prodrugs, and combinations thereof. In some embodiments, the method further comprises determining the sensitivity of HIV in the subject to one or both of 10-1074-LS and 3BNC117-LS. In some embodiments, the subject has viremia. In some embodiments, the subject is virologically suppressed. In some embodiments, the subject is receiving antiretroviral therapy (ART). In some embodiments, antiretroviral therapy (ART) has been interrupted before the administration of 10-1074-LS and 3BNC117-LS. In some embodiments, the subject 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 HIV infection at Fiebig stage V or Fiebig stage VI. In some embodiments, the subject is chronically infected with HIV. In some embodiments, the subject is infected with an HIV clade B virus.

[0011] In another aspect, a kit is provided. In some embodiments, the kit comprises one or more unit doses of a first antibody that binds to HIV gp120 V3 polysaccharides and a second antibody that binds to HIV gp120 CD4bs, wherein the first antibody and the second antibody have amino acid substitutions that extend serum half-life, and wherein the first antibody and the second antibody are formulated for administration twice a year (e.g., once every 6 months (Q6M), once every 26 weeks (Q26W), once every 25 weeks (Q25W), or once 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). Where appropriate, the unit doses may be the same or different. In some embodiments, the kit includes one or more unit doses of 3BNC117-LS (telopavirumab; GS-5423) and 10-1074-LS (zinlevumab; GS-2872), wherein 3BNC117-LS (telopavirumab) and 10-1074-LS (zinlevumab) are formulated for administration twice a year (e.g., once every 6 months (Q6M), once every 26 weeks (Q26W), once every 25 weeks (Q25W), or once every 24 weeks (Q24W)). In some embodiments, the unit dose of 10-1074-LS and 3BNC117-LS is independently in the range of about 500 mg to about 3000 mg (e.g., about 550 mg to about 2900 mg, for example, about 600 mg to about 2800 mg, for example, about 650 mg to about 2700 mg, for example, about 700 mg to about 2600 mg, for example, about 850 mg to about 2550 mg). In some embodiments, one or more unit doses of 10-1074-LS are 2550 mg, and one or more unit doses of 3BNC117-LS are 2550 mg. In some embodiments, one or more unit doses of 10-1074-LS are 850 mg, and one or more unit doses of 3BNC117-LS are 1275 mg. In some embodiments, one or more unit doses of 10-1074-LS are 850 mg, and one or more unit doses of 3BNC117-LS are 1700 mg. In some embodiments, one or more unit doses of 10-1074-LS is 850 mg and one or more unit doses of 3BNC117-LS is 2550 mg. In some embodiments, 10-1074-LS and 3BNC117-LS are formulated for intravenous administration.In some embodiments, one or more unit doses are contained in one or more containers. In some embodiments, one or more containers are selected from vials, ampoules and preloaded syringes. In some embodiments, the kit also includes one or more unit doses of one or more long-acting HIV drugs. In some embodiments, one or more unit doses of one or more long-acting HIV drugs are selected from long-acting capsid inhibitors, long-acting integrase chain transfer inhibitors (INSTI), long-acting non-nucleoside reverse transcriptase inhibitors (NNRTI), long-acting nucleoside reverse transcriptase inhibitors (NRTI) and long-acting protease inhibitors (PI). In some embodiments, long-acting capsid inhibitors are selected from lenacapsvir, VH4004280 and VH4011499. In some embodiments, long-acting capsid inhibitors include lenacapsvir. In some embodiments, the unit dose of lenacapsvir is in the range of 300mg to 1000mg. In some embodiments, lenacapsvir is formulated for oral or subcutaneous administration. In some embodiments, the long-acting INSTI is selected from bicagevir, 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, essavirine, 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, etafovir, 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 DESCRIPTION OF THE DRAWINGS

[0012] Figures 1A to 1C . Figure 1A The study protocol for the Phase 1b study GS-US-536-5816 (NCT04811040 on ClinicalTrials.gov) is shown. Figure 1B Participant disposition is shown. All randomized participants were included in the safety analysis (N=21); participants who received the full study regimen (oral LEN, SC LEN, and bNAbs) were included in the efficacy analysis (N=20). Figure 1C Virologic efficacy results from the Phase 1b study at Week 26 are shown by the FDA snapshot algorithm. 18 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 demonstrated virologic rebound at Week 16 and was re-suppressed on baseline oral ART.

[0013] Figure 2Shown are the pharmacokinetics of telopavir (TAB), zinurinumab (ZAB), and lenacapavir (LEN) in a Phase 1b study.

[0014] Figures 3A to 3D show simulated C at week 26 after IV administration of 30 mg / kg or 2550 mg GS-5423 (Panels A and C) and 10 mg / kg, 30 mg / kg, 850 mg, or 2550 mg GS-2872 (Panels B and D) every 6 months. max (Figures A and B) and C min (Panels C and D). Box: interquartile range, horizontal line: median, whiskers: 1.5 times the interquartile range, not exceeding the minimum and maximum values, dots: outliers.

[0015] Figures 4A-4B show the simulated median (line) and 5th-95th percentile (shaded area) concentration-time curves of GS-5423 (telopavir) (Figure 3A) and GS-2872 (zinlevimab) (Figure 3B) at different doses given every 6 months.

[0016] Figure 5 Figure 1 shows a schematic diagram of the PK-PD viral kinetic model used to evaluate GS-5423 (3BNC117-LS; telopavir; TAB) and GS-2872 (10-1074-LS; zinlivimab; ZAB) concentrations and predict duration of clearance. C1 and C2, 3BNC117 / TAB and 10-1074 / ZAB, respectively, are serum concentrations; EC 50,药物1 and EC 50,药物2 , are the concentrations that cause 50% maximal effects of 3BNC117 / TAB and 10-1074 / ZAB, respectively; f i , the initial fraction of the ith viral compartment; k g , maximum viral replication rate constant; k del,药物1 and k del,药物2 , are the virus elimination rate constants of 3BNC117 / TAB and 10-1074 / ZAB, respectively; r d,i , the virus elimination rate of the ith virus compartment; r g,i , viral replication rate of the i-th viral compartment; TAB, telopavir; VL1, copies of viruses sensitive to both 3BNC117 / TAB and 10-1074 / ZAB; VL2, copies of viruses sensitive to 3BNC117 / TAB and resistant to 10-1074 / ZAB; VL3, copies of viruses sensitive to 10-1074 / ZAB and resistant to 3BNC117 / TAB; VL4, copies of viruses resistant to both 3BNC117 / TAB and 10-1074 / ZAB (assumed to be 0); VL 总, total viral load; VL ss , steady-state viral load; ZAB, jinlivimab.

[0017] Figure 6 Observed and predicted bNAb serum concentrations from the PK model are shown. bNAb, broadly neutralizing antibody; PK, pharmacokinetics; TAB, telopavir; ZAB, zinurin. Circles represent individual data. Solid lines represent LOESS (locally estimated scatter smoothing) fits. Dashed lines represent lines of identity.

[0018] Figure 7 Model-predicted PK profiles after a single dose of 30 mg / kg IV infusion are shown. IV, intravenous; PWH, people with HIV. 1000 virtual subjects were simulated using the population PK model for 3BNC117, 10-1074, TAB, and ZAB. The solid and dashed lines represent the medians of the model predictions for monotherapy and combination therapy, respectively, and the shaded area represents the 90% prediction interval for the population.

[0019] Figure 8 Model-predicted and observed viral dynamics following bNAb treatment in viremic patients with HIV are shown. Q5, 5th percentile; Q50, 50th percentile; Q95, 95th percentile. 100 trial simulations were performed with the same number of subjects as the original data set used for model fitting. Predicted quantiles were calculated as the median of quantiles across all trial replicates. Arrows indicate bNAb dosing.

[0020] Fig. 9 Model-predicted and observed times of viral rebound during ATI after bNAb treatment are shown. ATI, analytical treatment interruption; bNAb, broadly neutralizing antibody; CI, confidence interval. Doses in ATI studies: NCT02446847, 2 doses of 30 mg / kg 3BNC117 every 3 weeks or up to 4 doses of 30 mg / kg 3BNC117 every 2 weeks; NCT02825797, up to 3 doses of 30 mg / kg 3BNC117 and 30 mg / kg 10-1074 every 3 weeks; NCT03526848, 3 doses of 30 mg / kg 3BNC117 and 30 mg / kg 10-1074 every 2 weeks, followed by up to 4 doses every 4 weeks (Group 1, ATI started on day 2; Group 2, ATI started at week 26 [1 participant started at week 21]). 100 trial simulations were performed with the same number of subjects as the original data set used for model fitting. The solid blue line (shaded area) indicates the median (2.5th to 97.5th percentile) of all experimental replicates. Arrows indicate bNAb administration. The dotted red line indicates the start of ATI.

[0021] Fig.10Model-predicted viral rebound kinetics after single-dose TAB / ZAB combination treatment with different ATI start times are shown. PD, pharmacodynamics. The horizontal dashed line indicates the threshold for viral rebound (200 cp / mL). 1000 virtual subjects were simulated using a population PK-PD model. The solid line represents the median predicted by the model, and the shaded area represents the 90% prediction interval for the population. Arrows indicate bNAb administration. The red dashed line indicates the start of ATI.

[0022] Fig.11 Simulated bNAb serum concentrations over time after single-dose TAB 30 mg / kg and ZAB 10 mg / kg IV administration and their relative to the in vivo EC 50 The ratio of EC 50 , the concentration that results in 50% maximal drug effect. 1000 virtual subjects were simulated using the population PK model. The solid line represents the median predicted by the model and the shaded area represents the 90% prediction interval for the population. EC based on the estimate from the PK-PD model 50 The black dashed line indicates the earliest start time of the proposed ATI.

[0023] Fig.12 The study protocol for Phase 2 study GS-US-539-5939 is shown. DETAILED DESCRIPTION

[0024] 1. Introduction

[0025] Thus, the methods of the present invention are based in part on the discovery that co-administration of a first anti-HIV broadly neutralizing antibody (bNAb) that binds to a gp120 epitope within the third variable loop (V3) and / or high mannose membrane patch comprising N332 mannooligosaccharide glycans and a second bNAb that binds to a gp120 epitope comprising a CD4 binding site (CD4bs) with Fc amino acid substitutions that extend serum half-life can be administered twice per year (e.g., Q6M, Q24W, Q25W, Q26W) and achieve therapeutic efficacy. To date, bNAbs, even with Fc amino acid substitutions that extend serum half-life, have been administered every 3 months or more frequently.

[0026] Typically, the method requires co-administering (i) an effective amount of a first antibody and (ii) an effective amount of a second antibody at a first time point, wherein the first antibody competes with or comprises a VH region and a VL region that binds to a gp120 epitope within the third variable loop (V3) comprising N332 mannooligosaccharide glycan and / or a high mannose membrane patch, and the second antibody competes with or comprises a VH region and a VL region that binds to a gp120 epitope that comprises a CD4 binding site (CD4bs), wherein both the first antibody and the second antibody 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) after the first time point.

[0027] 3BNC117 and 10-1074 have been modified to increase half-life, resulting in GS 5423 (telopavir; 3BNC117-LS) and GS-2872 (zinlivimab; 10-1074-LS) and allowing high bNAb concentrations to be maintained for long durations. Combination therapy consisting of long-acting bNAbs with ARV drugs may overcome the limitations of bNAbs alone and enable safe, long-acting treatment options for PWH. The modified LS version contains two amino acid substitutions in the Fc: methionine to leucine (M428L) at Fc position 428 and asparagine to serine (N434S) at Fc position 434 (EU numbering). These substitutions enhance the binding affinity of the antibody to the neonatal Fc receptor (FcRn) and extend the in vivo half-life of the bNAb. Affinity to other Fc receptors remains unchanged. These modifications do not alter the fragment antigen-binding domain (Fab) of the bNAbs and therefore do not change their interaction with antigen or safety profile.

[0028] 2. Co-administered broadly neutralizing antibodies

[0029] a. Generally speaking, broadly neutralizing antibodies

[0030] HIV-1 is the main family of HIV and accounts for 95% of all infections worldwide. HIV-2 is mainly found in a few West African countries.

[0031] HIV viruses are divided into specific groups, M, N, O and P, with M being the "major" group and responsible for most HIV / AIDS worldwide. Based on their genetic sequences, the M group is further subdivided into subtypes (also called clades) with prevalence in different geographic locations.

[0032] Group M "subtypes" or "clades" are subtypes of HIV-1 group M defined by genetic sequence data. Examples of group M subtypes include subtype AK. Some subtypes in the known subtypes are more toxic or resistant to different drugs. There are also "circulating recombinant forms" or CRFs derived from recombination between viruses of different subtypes, each of which has a number. For example, CRF12_BF is a recombination between subtypes B and F. Subtype A is common in West Africa. Subtype B is the main form in Europe, America, Japan, Thailand and Australia. Subtype C is the main form in parts of South Africa, East Africa, India, Nepal and China. Subtype D is usually only found in East and Central Africa. Subtype E has never been identified as a non-recombinant, only recombining with subtype A as CRF01_AE. Subtype F has been found in Central Africa, South America and Eastern Europe. Subtype G (as well as CRF02_AG) has been found in Africa and Central Europe. Subtype H is limited to Central Africa. Subtype I was originally used to describe the strain now considered to be CRF04_cpx, where cpx is used for a "complex" recombination of several subtypes. Subtype J is mainly found in North Africa, Central Africa and West Africa, while Caribbean subtype K is limited to the Democratic Republic of the Congo and Cameroon. These subtypes are sometimes further divided into sub-subtypes, such as A1 and A2 or F1 and F2. In 2015, strain CRF19 was found to be a recombinant of subtypes A, D and G, and its subtype D protease is closely related to the rapid development of AIDS in Cuba.

[0033] The present disclosure provides, inter alia, methods for administering human anti-HIV neutralizing antibodies (e.g., broadly neutralizing Abs) that target gp120 polypeptides on the surface of HIV-infected cells. Neutralizing antibodies directed 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. Therefore, the anti-HIV gp120 binding antibodies described herein have cross-clade binding activity.

[0034] In certain embodiments, the antibody administered is or is derived from a human neutralizing antibody (e.g., a monoclonal antibody) targeting HIV-1. "Neutralizing antibodies" are antibodies that can neutralize the ability of HIV to cause and / or maintain infection in a host and / or target cell in vitro. The present disclosure provides neutralizing monoclonal human antibodies, wherein the antibody recognizes an antigen from HIV, such as a gp120 polypeptide. In certain embodiments, "neutralizing antibodies" can inhibit the entry of HIV-1 viruses (e.g., SF162 and / or JR-CSF), with a neutralization index of >1.5 or >2.0 (Kostrikis et al., J. Virol., 70 (1): 445-458 (1996)).

[0035] In some embodiments, the antibody administered is or is derived from a broadly neutralizing antibody (e.g., a monoclonal antibody) targeting HIV-1. So-called "broadly neutralizing antibodies" means antibodies that neutralize more than one HIV-1 virus species (from different clades and different strains within clades) in a neutralization assay. Broadly neutralizing antibodies can neutralize at least 2, 3, 4, 5, 6, 7, 8, 9 or more different strains of HIV-1, which belong to the same or different clades. In specific embodiments, broadly neutralizing antibodies can neutralize a variety of HIV-1 species belonging to at least 2, 3, 4, 5, 6 or 6 different clades. In certain embodiments, the inhibitory concentration of the anti-HIV gp120 V3 glycan binding antibody or antigen-binding fragment may be less than 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 the input virus in a neutralization assay.

[0036] gp120

[0037] The envelope glycoprotein gp120 (or gp120) is a 120 kDa glycoprotein that is part of the outer layer of HIV. It itself exists as a viral membrane spike, consisting of three gp120 molecules linked 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 its interaction 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.

[0038] Gp120 is encoded by the HIV env gene. The env gene encodes a gene product of approximately 850 amino acids. The major 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).

[0039] Broadly neutralizing antibodies are reviewed in, for example, Walsh and Seaman, Front Immunol. (2021) 12:712122; Julg and Barouch, Semin Immunol. (2021) 51:101475; Hsu et al., Front Immunol. (2021) 12:710044; Karuna and Corey, Annu Rev Med. (2020) 71:329-346; Haynes et al., Sci Transl Med. (2019) 11(516):eaaz2686; Dashti et al., Trends Mol Med. (2019) 25(3):228-240; McCoy, Retrovirology (2018) 15:70; Sok and Burton, Nat Rev Med. (2019) 71:329-346; 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 hereby incorporated by reference in their entirety for all purposes.

[0040] b. Antibodies against the V3 glycan region of HIV gp120

[0041] The V3 glycan site on gp120 is formed in part by a portion of the CCR5 co-receptor site and in part by surrounding camouflaged glycans (the so-called "high mannose patch") (Sok et al., Immunity, (2016) 45, 31-45). Broadly neutralizing antibodies (bnAbs) to the V3 glycan site are the most common of all antibodies found in HIV infection (Walker et al., PLoS Pathog. (2010) 6: e1001028 (2010); Landais et al., PLoS Pathog. (2016) 12: e1005369; Georgiev et al. Science (2013) 340: 751-756). The consensus sequence of the V3 region of gp120 (Milich et al., J Virol., 67 (9): 5623-5634 (1993)) is provided below:

[0042] CTRPNNNTRKSIHIGPGRAFYTTGEIIGDIRQAHC (SEQ ID NO: 1).

[0043] The amino acid sequence of an exemplary gp160 polypeptide of HIV clone WITO is provided below (the V3 hypervariable loop is bolded, and the N332 potential N-linked glycosylation site is bolded and underlined):

[0044]

[0045]

[0046] The amino acid sequence of an exemplary gp160 polypeptide of an HIV clone identified in NCBI Reference Sequence No. NP_057856.1 is provided below (the V3 hypervariable loop is bolded, and the N332 potential N-linked glycosylation site is bolded and underlined):

[0047]

[0048] The amino acid sequence of an exemplary gp120 polypeptide of an HXB2 subtype B HIV-1 isolate (GenBank Accession No. K0345; corresponding to residues 1-511 of NCBI Reference Sequence No. NP_057856.1) is provided below (the V3 hypervariable loop is bold, and the N332 potential N-linked glycosylation site is bold and underlined; the signal peptide is underlined):

[0049]

[0050] The amino acid sequence of an exemplary gp120 polypeptide is provided below:

[0051]

[0052] The amino acid sequence of another exemplary gp120 polypeptide (see, bioafrica.net / proteomics / ENV-GP120prot.html) is provided below:

[0053]

[0054]

[0055] Genomic diversity between independent human immunodeficiency virus type 1 (HIV-1) isolates and, to a lesser extent, between serial isolates from the same patient and even within a single patient isolate is a well-known feature of HIV-1. Although this sequence heterogeneity is distributed throughout the genome, most of the heterogeneity is located in the env gene. Comparison of predicted amino acid sequences from several different isolates has shown that the 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 includes the proteins that mediate binding to CD4 + Determinants of cell-cell interactions. Increased variability in gp120 leads to higher levels of viral replication, thereby indicating increased viral fitness in individuals infected with different HIV-1 variants. Variability in potential N-linked glycosylation sites (PNGS) also leads to increased viral fitness. PNGS allows long-chain carbohydrates to bind to the hypervariable region of gp120. Therefore, the amount of PNGS in env can affect viral fitness by providing more or less sensitivity to neutralizing antibodies.

[0056] Exemplary broadly neutralizing antibodies that bind to gp120 in the third variable loop (V3) and / or high mannose membrane patch comprising N332 mannooligosaccharide glycans and can be used in the methods described herein include, but are not limited to, GS-9722 (epavirumab), 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-240, PGT-241, PGT-242, PGT-243, PGT-244, PGT-245, PGT-246, PGT-247, PGT-248, PGT-249, PGT-250, PGT-251, PGT-252, PGT-253, PGT-254, PGT-255, PGT-256, PGT-257, PGT-258, PGT-259, PGT-261, PGT-262, PGT-263, PGT-264, PGT-265 T-137, PGT-138, PGT-139, 10-1074, 10-1074-LS (jinlivimab; 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) comprising N332 oligomannose glycans and / or high mannose plaques and 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, WO2020 / 056145, and Kerwin et al., J Pharm Sci. 2020 Jan; 109(1):233-246, which are hereby incorporated by reference in their entirety for all purposes.

[0057] Exemplary sequences of complementarity determining regions (CDRs) of antibodies targeting HIV gp120 V3 glycan region are provided in Tables A1-A4. Exemplary sequences of VH and VL of antibodies targeting HIV gp120 V3 glycan region are provided in Table B.

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076] In some embodiments, the anti-HIV gp120 V3 glycan-binding antibody comprises a VH and a VL, wherein the VH comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3; the VL comprises a VL-CDR1, a VL-CDR2, and a second VH-CDR3; wherein the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 comprise the sequences shown 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 SEQ ID NO:21, 22, 27, 24, 25 and 26; SEQ ID NO:28, 29, 30, 31, 32 and 33; SEQ ID NO:34, 35, 36, 37, 25 and 38; SEQ ID NO:39, 40, 41, 42, 43 and 44; SEQ ID NO:45, 46, 47, 48, 49 and 50; SEQ ID NO:45, 51, 52, 53, 49 and 54; SEQ ID NO:55, 56, 57, 58, 59 and 44; SEQ ID NO:60, 46, 61, 58, 49 and 44; SEQ ID NO:62, 63, 64, 65, 66 and 67; SEQ ID NO:68, 69, 70, 71, 72 and 73; SEQ ID NO:74, 75, 76, 77, 78 and 73; SEQ ID NO: 79, 80, 81, 82, 83 and 73; SEQ ID NO: 84, 85, 86, 87, 88 and 89; SEQ ID NO: 84, 90, 91, 92, 93 and 89; SEQ ID NO: 84, 85, 86, 95, 96 and 89; SEQ ID NO: 84, 97, 98, 99, 100 and 101; SEQ ID NO: 84, 97, 98, 99, 100 and 102; SEQ ID NO: 84, 97, 98, 103, 100 and 89; SEQ ID NO: 84, 104, 91, 92, 93 and 89; SEQ ID NO: 84, 97, 98, 99, 100 and 105; SEQ ID NO: 106, 107, 108, 109, 110 and 111; SEQ ID NO: 106, 112, 113, 109, 114 and 115 or SEQ ID NO: 106, 116, 117, 109, 118 and 119 (CDR numbering according to Kabat).

[0077] In some embodiments, the anti-HIV gp120 V3 glycan-binding antibody comprises a VH and a VL, the VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3; the VL comprising a VL-CDR1, a VL-CDR2, and a second VH-CDR3; wherein the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 comprise the sequences shown 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 NO:128, 192, 30, 31, 32 and 33; SEQ ID NO:130, 131, 36, 37, 25 and 38; SEQ ID NO:132, 133, 41, 42, 43 and 44; SEQ ID NO:134, 135, 47, 48, 49 and 50; SEQ ID NO:134, 136, 52, 53, 49 and 54; SEQ ID NO:137, 56, 57, 58, 59 and 44; SEQ ID NO:138, 135, 61, 58, 49 and 44; SEQ ID NO:139, 140, 64, 65, 66 and 67; SEQ ID NO:141, 142, 70, 71, 72 and 71; SEQ ID NO:143, 144, 76, 77, 78 and 73; SEQ ID NO:144 SEQ ID NO:145, 144, 81, 82, 83 and 73; SEQ ID NO:146, 147, 86, 87, 88 and 89; SEQ ID NO:148, 147, 86, 87, 88 and 89; SEQ ID NO:149, 150, 91, 92, 93 and 89; SEQ ID NO:148, 147, 86, 95, 96 and 89; SEQ ID NO:149, 151, 98, 99, 100 and 101; SEQ ID NO:149, 151, 98, 99, 100 and 102; SEQ ID NO:149, 151, 98, 103, 100 and 89; SEQ ID NO:149, 151, 98, 99, 100 and 105; NO: 152, 153, 108, 109, 110 and 111; SEQ ID NO: 154, 155, 113, 109, 114 and 115; or SEQ ID NO: 154, 156, 117, 109, 118 and 119 (CDRs are numbered according to Chothia).

[0078] In some embodiments, the anti-HIV gp120 V3 glycan-binding antibody comprises a VH and a VL, the VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3; the VL comprising a VL-CDR1, a VL-CDR2, and a second VH-CDR3; wherein the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 comprise the sequences shown in 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, 165, 161, and 18; SEQ ID NO:170, 171, 172, 173, 161 and 26; SEQ ID NO:170, 171, 174, 173, 161 and 26; SEQ ID NO:175, 176, 177, 178, 161 and 38; SEQ ID NO:179, 180, 181, 182, 183 and 33; SEQ ID NO:184, 185, 186, 187, 188 and 44; SEQ ID NO:189, 190, 191, 192, 193 and 50; SEQ ID NO:189, 194, 195, 196, 193 and 54; SEQ ID NO:197, 198, 199, 200, 201 and 44; SEQ ID NO:202, 203, 204, 200, 193 and 44; SEQ ID NO:205, 206, 207, 208, 209 and 67; SEQ ID NO:210, 211, 212, 213, 214 and 73; SEQ ID NO:215, 216, 217, 218, 219 and 73; SEQ ID NO:220, 216, 221, 222, 223 and 73; SEQ ID NO:224, 225, 86, 226, 227 and 89; SEQ ID NO:228, 225, 86, 226, 227 and 89; SEQ ID NO:229, 230, 91, 231, 232 and 89; SEQ ID NO:229; 233, 91, 231, 232 and 89; SEQ ID NO:228, 225, 86, 234, 235 and 89; SEQ ID NO: 229, 236, 98, 231, 232 and 101; SEQ ID NO: 229, 236, 98, 231, 232 and 102; SEQ ID NO: 229, 236, 98, 237, 232 and 89;SEQ ID NO: 229, 238, 91, 231, 232 and 89; SEQ ID NO: 229, 236, 98, 231, 232 and 105; SEQ ID NO: 239, 240, 108, 241, 242 and 111; SEQ ID NO: 243, 244, 113, 241, 245 and 115; or SEQ ID NO: 243, 246, 117, 241, 242 and 119 (CDR numbering according to IMGT). ;

[0079] In some embodiments, the anti-HIV gp120 V3 glycan-binding antibody comprises a VH and a VL, wherein the VH comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3; the VL comprises a VL-CDR1, a VL-CDR2, and a second VH-CDR3; wherein the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 comprise the sequences shown below: SEQ ID NOs: 247, 248, 249, 250, 251, and 252; SEQ ID NOs: 247, 253, 249, 250, 251, and 252; SEQ ID NOs: 254, 255, 256, 257, 251, and 258; SEQ ID NOs: 259, 260, 261, 257, 251, and 258; SEQ ID NOs: 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 300, 301, 302, 303, 304, 305 SEQ ID NO:262, 263, 264, 265, 266 and 267; SEQ ID NO:262, 263, 268, 265, 266 and 267; SEQ ID NO:269, 270, 271, 272, 273 and 274; SEQ ID NO:275, 276, 277, 278, 279 and 280; SEQ ID NO:281, 282, 283, 284, 285 and 286; SEQ ID NO:287, 288, 289, 290, 291 and 286; SEQ ID NO:287, 292, 293, 294, 291 and 295; SEQ ID NO:296, 297, 298, 299, 300 and 286; SEQ ID NO: SEQ ID NO:301, 288, 302, 299, 291 and 286; SEQ ID NO:303, 304, 305, 306, 307 and 308; SEQ ID NO:309, 310, 311, 312, 313 and 314; SEQ ID NO:315, 316, 317, 318, 319 and 314; SEQ ID NO:320, 321, 322, 323, 324 and 314; SEQ ID NO:325, 326, 327, 328, 329 and 330; SEQ ID NO:331, 326, 327, 328, 329 and 330; SEQ ID NO:332, 333, 334, 335, 336 and 330; NO:332, 337, 334, 335, 336 and 330; SEQ ID NO:331, 326, 327, 338, 339 and 330; SEQ ID NO:340, 341, 342, 335, 343 and 344; SEQ ID NO: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 (CDR numbering according to Honegger). ;

[0080] Exemplary embodiments of CDR sequences of anti-HIV gpl20 V3 glycan binding antibodies useful in the methods described herein are provided in Tables A1-A4.

[0081] In some embodiments, the anti-HIV gp120 V3 glycan binding antibody comprises a VH and a VL, wherein the VH and VL respectively comprise an amino acid sequence having 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% identity to an amino acid sequence selected from the group consisting of: 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; 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; SEQ ID NOs: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: 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 gpl20 V3 glycan binding antibodies useful in the methods described herein are provided in Table B.

[0082] 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:

[0083] Heavy chain :

[0084] QVQLQESGPGLVKPSETLSVTCSVSGDSMNNYYWTWIRQSPGKGLEWIGYISDRESATYNPSLNSRVVISRDTSKNQLSLKLNSVTPADTAVYCATARRGQRIYGVVSFGEFFYYYSMDVWGKGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICVNHKPSNTKVDKKVEP KSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG(SEQ ID NO:433)

[0085] Light chain :

[0086] SYVRPLSVALGETARISCGRQALGSRAVQWYQHRPGQAPILLIYNNQDRPSGIPERFSGTPDINFGTRATLTISGVEAGDEADYYCHMWDSRSGFSWSFGGATRLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS(SEQ IDNO:434)

[0087] c. Antibodies against the CD4bs region of HIV gp120

[0088] The CD4 binding site (CD4bs) involves structurally conserved sites located within β1-α1, loop D, β20-β21 (bridging sheet), and β24-α5 of gp120 that determine CD4 binding and are included in the epitope of CD4bs binding antibodies (Qiao et al., Antiviral Res. 2016 August; 132: 252-61). The CD4bs of gp120 forms a conformational epitope recognized by anti-CD4bs antibodies that involve one or more amino acid residues selected from the following: Thr278, Asp279, Ala281, Thr283, Asp368, Trp427, Glu460, Ser461, Glu462, Leu452, Leu453, and Arg476. The amino acid residue and position numbers are referenced to the HXB2 subtype B HIV-1 isolate, which corresponds to residues 1-511 of the NCBI reference sequence number NP_057856.1 provided below. Residues Thr278, Asp279, Asn280, Ala281, Thr283, Asp368, Trp427, Leu452, Leu453, Gly459, Glu464, Ser465, Glu466, Ile467, Gly472, Gly473, and Arg476 that may contribute to the gp120 CD4bs are bolded and underlined:

[0089]

[0090] Three-dimensional models depicting the amino acid residues that contribute to the gp120 CD4bs are provided in, e.g., 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. 2016 Jul;22(7):522-31; 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 the anti-CD4bs antibodies GS-9723, GS-5423, b12, CH103, 1NC9, 12A12, VRC01, VRC07-523, N6, 3BNC117, NIH45-46 and / or PGV04 (VRC-PG04) for binding to gp120CD4bs. In some embodiments, the antibody variants described herein bind to an epitope that overlaps with or is identical to the epitope bound by the following anti-CD4bs antibodies: GS-9723, GS-5423 (telopavir), b12, CH103, 1NC9, 12A12, VRC01, VRC07-523, N6, 3BNC117, NIH45-46 and / or PGV04 (VRC-PG04).

[0091] Gp120 is encoded by the HIV env gene. The env gene encodes a gene product of approximately 850 amino acids. The major 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).

[0092] The amino acid sequence of an exemplary gp160 polypeptide of an HIV clone identified in NCBI Reference Sequence No. NP_057856.1 is provided below (CD4bs in bold and underlined):

[0093]

[0094] 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 Reference Sequence No. NP_057856.1) is provided below (CD4bs in bold and underlined):

[0095]

[0096] The amino acid sequence of an exemplary gp120 polypeptide is provided below:

[0097]

[0098] The amino acid sequence of another exemplary gp120 polypeptide (see, bioafrica.net / proteomics / ENV-GP120prot.html) is provided below:

[0099]

[0100] In certain embodiments of the methods described herein, an antibody that binds to HIV gp120 protein within the CD4bs region (e.g., an epitope or region of the gp120 CD4 binding site) is administered to a subject. In certain embodiments, the administered antibody binds to HIV-1 antigens expressed on the surface of cells and eliminates or kills infected cells.

[0101] Exemplary broadly neutralizing antibodies that bind to gp120 in CD4bs and can be used in the methods described herein include, but are not limited to, antibodies selected from the group consisting of: 3BNC117, GS-9723, GS-5423, 3BNC60, b12, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b01, VRC08, VRC0801, NIH45-46, PGV04 (VRC-PG04); CH103, 44-VRC13.01, 1NC9, 12A12, N6, 1-18, N49-P7, NC-Cow1, IOMA, CH235 and CH235.12, N49P6, N49P7, N49P11, N49P9, and N60P25.

[0102] Exemplary sequences of complementarity determining regions (CDRs) of antibodies targeting the HIV gp120 CD4bs region that can be used 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 that can be used in the methods described herein are provided in Table D.

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109] In some embodiments, the anti-HIV gp120 CD4bs binding antibody comprises a VH and a VL, the VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3; the VL comprising a VL-CDR1, a VL-CDR2, and a second VH-CDR3; wherein the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 comprise the sequences shown below: SEQ ID NOs: 442, 443, 444, 445, 446, and 447; SEQ ID NOs: 448, 443, 449, 445, 446, and 447; SEQ ID NOs: 450, 451, 452, 453, 454, and 455; SEQ ID NOs: 450, 456, 452, 453, 454, 455; SEQ ID NOs: NO: 457, 458, 459, 453, 454 and 455; SEQ ID NO: 460, 461, 462, 463, 464 and 465; SEQ ID NO: 466, 467, 468, 469, 470 and 471; or SEQ ID NO: 472, 473, 474, 475, 476 and 477 (CDR numbering according to Kabat).

[0110] In some embodiments, the anti-HIV gp120 CD4bs binding antibody comprises a VH and a VL, the VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3; the VL comprising a VL-CDR1, a VL-CDR2, and a second VH-CDR3; wherein the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 comprise the sequences shown below: SEQ ID NOs: 478, 479, 480, 481, 482, and 483; SEQ ID NOs: 484, 479, 485, 481, 482, 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: 486, 491, 488, 489, 490, and 483; SEQ ID NOs: 486, 491, 488, 489, 490, and 483; SEQ ID NOs: NO: 492, 487, 493, 489, 490 and 483; SEQ ID NO: 494, 495, 496, 497, 498 and 499; SEQ ID NO: 500, 501, 502, 503, 504 and 505; or SEQ ID NO: 506, 507, 508, 509, 510 and 511 (CDRs are numbered according to Chothia).

[0111] In some embodiments, the anti-HIV gp120 CD4bs binding antibody comprises a VH and a VL, wherein the VH comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3; the VL comprises a VL-CDR1, a VL-CDR2, and a second VH-CDR3; wherein the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 comprise the sequences shown below: SEQ ID NO: 512, 513, 514, 481, 482, and 447; SEQ ID NO: 515, 513, 516, 481, 482, and 447; SEQ ID NO: 517, 518, 519, 520, 490, and 455; SEQ ID NO: 517, 522, 519, 520, 521, and 455; SEQ ID NO: 518 NO: 522, 523, 524, 520, 490 and 455; SEQ ID NO: 525, 526, 527, 528, 498 and 465; SEQ ID NO: 529, 530, 531, 532, 504 and 471; SEQ ID NO: 533, 534, 535, 536, 510 and 477 (CDRs are numbered according to IMGT).

[0112] In some embodiments, the anti-HIV gp120 CD4bs binding antibody comprises a VH and a VL, wherein the VH comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3; the VL comprises a VL-CDR1, a VL-CDR2, and a second VH-CDR3; wherein the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VH-CDR3 comprise the sequences shown below: SEQ ID NOs: 538, 539, 540, 541, 542, and 483; SEQ ID NOs: 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: 546, 551, 548, 549, 550, and 483; SEQ ID NOs: NO: 555, 556, 557, 558, 559 and 499; SEQ ID NO: 560, 561, 562, 563, 564 and 505; SEQ ID NO: 565, 566, 567, 568, 569, 569 and 511 (CDR numbering according to Honegger).

[0113] In some embodiments, the anti-HIV gp120 CD4bs binding antibody comprises a VH and a VL, wherein the VH and VL respectively comprise an amino acid sequence having 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% identity to the amino acid sequence selected from the group consisting of: 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; or SEQ ID NOs: 585 and 586; 587 and 588.

[0114] 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:

[0115] Heavy chain :

[0116] QVQLLQSGAAVTKPGASVRVSCEASGYNIRDYFIHWWRQAPGQGLQWVGWINPKTGQPNNPRQFQGRVSLTRHASWDFDTFSFYMDLKALRSDDTAVYFCARQRSDYWDFDVWGSGTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG(SEQ ID NO:589)

[0117] Light chain :

[0118] DIQMTQSPSSLSASVGDTVTITCQANGYLNWYQQRRGKAPKLLIYDGSKLERGVPSRFSGRRWGQEYNLTINNLQPEDIATYFCQVYEFVVPGTRLDLKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:590)

[0119] d. Fc amino acid substitutions to increase serum half-life

[0120] In some embodiments, the Fc region or Fc domain of anti-HIV gp120 bNAb comprises an amino acid modification that promotes the serum half-life extension of the anti-binding molecule. Amino acid substitutions that increase the half-life of antibodies have been described. In one embodiment, the Fc region or Fc domain of one or both of the s 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, for example, U.S. Patent No. 7,658,921. This type of mutant (named "YTE") exhibits a four-fold increased half-life relative 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 two heavy chains comprises an IgG constant domain, and the IgG constant domain comprises one, two, three or more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308-314, 385-389 and 428-436 (EU numbering). Alternatively, M428L and N434S ("LS") amino acid substitutions can increase the pharmacokinetic half-life of the multispecific antigen-binding molecule. In other embodiments, the Fc region or Fc domain of one or two heavy chains comprises M428L and N434S substitutions (EU numbering). In other embodiments, the Fc region or Fc domain of one or two heavy chains comprises T250Q and M428L (EU numbering) amino acid substitutions, for example as described in U.S. Patent Nos. 7,217,797 and 7,217,798. In other embodiments, the Fc region or Fc domain of one or both heavy chains comprises H433K and N434F (EU numbering) amino acid substitutions, for example, 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, for example, 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 aspartic acid at position 309, histidine at position 311, and serine (DHS) at position 434, for example, as described in U.S. Patent No. 11,059,892.

[0121] 3. Arrangement plan

[0122] Typically, the methods of the invention require treating or preventing HIV in human subjects in need thereof by co-administering twice a year an effective amount of a bNAb that binds to a gp120 epitope within the third variable loop (V3) and / or high mannose membrane patch comprising N332 mannooligosaccharide glycans and an effective amount of a bNAb that binds to a gp120 epitope comprising a CD4 binding site (CD4bs), both bNAbs having Fc amino acid substitutions that extend serum half-life. In various embodiments, the rhythm of co-administration can be once every six months (i.e., Q6M), once every 24 weeks (i.e., Q24W), once every 25 weeks (i.e., Q25W), once every 26 weeks (i.e., Q26W).

[0123] "Subject," "individual," or "patient" refers to any mammal, including humans and non-human primates. In certain embodiments, the mammal is a human.

[0124] "Effective amount" or "therapeutically effective amount" refers to an amount of an antibody sufficient to achieve a therapeutic or beneficial result in a subject when administered alone or in combination with another therapeutic agent to a cell, tissue or subject. The amount constituting an "effective amount" will vary depending on the antibody and its specific use, as well as the underlying disorder and its severity, the mode of administration and the age of the subject to be treated, but can be routinely determined by one of ordinary skill in the art with reference to his or her own knowledge and this disclosure. A therapeutically effective dose also refers to an amount of an antibody sufficient to treat, prevent or ameliorate an infection or disease condition or infection or disease progression, and an amount sufficient to achieve an increase in the rate of treatment, cure, prevention or improvement of such conditions. When applicable to a single antibody administered alone, a therapeutically effective dose refers to a single active ingredient. When applicable to a combination, a therapeutically effective dose refers to the combined amount of active ingredients that result in a therapeutic effect, whether administered in combination, continuously or simultaneously. In some embodiments, a therapeutically effective dose allows for an effective blood or serum concentration of the antibody at the time of a second or subsequent administration (e.g., 6 months, 24 weeks, 25 weeks or 26 weeks after the first or previous administration).

[0125] In certain embodiments, the anti-HIV gp120 V3 glycan binding antibodies and anti-HIV gp120CD4bs binding antibodies described herein are each administered intravenously at a therapeutically effective 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 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 (eg, 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 (eg, 3BNC117-LS) is administered intravenously at a dose of 30 mg / kg.

[0126] As used herein, "treat", "treating" or "treatment" encompasses treating a disease, injury or condition of interest, such as 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., preventing its development; (ii) reducing or alleviating the disease, injury or condition, i.e., causing regression of the disease or condition; or (iii) alleviating the symptoms caused by the disease, injury or condition. As used herein, the terms "disease", "disorder" and "disorder" are used interchangeably. As used herein, "inhibit", "treatment", "treating" and "improve" are used interchangeably and refer to, for example, stagnation of symptoms, prolonged survival, partial or complete improvement of symptoms, and partial or complete eradication of a condition, disease or disorder.

[0127] As used herein, "prevent" or "prevention" includes (i) preventing or inhibiting the occurrence of a disease, injury or condition in a subject, particularly when such subject is susceptible to the condition but has not yet been diagnosed as having the condition; or (ii) reducing the likelihood of a subject developing a disease, injury or condition.

[0128] Co-administration includes simultaneous administration and administration of unit doses of anti-HIV gp120 V3 glycan binding antibodies and anti-HIV gp120 CD4bs binding antibodies as described herein. For example, anti-HIV gp120 V3 glycan binding antibodies and anti-HIV gp120 CD4bs binding antibodies as described herein can be administered simultaneously or within seconds, minutes, hours, or days of each other. In some embodiments, unit doses of anti-HIV gp120 V3 glycan binding antibodies and anti-HIV gp120 CD4bs binding antibodies disclosed herein are administered within hours of each other (e.g., within 1-12 hours, 1-24 hours, 1-36 hours, 1-48 hours, 1-60 hours, 1-72 hours).

[0129] In certain embodiments, an anti-HIV gp120 V3 glycan binding antibody and an anti-HIV gp120 CD4bs binding antibody as described herein are combined in a single dosage form, separately or as a mixture, for simultaneous administration to a patient, e.g., as a liquid or suspension dosage form for intravenous, intramuscular or subcutaneous administration.

[0130] In certain embodiments, the anti-HIV gp120 V3 glycan binding antibody and the anti-HIV gp120 CD4bs binding antibody are formulated separately or as a mixture as a liquid solution or suspension, which may optionally contain one or more other agents useful for treating HIV (e.g., HIV capsid inhibitors, such as lenacapvir). In certain embodiments, the liquid solution or suspension may contain another active ingredient for treating HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0131] In certain embodiments, such liquid solutions or suspensions are suitable for administration twice per year (e.g., once every six months (i.e., Q6M), once every 24 weeks (i.e., Q24W), once every 25 weeks (i.e., Q25W), once every 26 weeks (i.e., Q26W)).

[0132] In some embodiments, following 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.

[0133] In some embodiments, following 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.

[0134] 4. Patient Selection

[0135] Infection Stage

[0136] In various embodiments, the human subject is an adult, teenager or infant. The subject may be symptomatic (e.g., viremia) or asymptomatic (e.g., acute infection or ART inhibition). In some embodiments, the human subject is acutely infected or recently infected with HIV. In certain embodiments, there is no seroconversion in the subject. In some embodiments, the human subject is chronically infected with HIV. The subject may or may not be receiving an antiretroviral therapy (ART) regimen.

[0137] Patients can be classified into Fiebig stages I to VI, based on the sequential gain in positive HIV-1 clinical diagnostic assays (viral RNA measured by PCR, p24 and p31 viral antigens measured by enzyme-bound immunosorbent assay (ELISA)). The p24 antigen is a viral core protein that appears briefly in the blood during the rising phase once HIV-1 RNA levels rise to more than 10,000 copies / ml and before detectable HIV antibodies are formed. In Fiebig stage I, only HIV-1 RNA can be detected in the blood during the rising viremia. Fiebig stage II begins after about 7 days, when the test result for detecting p24 antigen is positive. In Fiebig stage III, within about 5 days after the p24 antigen test result is positive, IgM anti-HIV-1 antibodies can be detected by a sufficiently sensitive enzyme immunoassay (EIA) (e.g., third generation EIA). Stage III usually occurs 1 to 2 weeks after the onset of acute retroviral symptoms. Fiebig stage IV represents the development of an undetermined Western blot test and occurs about 3 days after the EIA test shows a positive result. Transformation to a clearly positive Western blot test, i.e., Fiebig stage V, usually occurs 7 days or about 1 month after the initial infection. The Fiebig stage of HIV infection is described in the following literature: for example, 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 hereby incorporated by reference in their entirety for all purposes. In some embodiments, the biological sample evaluated is from a human subject with HIV infection of Fiebig stage IV or earlier, such as Fiebig stage I, Fiebig stage II, Fiebig stage III or Fiebig stage IV. In some embodiments, the biological sample evaluated is from a human subject with HIV infection at Fiebig stage V or Fiebig stage VI.

[0138] Susceptibility of HIV in the subjects to one or two bNAbs

[0139] In some embodiments, the method further comprises the step of obtaining a biological sample (e.g., blood, serum, plasma, semen, lymph node) from the subject. In some embodiments, the method entails receiving a report of HIV gp120 amino acid residues present at specified positions of interest, such as 332 and 325, and one or more amino acid positions selected from 63, 179, 320, and 330, wherein the amino acid positions are referenced to SEQ ID NO:4.

[0140] In various embodiments, the method further comprises the step of identifying patients who are 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 the 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 a bNAb less than or equal to (≤) 2 μg / mL in the PhenoSense mAb assay (Monogram).

[0141] HIV sensitive to anti-HIV gp120 V3 glycan antibodies

[0142] In some embodiments, the patient is identified by receiving a report of the HIV species that infects the patient, the report identifying the HIV gp120 amino acid residues present at specified amino acid positions of interest (e.g., positions 332 and 325), and one or more amino acid positions selected from the group consisting of: 63, 179, 320, and 330, wherein the amino acid positions are referenced to SEQ ID NO:4 (supra, HXB2 subtype B HIV-1 isolate (GenBank Accession No. K0345; corresponding to residues 1-511 of NCBI Reference Sequence No. NP_057856.1). Assays that can be used to determine 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 herein by reference in its entirety for all purposes.

[0143] In some embodiments, the patient is identified by performing one or more assays (e.g., polynucleotide or polypeptide sequencing) to determine the amino acid sequence of gp120 or the amino acid residues present at a specified amino acid position of interest in the gp120 protein of the HIV species that infected the patient. The identification of the full-length or partial sequence of the gp120 protein obtained from the subject can be determined at the polynucleotide or polypeptide level. In some embodiments, the amino acids present at the gp120 residue positions of interest are determined at the polypeptide level.

[0144] In various embodiments, the method entails identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising: N332 glycan, D325, and T63, wherein the amino acid positions refer to SEQ ID NO:4.

[0145] In various embodiments, the method entails identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising: N332 glycan, D325, and L179, wherein the amino acid positions refer to SEQ ID NO:4.

[0146] In various embodiments, the method entails identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising: N332 glycan, D325, and T320, wherein the amino acid positions refer to SEQ ID NO:4.

[0147] In various embodiments, the method entails identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising: N332 glycan, D325, and H330, wherein the amino acid positions refer to SEQ ID NO:4.

[0148] In various embodiments, the method entails identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising: N332 glycan, D325, T63, and L179, wherein the amino acid positions refer to SEQ ID NO:4.

[0149] In various embodiments, the method entails identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising: N332 glycan, D325, T63, and T320, wherein the amino acid positions refer to SEQ ID NO:4.

[0150] In some embodiments, the subject is infected with an HIV clade B virus. In various embodiments, the method entails identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising: N332 glycan, D325, T63, and H330, wherein the amino acid positions are referenced to SEQ ID NO: 4. In various embodiments, the method entails identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising: N332 glycan, D325, T63, L179, T320, and H330, wherein the amino acid positions are referenced to SEQ ID NO: 4.

[0151] In various embodiments, the method entails identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising: N332 glycan, D325, T320, and H330, wherein the amino acid positions refer to SEQ ID NO:4.

[0152] In various embodiments, the method entails identifying a subject infected with HIV or a population of HIV expressing a gp120 comprising: N332 glycan, D325, L179, T320, and H330, wherein the amino acid positions are referenced to SEQ ID NO: 4. In some embodiments, the subject is infected with HIV clade A and / or HIV clade C virus. In some embodiments, the subject is infected with HIV clade A, clade B, and / or HIV clade C virus.

[0153] In various embodiments, the method entails identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising: N332 glycan, D325, T63, L179, and T320, wherein the amino acid positions refer to SEQ ID NO:4.

[0154] In various embodiments, the method entails identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising: N332 glycan, D325, T63, L179, and H330, wherein the amino acid positions refer to SEQ ID NO:4.

[0155] HIV sensitive to anti-HIV gp120 CD4bs antibodies

[0156] In some embodiments, the patient is identified by receiving a report of the HIV species that infects the patient, the report identifying the HIV gp120 amino acid residue present at a designated amino acid position of interest (e.g., position 201), and one or more amino acid positions selected from the group consisting of: 102, 108, 281, 318, and 353, wherein 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 or polypeptide sequencing) to determine the amino acid sequence of gp120 or the amino acid residues present at the designated amino acid position of interest of the gp120 protein of the HIV species that infects the patient. The identification of the full-length or partial sequence of the gp120 protein obtained from the subject can be determined at the polynucleotide or polypeptide level. In some embodiments, the amino acid present at the gp120 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 herein by reference in its entirety for all purposes.

[0157] In various embodiments, the method entails identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising: I201 and F353, wherein the amino acid positions refer to SEQ ID NO:439.

[0158] In various embodiments, the method entails identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising: I201, I108, and F353, wherein the amino acid positions refer to SEQ ID NO:439.

[0159] In various embodiments, the method entails identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising: I201, I108, A281, and F353, wherein the amino acid positions refer to SEQ ID NO:439.

[0160] In various embodiments, the method entails identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising: I201, E102, I108, A281, and F353, wherein the amino acid positions refer to SEQ ID NO:439.

[0161] In various embodiments, the method entails identifying a subject infected with HIV or a population of HIV that expresses a gp120 comprising: I201, E102, I108, A281, Y318, and F353, wherein the amino acid positions refer to SEQ ID NO:439.

[0162] In some embodiments, the subject is infected with HIV clade (also known as HIV subtype) B virus. In some embodiments, the subject is infected with HIV clade (also known as HIV subtype) A and / or HIV clade (also known as HIV subtype) C virus. In some embodiments, the subject is infected with HIV clade (also known as HIV subtype) A, clade B, and / or HIV clade (also known as HIV subtype) C virus.

[0163] Identification of gp120 amino acids of interest

[0164] The amino acid residues at the designated positions of interest (e.g., 332 and 325, and one or more amino acid positions selected from 63, 179, 320, and 330) of the HIV gp120 sequence of the subject can be determined at the polynucleotide or polypeptide level, wherein the amino acid position is referenced to SEQ ID NO: 3. At the polynucleotide level, methods known in the art can be used to sequence HIV RNA or proviral DNA isolated from one or more biological samples. In some embodiments, HIV RNA or proviral DNA isolated from two or more biological samples of the subject are sequenced. In some embodiments, the two or more biological samples are obtained from different tissue sources (e.g., blood, peripheral blood mononuclear cells, lymph nodes, and / or semen). In some embodiments, two or more biological samples are obtained at different time points, for example, at intervals of 1, 2, 3, 4, 5, 6, 7, or 8 weeks, at intervals of 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0165] As appropriate, primers annealed and amplified with HIV env coding sequences, especially the CD4bs region of gp120, can be used. In some embodiments, nested primer sets can be used. In various embodiments, RNA is directly sequenced or reverse transcriptase polymerase chain reaction (RT-PCR) can be performed. In some embodiments, Sanger sequencing can be performed, for example, when sequencing to determine the amino acid residues in the CD4bs region, or when sequencing samples from patients in the early Fiebig stage of the disease (for example, before Fiebig stage III, such as Fiebig stage I or II). In various embodiments, single genome amplification (SGA) and sequencing are performed. The method for single genome amplification (SGA) and sequencing for plasma HIV virion RNA is described in, for example, 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 use of SGA for determining amino acid sequence changes in HIV gp120 sequences and for the methods described herein is described in, for example, 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 technology are used to sequence the gp120 (including at least the CD4bs region) of a population of HIV species in one or more biological samples from a single patient or subject. In such cases, multiple nucleic acid sequences encoding at least the CD4bs region of gp120 are sequenced and compared. In some embodiments, the full length of gp120 is sequenced. Exemplary platforms for performing NGS sequencing that can be used to determine the gp120 sequence of HIV species in one or more 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 patients and that can be applied to the methods of the present invention are described, for example, in Shioda et al., J Virol. (1997) 71(7):4871-81; Colón 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. As appropriate, shorter sequence reads ("contigs") of nucleic acid sequences can be assembled into longer sequences, including at least the CD4bs region of gp120. Contig assembly methods for HIV genomic sequences that can be applied in the methods of the present invention are described in, for example, Huang et al., Bioinformation. (2018) 14(8): 449-454; Hiener et al., J Vis Exp. (2018) 10 / 16; (140). doi: 10.3791 / 58016; and Wymant et al., Virus Evol. (2018) 5 / 18; 4(1): vey007. doi: 10.1093 / ve / vey007.

[0166] 5. Combination therapy

[0167] In certain embodiments, methods for treating or preventing HIV infection in a human having infection or at risk of infection are provided, 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, as disclosed herein, and a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three or one to four) additional therapeutic agents. In one embodiment, methods for treating HIV infection in a human having infection or at risk of infection are provided, 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, as disclosed herein, and a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three or one to four) additional therapeutic agents.

[0168] In one embodiment, a pharmaceutical composition is provided, comprising an anti-HIV gp120 V3 glycan and an anti-HIV gp120 CD4bs binding antibody, as disclosed herein, and one or more (e.g., one, two, three, four, one or two, or one to three or one to four) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0169] In certain embodiments, methods for treating HIV infection are provided, comprising administering to a patient in need thereof a therapeutically effective amount of an anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibody or antigen-binding fragment thereof, as described herein, and a therapeutically effective amount of one or more additional therapeutic agents suitable for treating HIV infection.

[0170] In certain embodiments, anti-HIV gp120 V3 glycans and anti-HIV gp120 CD4bs binding antibodies or antigen-binding fragments thereof are combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, anti-HIV gp120 V3 glycans and anti-HIV gp120 CD4bs binding antibodies or antigen-binding fragments thereof are combined with two additional therapeutic agents. In other embodiments, anti-HIV gp120 V3 glycans and anti-HIV gp120 CD4bs binding antibodies or antigen-binding fragments thereof are combined with three additional therapeutic agents. In other embodiments, anti-HIV gp120 V3 glycans and anti-HIV gp120 CD4bs binding antibodies or antigen-binding fragments thereof are combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents (e.g., one or more anti-HIV broadly neutralizing antibodies), and / or they may be selected from different classes of therapeutic agents.

[0171] Administration of HIV combination therapy

[0172] In certain embodiments, as described herein, anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies or antigen-binding fragments thereof are co-administered with one or more additional therapeutic agents. Co-administration of anti-HIV gp120 CD4bs binding antibodies disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of anti-HIV gp120 CD4bs binding antibodies disclosed herein with one or more additional therapeutic agents, such that therapeutically effective amounts of anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies disclosed herein and the one or more additional therapeutic agents are present in the patient. When administered sequentially, the combination can be administered in two or more administrations.

[0173] Co-administration includes simultaneous administration as well as administration of a unit dose of anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibody or antigen-binding fragment thereof, as described herein, before or after administration of a unit dose of one or more additional therapeutic agents. For example, as described herein, anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibody or antigen-binding fragment thereof 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 anti-HIV gp120 V3 glycan and 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 anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibody disclosed herein within seconds, minutes, hours, or days. In other embodiments, a unit dose of the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies disclosed herein are administered first, and then a unit dose of one or more additional therapeutic agents is administered after a period of hours (e.g., 1 hour to 12 hours, 1 hour to 24 hours, 1 hour to 36 hours, 1 hour to 48 hours, 1 hour to 60 hours, 1 hour to 72 hours). In still other embodiments, a unit dose of one or more additional therapeutic agents is administered first, and then a unit dose of the anti-HIV gp120 CD4bs binding antibodies disclosed herein are administered after a period of hours (e.g., 1 hour to 12 hours, 1 hour to 24 hours, 1 hour to 36 hours, 1 hour to 48 hours, 1 hour to 60 hours, 1 hour to 72 hours).

[0174] In certain 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 therapeutic agents in a single dosage form for simultaneous administration to a patient, e.g., as a solid, liquid or suspension dosage form for oral, intravenous, intramuscular or subcutaneous administration.

[0175] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies with extended serum half-life are formulated as a liquid solution or suspension, which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the liquid solution or suspension may contain another active ingredient for treating HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0176] In certain embodiments, such liquid solutions or suspensions are suitable for administration twice per year (e.g., once every 6 months (Q6M), once every 26 weeks (Q26W), once every 25 weeks (Q25W), or once every 24 weeks (Q24W)).

[0177] HIV combination therapy

[0178] In the above embodiments, the additional therapeutic agent can be an anti-HIV agent. Exemplary anti-HIV agents that can be combined or co-administered include, but are not limited to, a third anti-HIV antibody, an HIV protease inhibitor, a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase, a nucleoside or nucleotide inhibitor of HIV 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, immunomodulators (e.g., immunostimulators), immunotherapeutics, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T cells CAR-T and engineered T cell receptors TCR-T, autologous T cell therapy, engineered B cells, NK cells), latency reversal agents, 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 infection factor inhibitors, HIV-1Nef modulators, TNFα 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 factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, IFN antagonists, defensin modulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, cytochrome P450 3 inhibitors, CXCR4 modulators, dendritic ICAM-3 grabbing non-integrin 1 inhibitors, HIVGAG protein inhibitors, HIVPOL protein inhibitors, complement factor H regulators, 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 initiation 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 vaccine, anti-HIV peptides and their combinations.

[0179] In some embodiments, the additional therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, HIV capsid inhibitors, HIV Tat or Rev inhibitors, immunomodulators (e.g., immunostimulators), immunotherapeutics, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0180] In some embodiments, the one or more additional therapeutic agents are selected from HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reversal agents, HIV bNAbs, agonists of TLR7, TLR8 and / or TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, bispecific antibodies that recruit T cells and NK cells, chimeric T cell receptors targeting HIV antigens, pharmacokinetic enhancers, and other drugs used to treat HIV, and combinations thereof.

[0181] In some embodiments, the one or more additional therapeutic agents are selected from dolutegravir, cabotegravir, islatravir, darunavir, bicagavir, essavirine, rilpivirine, and lenacapavir, and combinations thereof.

[0182] Additional anti-HIV antibodies

[0183] 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 vertex; (ii) the gp120 / gp41 interface; or (iii) the silent face of gp120. The aforementioned epitopes or regions of gp120 to which broadly neutralizing antibodies bind are described in, e.g., 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 hereby incorporated by reference in their entirety for all purposes.

[0184] In some embodiments, the combination therapy requires co-administration of an anti-HIV gp120 V3 glycan binding antibody and an anti-HIV gp120 CD4bs binding antibody and one or more additional anti-HIV broadly neutralizing antibodies or bNAbs (i.e., neutralizing antibodies that neutralize multiple HIV-1 viral strains). Various bNAbs are known in the art and can be used as combination therapeutic agents. Additional exemplary bNAbs used include antibodies comprising 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 vertex; (ii) the gp120 / gp41 interface; or (iii) the silent face of gp120.

[0185] In some embodiments, the combination therapy includes an antibody that binds to an epitope or region of gp120 in the second variable loop (V2) and / or the apex of the Env trimer and competes with or comprises the CDRs and / or VH and VL regions of 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.

[0186] In some embodiments, the combination therapy includes an antibody that binds to an epitope or region of gp120 in the gp120 / gp41 interface and competes with or comprises the CDRs and / or VH and VL regions of an antibody selected from the group consisting of PGT-151, CAP248-2B, 35022, 8ANC195, ACS202, VRC34, and VRC34.01.

[0187] In some embodiments, the combination therapy includes an antibody that binds to an epitope or region of the silent face of gp120 and competes with or encompasses the second VH and VL regions of antibody VRC-PG05.

[0188] 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 comprises a second VH region and VL region of 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", as disclosed in SEQ ID NO: 496) (an invariable site of the transmembrane protein gp41) and competes with or comprises a second VH region and VL region of clone 3 human monoclonal antibody (Cl3hmAb) (Protheragen). See, e.g., Vanini et al., AIDS. (1993) 7(2): 167-74.

[0189] In some embodiments, the combination therapy includes an antibody that binds to an epitope or region of a gp41 fusion peptide and competes with or comprises a second VH region and a VL region of an antibody selected from the group consisting of: VRC34 and ACS202.

[0190] In some embodiments, the combination therapy includes a multispecific antibody, such as 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.

[0191] Prior to administration, bNAbs can be improved to have enhanced drug-like properties, reduced immunogenicity, enhanced ADCC, and suitable pharmacokinetic properties. Such antibodies are shown to bind to HIV envelope glycoproteins expressed on the surface of virions or infected cells, and mediate direct neutralization of the virus and potent NK, monocyte, and PBMC killing of these cells. This property allows antibodies to treat HIV infection by neutralizing the virus, and also kill and eliminate latent HIV-infected cells in infected individuals, potentially leading to sterilization therapy of HIV.

[0192] 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.

[0193] In various embodiments, anti-HIV gp120 CD4bs binding antibodies or antigen binding fragments, and optionally combined bNAbs, can be delivered in vivo, for example, expressed in vivo by administered mRNA or engineered B cells. Examples of bNAbs delivered in vivo include AAV8-VRC07, mRNA encoding anti-HIV antibody VRC01, and engineered B cells encoding 3BNC117 (Hartweger et al., J. Exp. Med., 2019, 1301).

[0194] HIV combination drugs

[0195] 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. Exemplary anti-HIV combination drugs that can be co-administered include, but are not limited to (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); ( rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); (darunavir, 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 hemifumarate, emtricitabine, cobicistat and elvitegravir; tenofovir analogs; (zidovudine and lamivudine; AZT+3TC); ( abacavir sulfate and lamivudine; ABC+3TC); ( lopinavir and ritonavir); (dolutegravir, abacavir, and lamivudine); (Bicagavir + Emtricitabine + Tenofovir Alafenamide), (dolutegravir and lamivudine), (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and ritonavir (ATZ+RTV); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; (Darivir 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 Fumarate; Dolutegravir + Lamivudine, Lamivudine + Abacavir + Zidovudine, 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 fumarate, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, lopinavir + ritonavir + abacavir + lamivudine, and lamivudine; cabotegravir + rilpivirine; 3-BNC117 + abovirte, (esavirine; VM-1500), VM-1500A, lenacapasvir + islatravir (oral, injectable) and dual-targeted HIV-1 reverse transcriptase / nucleocapsid protein 7 inhibitors.

[0196] Other HIV medicines

[0197] Examples of other drugs used to treat HIV include, but are not limited to, aspernigin C, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, bevirimab, ABBV-382, obefazimod (ABX-464), AG-1105, APH-0812, APH0202, bryostatin-1, bryostatin-23, bryostatin analogs, SUW-133, BIT-225, BRII-732, BRII-778, Codivir, CY T-107, CS-TATI-1, fluoro-β-D-arabinonucleotide (FANA) modified antisense oligonucleotide, FX-101, Grefsen, 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, OD E-Bn-TFV, PA-1050040 (PA-040), PC-707, PGN-007, QF-036, S-648414, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, DIACC-1010, Fasnall, Immuglo, 2-CLIPS peptide, HRF-4467, thrombospondin analog, TBL-1004HI, VG-1177, xl-081, AV I-CO-004, rfhSP-D, [18F]-MC-225, URMC-099-C, RES-529, Verdinexor, IMC-M113V, IML-106, antiviral Fc conjugate (AVC), WP-1096, WP-1097, Gammora, ISR-CO48, ISR-48, ISR-49, MK-8527, cannabinoids, ENOB-HV-32, T-1144, VIR-576, nipamovir, Covimro, WP-1122, ZFP-362 and ABBV-1882.

[0198] HIV protease inhibitors

[0199] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with HIV protease inhibitors. 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, eluonavir (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 in, for example, U.S. Pat. No. 10,294,234 and U.S. Patent Application Publication Nos. US2020030327 and US2019210978.

[0200] HIV RNase H Inhibitors

[0201] In certain embodiments, the anti-HIV gpl20 V3 glycan and anti-HIV gpl20 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.

[0202] HIV Nef inhibitors

[0203] In certain embodiments, the anti-HIV gpl20 V3 glycan and anti-HIV gpl20 CD4bs binding antibodies described herein are combined with HIV Nef inhibitors. Examples of HIV Nef inhibitors that can be combined include, but are not limited to, FP-1.

[0204] HIV reverse transcriptase inhibitors

[0205] In certain embodiments, the anti-HIV gpl20 V3 glycan and anti-HIV gpl20 CD4bs binding antibodies described herein are combined with a non-nucleoside or non-nucleotide inhibitor. Examples of HIV non-nucleoside or non-nucleotide 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, esavirine (extended release oral), doravirine + esavirine (fixed dose combination / oral tablet formulation), esavirine (long-acting injectable nanosuspension), and esavirine (VM-1500).

[0206] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with HIV nucleoside or nucleotide inhibitors. Examples of nucleosides or nucleotides of HIV reverse transcriptase include, but are not limited to, adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir octadecyloxyethyl ester (AGX-1009), tenofovir fumarate (HS-10234), tenofovir disoproxil fumarate, and VIDEX (didanosine, ddl), abacavir, abacavir sulfate, alovudine, aritibactam, sinavudine, didanosine, efavirenz, fosfodine tibactam, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tibactam, lamivudine, phosphinothricin, stavudine, zalcitabine, zidovudine, etafovir (GS-9131), GS-9148, GS-1614, GSK-4023991, MK-8504, islavir, MK-8583, VM-2500 and KP-1461.

[0207] Additional examples of nucleoside or nucleotide inhibitors of HIV reverse transcriptase include, but are not limited to, those described in patent publications US2007049754, US2016250215, US2016237062, US2016251347, US2002119443, US2013065856, US2013090473, US2014221356, and WO04096286.

[0208] HIV integrase inhibitors

[0209] In certain embodiments, the anti-HIV gp120 V3 glycans and anti-HIV gp120 CD4bs binding antibodies described herein are combined with HIV integrase inhibitors. Examples of HIV integrase inhibitors include, but are not limited to, elvitegravir, elvitegravir (extended release microcapsules), curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrosine kinase inhibitors, derivatives of tyrosine kinase inhibitors, quercetin, derivatives of quercetin, raltegravir, pegylated raltegravir, dolutegravir, JTK-351, bicarbavi, AVX-15567, cabotegravir (long-acting injectable), diketoquinoline-4-1 derivatives, GS- 1720, GS-6212, GS-1219, GS-3242, VH4524184, integrase-LEDGF inhibitor, ledgins, 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.

[0210] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with HIV non-catalytic site or allosteric integrase inhibitors (NCINIs). Examples of HIV non-catalytic site or allosteric integrase inhibitors (NCINIs) include, but are not limited to, CX-05045, CX-05168, and CX-14442.

[0211] Capsid inhibitors

[0212] In certain embodiments, the anti-HIV gpl20 V3 glycan and anti-HIV gpl20 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 AVI-CAN1-15 series, PF-3450074, and compounds described in International Patent Publication No. WO 2019 / 087016 and U.S. Patent Publication Nos. US2014 / 0221356, US2016 / 0016973, US2018 / 0051005, and US2016 / 0108030.

[0213] HIV virus infectious factor inhibitor

[0214] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with HIV viral infectivity factor inhibitors. Examples of HIV viral infectivity factor inhibitors include 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide derivatives and Irino-L.

[0215] HIV entry inhibitors

[0216] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with HIV entry inhibitors. Examples of HIV entry (fusion) inhibitors include AAR-501, LBT-5001, Cenikvir, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, gp160 inhibitors, and CXCR4 inhibitors.

[0217] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with CCR5 inhibitors. Examples of CCR5 inhibitors include apuviro, vicoviro, maraviroc, maraviroc (long-acting injectable nanoemulsion), seneviro, lerolizumab (PRO-140), adatasvir (RAP-101), nifeviro (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, seraviro and vMIP (Haimipu).

[0218] In certain embodiments, the anti-HIV gpl20 V3 glycan and anti-HIV gpl20 CD4bs binding antibodies described herein are combined with a CXCR4 inhibitor.Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, barifolide, and vMIP (Haimipu).

[0219] 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 Abuvirtide, Enfuvirtide, Greifsom (gp41 / gp120 / gp160 inhibitor), BMS-986197, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, CPT-31, Cl3hmAb, Lepvirtide, PIE-12 trimer, and Sifuvirtide.

[0220] In certain embodiments, the anti-HIV gpl20 V3 glycan and anti-HIV gpl20 CD4bs binding antibodies described herein are combined with a CD4 attachment inhibitor. Examples of CD4 attachment inhibitors include ibalizumab and CADA analogs.

[0221] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with gp120 inhibitors. Examples of gp120 inhibitors include anti-HIV microbicides, Radha-108 (receptol) 3B3-PE38, BMS818251, BanLec, bentonite-based nanomedicines, fostemsavir tromethamine, IQP-0831, VVX-004, and BMS-663068.

[0222] 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 tetrandrine.

[0223] HIV maturation inhibitors

[0224] In certain embodiments, the anti-HIV gpl20 V3 glycan and anti-HIV gpl20 CD4bs binding antibodies described herein are combined with HIV maturation inhibitors. Examples of HIV maturation inhibitors include BMS-955176, GSK-3640254, VH-3739937 (GSK-3739937), HRF-10071, and GSK-2838232.

[0225] Latency reversal agents

[0226] In certain embodiments, the anti-HIV gpl20 V3 glycan and anti-HIV gpl20 CD4bs binding antibodies described herein are combined with an HIV latency reversal agent. Examples of latency reversal 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, such as visammod (GS-9620); TLR8 agonists, such as sergantomod (GS-9688); TLR9 agonists, such as lefitolimod (MGN-1703)), histone deacetylase (HDAC) inhibitors, proteasome inhibitors (such as Velcade), protein kinase C (PKC) activators, Smyd2 inhibitors, B ET-bromodomain 4 (BRD4) inhibitors (such as ZL-0580, apabetalone), ionomycin, IAP antagonists (inhibitors of apoptosis proteins, such as APG-1387, LBW-242), SMAC mimetics (including TL32711, LCL161, GDC-0917, HGS1029, xevinapant (AT-406)), Debio-1143, PMA, SAHA (suberylamine hydroxamic acid or suberoyl, aniline and hydroxamic acid), NIZ-985, IL-15 modulating antibodies (including IL-15, IL-15 fusion proteins and IL-15 receptor agonists, such as ALT-803), JQ1, disulfiram, amphotericin B and ubiquitin inhibitors (such as ragozola analogs, APH-0812, GSK-343). Examples of PKC activators include indole lactams, prostratin, ingenol B, and DAG-lactone.

[0227] Toll-like receptor (TLR) agonists

[0228] In certain embodiments, the anti-HIV gp120 V3 glycan 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).

[0229] Exemplary TLR7 agonists that can be co-administered or combined with one or more multispecific antigen-binding molecules described herein include, but are not limited to, AL-034, DSP-0509, GS-9620 (visamod), visamod 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 US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), US20090047249 (Gilead Sciences), US2010143301 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Ja nssen), WO2014 / 128189(Janssen), US20140350031(Janssen), WO2014 / 023813(Janssen), US20080234251(Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics) and US20130251673 (Novira Therapeutics).

[0230] TLR7 / TLR8 agonists that may be co-administered are NKTR-262, teramod, and BDB-001.

[0231] Exemplary TLR8 agonists that can be co-administered or combined with one or more multispecific antigen-binding molecules described herein include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motomod, resiquimod, selganomod (GS-9688), VTX-1463, VTX-763, 3M-051, 3M-052, and US2017071944 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Ja nssen), WO2014 / 128189(Janssen), US20140350031(Janssen), WO2014 / 023813(Janssen), US20080234251(Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics) and US20130251673 (Novira Therapeutics).

[0232] Example TLR9 agonists that can be co-administered include, but are not limited to, AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, litenimod, 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 retamod, polyICLC, Apoxxim, IPH-33, MCT-465, MCT-475 and ND-1.1. Examples of TLR4 agonists include G-100 and GSK-1795091.

[0233] Histone deacetylase (HDAC) inhibitors

[0234] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with a histone deacetylase, e.g., 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, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), resminostat, ricolinostat, romidepsin, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.

[0235] Cytochrome P450 3 inhibitors

[0236] In certain embodiments, the anti-HIV gpl20 V3 glycan and anti-HIV gpl20 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 US Pat. No. 7,939,553.

[0237] RNA polymerase modulators

[0238] In certain embodiments, the anti-HIV gpl20 V3 glycan and anti-HIV gpl20 CD4bs binding antibodies described herein are combined with RNA polymerase modulators.Examples of RNA polymerase modulators include, but are not limited to, those described in US Pat. Nos. 10,065,958 and 8,008,264.

[0239] Cyclin-dependent kinase (CDK) inhibitors or antagonists

[0240] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with inhibitors or antagonists of cyclin-dependent kinases (CDKs), such as cyclin-dependent kinase 4 (CDK4; NCBI gene ID: 1019), cyclin-dependent kinase 6 (CDK6; NCBI gene ID: 1021), cyclin-dependent kinase 9 (CDK9; NCBI gene ID: 1025). In some embodiments, the CDK4 / CDK6 / CDK9 inhibitor or antagonist is selected from VS2-370.

[0241] Stimulator of interferon genes (STING) agonists

[0242] In some embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with stimulator of interferon genes (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP) and cyclic diAMP.

[0243] RIG-I agonists

[0244] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with an agonist of DExD / H-box helicase 58 (DDX58; 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 (such as SB-9200, also known as GS 9992; inarigivir) and IR-103. An exemplary RIG-I agonist is KIN1148, described in Hemann et al., J Immunol, May 1, 2016, 196(1 Suppl) 76.1. Additional RIG-I agonists are described in, for example, 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).

[0245] LAG-3 and TIM-3 inhibitors

[0246] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with anti-TIM-3 (also known as hepatitis A virus cellular receptor 2 antibody (HAVCR2; NCBI gene ID: 84868), such as 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 activation) (NCBI gene ID: 3902) antibodies (such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385).

[0247] Immune-based therapies

[0248] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with immune-based therapies. Examples of immune-based therapies include toll-like receptor (TLR) modulators, such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13; programmed cell death protein 1 (PD-1) modulators; programmed death ligand 1 (PD-L1) modulators; IL-15 modulators (e.g., 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)); Der maVir; interleukin-7; plaquenil (hydroxychloroquine); prilocaine (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 (PEI); gepon; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, noferon, pegylated interferon alpha-2a, pegylated interferon alpha-2b, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103.

[0249] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with TLR agonists. Examples of TLR agonists include, but are not limited to, visammod (GS-9620), lefitimmod, tilsotolimod, retamod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motomod, GSK-1795091, GSK-2245035, VTX-1463, sergantomod (GS-9688), LHC-165, BDB-001, RG-7854, tirammod.

[0250] Immune checkpoint receptor protein modulators

[0251] 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 inhibitory immune checkpoint proteins or receptors and / or with one or more stimulators, activators or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blocking or inhibition of inhibitory immune checkpoints can positively regulate T cell or NK cell activation and prevent immune escape of infected cells. Activation or stimulation of stimulating immune checkpoints can enhance the effect of immune checkpoint inhibitors in infectious treatment. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., Xu et al., J Exp Clin Cancer Res. (2018) 37: 110). In various embodiments, immune checkpoint proteins or receptors regulate NK cell responses (e.g., reviewed in the following literature: Davis et al., Semin Immunol. (2017) 31: 64–75; and Chiossone et al., Nat Rev Immunol. (2018) 18 (11): 671-688).

[0252] Examples of immune checkpoint proteins or receptors that can be combined with the anti-HIV gp120 V3 glycan 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 immunomodulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); inducible T cell co-stimulator (ICOS, CD278); inducible T cell co-stimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137 ), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC Class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-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 (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain-containing protein 4 (TIMD4; TIM4);Hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activation 3 (LAG3, CD223); signal transducer lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD31 9); 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 cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1); and hematopoietic progenitor cell kinase 1 (HPK1, MAP4K1). ;

[0253] In various embodiments, the anti-HIV gpl20 V3 glycan and anti-HIV gpl20 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 T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated immune immunoglobulin domain (PVRIG, CD112R); T-cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cellular 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, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In various embodiments, the anti-HIV gpl20 V3 glycan and anti-HIV gpl20 CD4bs binding antibodies described herein are combined with one or more agonists or activators of one or more T cell stimulating 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 co-stimulator (ICOS, CD278); inducible T cell co-stimulator 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.

[0254] In various embodiments, the anti-HIV gpl20 V3 glycan and anti-HIV gpl20CD4bs 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 a long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and a 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); SLAM family member 7 (SLAMF7). See, for example, 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.

[0255] In some embodiments, one or more immune checkpoint inhibitors include protein (e.g., antibody or fragment thereof or antibody mimetic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, one or more immune checkpoint inhibitors include organic small molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4.

[0256] Examples of CTLA4 inhibitors that can be co-administered include, but are not limited to, 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, ATO R-1144, 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).

[0257] Examples of inhibitors of programmed cell death 1 (PDCD1; NCBI Gene ID: 5133; CD279, PD-1, PD1) that can be combined or co-administered include, but are not limited to, sepalizumab (AB122, GLS-010, WBP-3055), pembrolizumab ( MK-3475, SCH900475), nivolumab ( BMS-936558, MDX-1106), Cimiprilimab ( Cimiprizumab-rwlc, REGN-2810), pidilizumab (CT-011), AMG-404, MEDI0680 (AMP-514), spartalizumab (PDR001), tislelizumab (BGB-A317), toripalizumab (JS-001), genoluzumab (CBT-501, APL-501, GB 226), SHR-1201, carrelizumab (SHR-1210), sintilimab ( IBI-308), dotalimumab (TSR-042, WBP-285), lanrolizumab (MK-3475); saxanthlimab (PF-06801591), cilizumab (JNJ-63723283), slulizumab (HLX-10), rivolimab (MGA-012), bastimumab (AGEN2034), palollimumab (BCD100), bruglimumab (ABBV-181), woprelizumab (JTX-4014), AK-103 (HX-008), AK-105, CS-1003, BI-754091, LZM-009, Sym-021, BAT-1306, P D1-PIK, terpolizumab (MGD013; PD-1 / LAG-3), RO-7247669 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7121661 (PD-1 / TIM-3), RG7769 (PD-1 / TIM-3), PF-06 936308(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 antigen binding domain and / or the second antigen binding domain comprises the extracellular domain of human programmed cell death 1 ligand 2 (PD-L2) and binds to PD1 (eg, AMP-224).

[0258] Examples of inhibitors of CD274 molecules (NCBI gene ID: gene ID: 29126; B7-H, B7H1, PD-L1) that can be combined or co-administered include, but are not limited to, atezolizumab Avelumab ( MSB0010718C), Envolizumab (ASC22), Durvalumab ( MEDI-4736), BMS-936559 (MDX1105), coxilimab (CK-301), lodalimab (LY 3300054), galifoliumab (BGB A333), envolimab (KN035), oclimab (HLX 20), manellimab (BCD 135), CX-072, CBT-502 (TQB2450), MSB-2311, SHR-1316, sugemalimab (CS-1001; WBP3155), A167 (KL-A167, HBM 9167), STI-A1015 (IMC-001), FAZ-053, BMS-936559 (MDX1105), INCB086550, GEN-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), and also include human-derived allogeneic natural killer cells engineered to express a chimeric antigen receptor (CAR) targeting PD-L1, such as PD-L1 t-haNK.

[0259] In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of: GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 includes BPI-002.

[0260] In various embodiments, an antibody as described herein is combined with an anti-TIGIT antibody (such as dovanalimab, ralzapastotug, vembryomab, osperlimab, tisleliumab, rilvegostomig, berisutuzumab, etilizumab, BMS-986207, RG-6058, or AGEN-1307).

[0261] TNF receptor superfamily (TNFRSF) member agonists or activators

[0262] In various embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with an agonist of one or more TNF receptor superfamily (TNFRSF) members, such as an agonist of one or more of the following: 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: 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, NC BI 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: 23496), and TNFRSF14A (CD269, NCBI gene ID: 3761). :115650), 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).

[0263] Exemplary anti-TNFRSF4 (OX40) antibodies that may be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tavolizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0264] Exemplary anti-TNFRSF5 (CD40) antibodies that may be co-administered include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0265] In some embodiments, the anti-TNFRSF7 (CD27) antibody varilutumab (CDX-1127) is co-administered.

[0266] Exemplary anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include, but are not limited to, usurelumab, utolumab (PF-05082566), AGEN2373, and ADG-106.

[0267] Exemplary anti-TNFRSF18 (GITR) antibodies that can be co-administered include, but are not limited to, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, antibodies or fragments thereof that co-target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in WO 2017096179 and WO2018089628.

[0268] Interleukin receptor agonists

[0269] 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, such as IL-2, IL-7, IL-15, IL-10, IL-12 agonists; examples of IL-2 receptor agonists, such as proleukin (aldesleukin, IL-2); PEGylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707), bepeg aldesleukin, AIC-284, ALKS -4230, CUI-101, Neo-2 / 15; IL-15 receptor agonists such as ALT-803, NKTR-255 and hetIL-15, interleukin-15 / Fc fusion protein, 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.

[0270] 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; nomofuron, pegylated interferon alpha-2a, pegylated interferon alpha-2b, RPI-MN.

[0271] In certain embodiments, the anti-HIV gpl20 V3 glycan and anti-HIV gpl20 CD4bs binding antibodies described herein are combined with a Flt3 agonist, such as GS-3583 or CDX-301.

[0272] Bispecific and trispecific natural killer (NK) cell engagers

[0273] In various embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with a bispecific NK cell engager (BiKE) or a trispecific NK cell engager (TriKE) (e.g., without Fc) or a bispecific antibody (e.g., with Fc) against the following items: NK cell activation 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 receptor FcγR (which mediates 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). Exemplary anti-CD16 bispecific antibodies, BiKEs or TriKEs that can be co-administered include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). Depending on the circumstances, 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-associated antigens as described herein. BiKE and TriKE are described, for example, in the following literature: Felices et al., Methods Mol Biol. (2016) 1441: 333–346; Fang et al., Semin Immunol. (2017) 31: 37-54. Examples of trispecific NK cell engagers (TRiKE) include OXS-3550, HIV-TriKE, and CD16-IL-15-B7H3 TriKe.

[0274] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

[0275] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, icadolstat, F-001287, GBV-1012, GBV-1028, GDC-0919, indomod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, LY-3381916.

[0276] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0277] 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, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puroquitinib mesylate, regoratinib, regoratinib sodium, sonolisib, 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.

[0278] Alpha-4 / beta-7 antagonists

[0279] 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 integrin alpha-4 / beta-7 antagonists include PTG-100, TRK-170, alirocumab, edrolizumab, carotegrast methyl, and vedolizumab.

[0280] HPK1 / MAP4K1 inhibitors

[0281] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with mitogen-activated protein kinase kinase kinase 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.

[0282] Pharmacokinetic enhancers

[0283] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with a pharmacokinetic enhancer. Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

[0284] Additional therapeutic agents

[0285] Examples of additional therapeutic agents include compounds disclosed in WO 2004 / 096286 (Gilead Sciences); WO 2006 / 015261 (Gilead Sciences); WO 2006 / 110157 (Gilead Sciences); WO 2012 / 003497 (Gilead Sciences); WO 2012 / 003498 (Gilead Sciences); WO 2012 / 145728 (Gilead Sciences); WO 2013 / 006738 (Gilead Sciences); WO 2013 / 159064 (Gilead Sciences); WO 2014 / 100323 (Gilead Sciences); US 2013 / 0165489 (University of Pennsylvania); US 2014 / 0221378 (Japan); Tobacco), US2014 / 0221380 (Japan Tobacco); WO 2009 / 062285 (Boehringer Ingelheim); WO 2010 / 130034 (Boehringer Ingelheim); WO 2013 / 006792 (Pharma Resources), US20140221356 (Gilead Sciences), US20100143301 (GileadSciences) and WO 2013 / 091096 (Boehringer Ingelheim).

[0286] HIV combination therapy

[0287] In a specific embodiment, 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 therapeutic agents selected from (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); (Bicagavir + Emtricitabine + Tenofovir Alafenamide), ( rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); adefovir; adefovir disoproxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; (dulutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ( lopinavir and ritonavir); (zidovudine and lamivudine; AZT+3TC); ( abacavir sulfate and lamivudine; ABC+3TC); (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; platinum; 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 alcohol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphinothricin; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0288] It will be appreciated by those skilled in the art that the additional therapeutic agents listed above may be included in more than one of the categories listed above. The specific categories are not intended to limit the functionality of those compounds listed in those categories.

[0289] In a specific embodiment, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with nucleoside or nucleotide inhibitors of HIV reverse transcriptase and non-nucleoside inhibitors of HIV reverse transcriptase. In another specific embodiment, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with nucleoside or nucleotide inhibitors of HIV reverse transcriptase and HIV protease inhibitory compounds. In an additional embodiment, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with nucleoside or nucleotide inhibitors of HIV reverse transcriptase, non-nucleoside inhibitors of HIV reverse transcriptase, and pharmacokinetic enhancers. In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with at least one nucleoside inhibitor of HIV reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the anti-HIV gpl20 V3 glycan and anti-HIV gpl20 CD4bs binding antibodies described herein are combined with two nucleoside or nucleotide inhibitors of HIV reverse transcriptase.

[0290] In a specific embodiment, 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.

[0291] In specific 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.

[0292] 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 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.

[0293] 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 and a second additional therapeutic agent, the first additional therapeutic agent being selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, wherein the second additional therapeutic agent is emtricitabine.

[0294] 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, and the therapeutically effective dose of the additional therapeutic agent ranges from, for example, 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. 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, wherein the therapeutically effective dose of the additional therapeutic agent ranges from, for example, 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. 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, wherein the therapeutically effective dose of the additional therapeutic agent ranges from, for example, 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.

[0295] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with 5mg-30mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200mg of emtricitabine. In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with 5mg-10mg, 5mg-15mg, 5mg-20mg, 5mg-25mg, 25mg-30mg, 20mg-30mg, 15mg-30mg, or 10mg-30mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200mg of emtricitabine. In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine.

[0296] In certain embodiments, the anti-HIV gp120 V3 glycans and anti-HIV gp120 CD4bs binding antibodies described herein are combined with 200mg-400mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200mg of emtricitabine. In certain embodiments, the anti-HIV gp120 V3 glycans and anti-HIV gp120 CD4bs binding antibodies described herein are combined with 200mg-250mg, 200mg-300mg, 200mg-350mg, 250mg-350mg, 250mg-400mg, 350mg-400mg, 300mg-400mg, or 250mg-400mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200mg of emtricitabine. In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil fumarate and 200 mg of emtricitabine. The anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies can be combined with the agents provided herein at any dose (e.g., 1 mg to 500 mg of anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies), as if each combination of doses is specifically and individually listed.

[0297] Long-acting HIV inhibitors

[0298] 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., once every 6 months (Q6M), once every 24 weeks (Q24W), once every 25 weeks (Q25W), once 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 lenacapvir; long-acting integrase inhibitors, such as long-acting bicaltegravir (GS-9883), GS-6212, long-acting (LA) cabotegravir, long-acting raltegravir (RAL); long-acting NRTIs, such as EFdA / MK-8591 (4-ethynyl-2-fluoro-2-deoxyadenosine; isclatravir) implant, tenofovir alafenamide fumarate (TAF) implant, injectable etanercept (GS-9131); long-acting NNRTiS, such as GS-5894, long-acting dapivirine (DPV), long-acting rilpivirine (RPV), essavirine; and VM-1500LAI, maraviroc (LAI) and long-acting dolutegravir (RPV). Long-acting anti-HIV drugs are reviewed in Singh et al., Pharmaceuticals (2019) 12:62.

[0299] HIV vaccine

[0300] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with HIV vaccines. Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, HIV MAG DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, adenovirus vector vaccines (e.g., Ad5, Ad26, or Ad35), monkey adenovirus (chimpanzee, gorilla, rhesus monkey, i.e., rhAd), adeno-associated virus vector vaccines, chimpanzee adenovirus vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), coxsackievirus-based vaccines, enterovirus-based vaccines, gorilla adenovirus vaccines, lentiviral vector-based vaccines, vaccines based on bi-segmented or tripartite arenaviruses (e.g., LCMV, Pichinde), trimer-based HIV-1 vaccines, Measles virus vaccines, flavivirus vector-based vaccines, tobacco mosaic virus vector-based vaccines, varicella-zoster virus-based vaccines, human parainfluenza virus 3 (PIV3)-based vaccines, poxvirus-based vaccines (modified vaccinia virus Ankara (MVA), orthopoxvirus-derived NYVAC, and fowlpox virus-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, alpha-virus-based vaccines such as Semliki Forest virus, Venezuelan equine encephalitis virus, and Sindbis virus (see, e.g., 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.

[0301] Examples of HIV vaccines include, but are not limited to, AAVLP-HIV vaccines described in WO2021011544 and WO2022155258, AdC6-HIVgp140, AE-298p, anti-CD40.Env-gp140 vaccine, Ad4-EnvC150, BG505SOSIP.664gp140 adjuvant vaccine, BG505 SOSIP.GT1.1gp140 adjuvant vaccine, ChAdOx1.tHIVconsv1 vaccine, CMV-MVA triple vaccine, ChAdOx1.HTI, Chimigen HIV vaccine, ConM SOSIP.v7 gp140, rgp120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomeric gp120 HIV-1C subtype vaccine, MPER-656 liposome subunit vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multi-stage 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 / VSSPISA-51, poly-ICLC adjuvant vaccine, TatImmune, GTU-multiHIV (FIT-06), ChAdV63.HIVconsv, gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-EnvF, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, based on N123-VRC-34.01 HIV vaccines with induced antigens, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, GOVX-C55, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, ENOB-HV-11, ENOB-HV-12, exoVACC, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, MagaVax, DNA-Ad5 gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, DNA expressing SCaVII and Sev vector vaccine, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV+MVA mosaic vaccine+gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, VIR-1111, IHV-001 and virus-like particle vaccines (such as pseudovirion vaccines), CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccines, conjugated peptide vaccines, dendritic cell vaccines (such as DermaVir), gag-based DNA vaccines, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), i-key / MHC class II antigen hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-stage Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x+romidepsin, variant gp120 peptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI and MVA.HTI, MVA.tHIVconsv3, MVA.tHIVconsv4, VRC-HIVDNA016-00-VP+VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60mer-based 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 EnvsHIV-1 vaccine (GLA-SE adjuvant), HIV p24gag primary-enhanced plasmid DNA vaccine, HIV-1iglb12 neutralizing VRC-01 antibody-stimulated anti-CD4 vaccine, arenavirus vector-based vaccine (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimen, mRNA-based vaccines, VPI-211, HIV ANTI-CD40.ENV GP140, HIV ANTI-CD40.HIV5PEP, multimeric HIV gp120 vaccine TBL-1203HI, CH505 TF chTrimer, CD40.HIVRI.Env vaccine, VRC-HIVRGP096-00-VP, Drep-HIV-PT-1, BG505 MD39.3 mRNA, BG505MD39.3 gp151 CD4KO mRNA, BG505MD39.3 gp151 mRNA, mRNA-1644, mRNA-1547, mRNA-1574, and anti-HIV vaccines. .

[0302] Birth control pill combination therapy

[0303] 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 for birth control (contraceptives) include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, norethindrone, etonogestrel, levonorgestrel, levonorgestrel, linegestrel, medroxyprogesterone acetate, ethinyl estradiol methyl ether, mifepristone, misoprostol, nomegestrol acetate, norgestrel, norgestrel, ormeloxifene, segestersone acetate, ulipristal acetate, and any combination thereof.

[0304] Gene therapy and cell therapy

[0305] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with gene or cell therapy regimens. Gene therapy and cell therapy include, but are not limited to, gene modifications that silence genes; gene methods that directly kill infected cells; infusion of immune cells designed to replace most of the patient's own immune system to enhance the immune response to infected cells, or activate the patient's own immune system to kill infected cells, or find and kill infected cells; genetic methods that modify cell activity to further change the endogenous immune response to infection. Examples of cell therapies include LB-1903, ENOB-HV-01, ENOB-HV-21, ENOB-HV-31, GOVX-B01, HSPCs (LV-800, HIV infection) overexpressing ALDH1, AGT103-T, and SupT1 cell-based therapies. Examples of dendritic cell therapies include AGS-004. CCR5 gene editors include, but are not limited to, SB-728T and SB-728-HSPC. CCR5 gene inhibitors include Cal-1 and autologous CD34-positive hematopoietic progenitor cells (HIV infection / HIV-related lymphoma) transduced with lentiviral vector CCR5 shRNA / TRIM5α / TAR decoy. In some embodiments, CD4-positive T cells expressing C34-CCR5 / C34-CXCR4 are co-administered with one or more multispecific antigen binding molecules. In some embodiments, the anti-HIVgp120 V3 glycans and anti-HIV gp120 CD4bs binding antibodies described herein are co-administered with autologous T cell therapy transduced with AGT-103 or AAV-eCD4-Ig gene therapy.

[0306] Gene editing

[0307] In certain embodiments, the anti-HIV gp120 V3 polysaccharide and anti-HIV gp120CD4bs binding antibodies described herein are combined with gene editing (e.g., HIV targeted gene editing). In various embodiments, the genome editing system can be selected from the group consisting of: CRISPR / Cas9 complex, zinc finger nuclease complex, TALEN complex, homing endonuclease complex, and meganuclease complex. Exemplary HIV targeting CRISPR / Cas9 systems include but are not limited to EBT-101 and XVIR-TAT.

[0308] CAR-T cell therapy

[0309] In some embodiments, the anti-HIV gp120 V3 polysaccharide and anti-HIV gp120CD4bs binding antibodies described herein can be co-administered with an immune effector cell population engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen binding domain. HIV antigens include HIV envelope proteins or portions thereof, gp120 or portions thereof, CD4 binding sites on gp120, CD4-induced binding sites on gp120, N polysaccharides on gp120, V2 of gp120, and membrane proximal regions on gp41. Immune effector cells are T cells or NK cells. In some embodiments, T cells are CD4+T cells, CD8+T cells, or combinations thereof. 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-120CAR-T therapy, and autologous hematopoietic stem cells genetically engineered to express CD4 CAR and C46 peptide.

[0310] TCR-T cell therapy

[0311] In certain embodiments, the anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibodies described herein are combined with a population of TCR-T cells. The TCR-T cells are engineered to target HIV-derived peptides present on the surface of virus-infected cells, such as IMC-M113V, a TCR bispecific having a TCR binding domain targeting a peptide derived from Gag protein presented by HLA*A02 on the surface of HIV-infected cells and a second antigen binding domain targeting CD3.

[0312] 6. Test kit

[0313] Also provided is 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 amino acid substitutions that extend serum half-life, and the first antibody and the second antibody are formulated for administration twice a year (e.g., once every 6 months (Q6M), once every 26 weeks (Q26W), once every 25 weeks (Q25W), or once every 24 weeks (Q24W)).

[0314] In certain embodiments, the kit comprises an anti-HIV gp120 V3 glycan binding antibody and an anti-HIV gp120 CD4bs binding antibody as described herein, combined in a single dosage form, separately or as a mixture for simultaneous administration to a patient, e.g., as a liquid or suspension dosage form for intravenous, intramuscular or subcutaneous administration.

[0315] 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 are independently in the range of about 500 mg to about 3000 mg (e.g., about 550 mg to about 2900 mg, for example, about 600 mg to about 2800 mg, for example, about 650 mg to about 2700 mg, for example, about 700 mg to about 2600 mg, for example, about 850 mg to about 2550 mg). In some embodiments, the unit dose of the anti-HIV gp120 V3 glycan binding antibody (e.g., 10-1074-LS) is 850 mg. In some embodiments, the unit dose of the anti-HIV gp120 V3 glycan binding antibody (e.g., 10-1074-LS) is 2550 mg. In some embodiments, the unit dose of the anti-HIV gp120 CD4bs binding antibody (e.g., 3BNC117-LS) is 2550 mg. In some embodiments, the unit dose of anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibody (e.g., 3BNC117-LS) is 1700 mg. In some embodiments, the unit dose of anti-HIV gp120 V3 glycan and anti-HIV gp120 CD4bs binding antibody (e.g., 3BNC117-LS) is 2550 mg. In some embodiments, the unit dose of anti-HIV gp120 V3 glycan binding antibody (e.g., 10-1074-LS) is 850 mg and the unit dose of anti-HIV gp120 CD4bs binding antibody (e.g., 3BNC117-LS) is 2550 mg. In some embodiments, the unit dose of anti-HIV gp120 V3 glycan binding antibody (e.g., 10-1074-LS) is 850 mg and the unit dose of anti-HIV gp120 CD4bs binding antibody (e.g., 3BNC117-LS) is 1700 mg. In some embodiments, the unit dose of anti-HIV gp120 V3 glycan binding antibody (e.g., 10-1074-LS) is 850 mg and the unit dose of anti-HIV gp120 CD4bs binding antibody (e.g., 3BNC117-LS) is 1275 mg.

[0316] In some embodiments, the kit also includes one or more unit doses of long-acting anti-HIV drugs. In some embodiments, one or more long-acting HIV drugs are selected from long-acting capsid inhibitors, long-acting integrase chain transfer inhibitors (INSTI), long-acting non-nucleoside reverse transcriptase inhibitors (NNRTI), long-acting nucleoside reverse transcriptase inhibitors (NRTI) and long-acting protease inhibitors (PI). In some embodiments, long-acting capsid inhibitors include lenacapasvir. In some embodiments, the unit dose of lenacapasvir is in the range of 300mg to 1000mg, for example, 300mg, 600mg, 900mg, 927mg. Where appropriate, a unit dose of lenacapasvir can be formulated for oral, subcutaneous or intravenous administration. In some embodiments, long-acting INSTI is selected from bicarbavi, raltegravir, elvitegravir, dolutegravir and cabotegravir. In some embodiments, long-acting NNRTI is selected from rilpivirine, essavirine, 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, etafovir, 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.

[0317] In one embodiment, the kit includes one or more pharmaceutical packages or one or more containers (e.g., vials, ampoules, preloaded syringes) containing one or more ingredients 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 cases, the kit contains the pharmaceutical compositions described herein. In one embodiment, a kit is provided, which includes the anti-HIV gp120 V3 glycan binding antibodies and anti-HIV gp120 CD4bs binding antibodies described herein, or pharmaceutical compositions thereof, and one or more (e.g., one, two, three, four, one or two, or one to three or one to four) additional therapeutic agents (such as those disclosed above).

[0318] Optionally associated with such container(s) may be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[0319] Example

[0320] The following examples are provided to illustrate but not to limit the claimed invention.

[0321] Example 1

[0322] Ph1b study: 26-week primary results of a long-acting broadly neutralizing antibody in combination with lenacapavir

[0323] GS-US-536-5816 (NCT04811040 on ClinicalTrials.gov) is a randomized, blinded, proof-of-concept (POC) Phase 1b study to evaluate the safety and efficacy of a single dose of each of the long-acting regimens of lenavapavir, telopavir (GS 5423; 3BNC117-LS; TAB), and zirivimab (GS2872; 10-1074-LS; ZAB) in HIV-1-infected adults who are virologically suppressed (HIV-1 RNA <50 copies / mL) on oral ART.

[0324] Drug administration

[0325] Participants were adults with HIV viral suppression for ≥2 years (HIV-1 RNA <50 copies / mL) on ART with concomitant antiretroviral therapy, sensitive to two bNAbs by HIV proviral DNA phenotype (PhenoSense mAb IC90 ≤2ug / mL, Monogram Biosciences), CD4 nadir ≥350 and CD4 count ≥500 at study entry. Participants who provided written consent and met all eligibility criteria were randomized to 1 of 2 treatment groups in a 1:1 ratio based on the dose of GS2872 (10 mg / kg or 30 mg / kg administered IV). All participants received GS-5423 (30 mg / kg IV) and oral lenacapsvir 600 mg on days 1 and 2, and lenacapsvir 927 mg subcutaneously on day 1. Participants were clinically monitored with plasma HIV-1 RNA every four weeks until the primary endpoint of week 26. The primary endpoint was safety; secondary endpoints included virological outcomes by FDA snapshot analysis.

[0326] In the first-in-human study of 3BNC117-LS (NCT03254277), 39 participants received a single dose of 3BNC117-LS ranging from 3 mg / kg to 30 mg / kg (IV) or 150 mg or 300 mg (SC); 5 participants received placebo. Five of the 43 enrolled participants reported 5 solicited adverse events (AEs) within 4 weeks of dosing, all of grade 1 severity: application site tenderness (2%), headache (2%), discomfort / fatigue (2%), and nausea (4%). In addition, 28 of the 43 enrolled participants reported 48 unsolicited adverse events, and 29 of the reported events (58%) occurred within 4 weeks of administration of the investigational product (IP). Of the reported events, 9 were of Grade 2 severity (17%), and 2 were of Grade 3 severity (4%): proteinuria and cellulitis requiring hospitalization for IV antibiotics), and 1 was of Grade 4 severity (hypokalemia). One participant was hospitalized for a transient ischemic attack secondary to a right carotid artery thrombosis. Further evaluation revealed abnormal vascular anatomy that may have contributed to the thrombotic event. This severe AE was considered unrelated to the IP. The most commonly reported AEs were those related to upper respiratory tract infection (14%), nausea (4%), and dizziness (4%).

[0327] In the first human study of 10-1074-LS (NCT03554408), 77 participants were recruited: 27 participants received a single dose of 10-1074-LS, ranging from 3 mg / kg to 30 mg / kg (IV, n=15) or 140 mg or 280 mg (SC, n=12); 12 additional participants received a single SC injection of a combination of 10-1074-LS and 3BNC117-LS, and 18 participants received 3 repeated SC injections of the antibody admixture (every 12 weeks); 10 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, 15 of 77 enrolled participants reported 20 solicited AEs, all of which were Grade 1 severity: erythema / skin discoloration at the application site (8%), pain (4%) and induration (2%), headache (4%), fever (4%), malaise / fatigue (3%), and myalgia (1%). In addition, 46 participants reported 86 unsolicited AEs. Of these, 29 of the 86 AEs (33.7%) occurred within 4 weeks of IP administration. Of the reported unsolicited AEs, 10 were Grade 2 severity (11.6%), and 8 reported events were Grade 3 severity (9.3%): kidney stones (1%), increased blood pressure (4%), decreased hemoglobin (1%), proteinuria (1%), and increased left-sided weakness (1%). The three participants who experienced a transient Grade 3 increase in blood pressure on the day of IP administration had a history of hypertension. The most common AEs were those related to upper respiratory tract infection (25%), local musculoskeletal pain (8%), and gastroenteritis symptoms (8%).

[0328] NCT04811040 Ph1b Study Overview

[0329] Participants interrupted their background oral ART regimen 1 day before receiving study drug 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% were Asian, and 33% were Hispanic or Latino; the median CD4 count was 909 (IQR 687, 1270).

[0330] At Week 26, all participants resumed their background oral ART baseline regimen (or a compatible regimen selected by the investigator) and returned to the clinic for visits at Weeks 38 and 52.

[0331] Approximately 20 participants are in the main cohort. Adults with HIV-1, no history of virological failure (VF) or antiretroviral drug resistance, CD4 nadir ≥ 350 cells / μL, on first-line ART for at least 2 years, showing virological suppression (HIV-1 RNA < 50 copies / mL) for at least 18 months before screening, who are willing to modify their ART regimen for the study strategy. A schematic diagram of the study is provided in Figure 1.

[0332] Twenty-one participants were recruited to the main cohort and randomized, 20 participants received the full study regimen (10 in each treatment group), and one participant received oral lenacapvir and withdrew consent before completing the dosing schedule. The median age of the participants was 44 years (range 25-61), 18 (86%) were male at birth, and all had HIV-1 RNA <50 copies / mL and CD4 counts >500 cells / μL. The demographic and baseline characteristics of the recruited participants are summarized in Table 1.

[0333] Therapeutic concentrations of telopavir (TAB), zimbab (ZAB), and lenacapavir (LEN) were maintained until week 26. Figure 1B Depicted in.

[0334]

[0335] 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 524 copies / mL) and was resuppressed by restarting baseline ART; one participant in Group 2 withdrew consent at Week 12 (with HIV-1 RNA < 50 copies / mL). 18 / 20 (90%) participants had HIV-1 RNA < 50 copies / mL at Week 26. The primary efficacy results are presented in Tables 2 and Figure 1C Summarized in.

[0336] Table 2 - By US Efficacy determined by the FDA-defined snapshot algorithm at Week 26

[0337]

[0338] ^Resistance testing pending

[0339] *Withdrawn from study after week 12

[0340] $Causes other than AE / death or inefficacy

[0341] There were no treatment-emergent serious adverse events, no treatment-emergent adverse events leading to study drug or study discontinuation, and no deaths. The most common treatment-emergent adverse events were injection site reactions related to subcutaneous nacapasvir (LEN) administration (17 / 20 patients or 85%). Two participants had grade 3 AEs: one subject developed injection site cellulitis and one subject developed injection site erythema at the site of LEN injection. The combination of LEN + GS-5423 (telopavir) + GS-2872 (zinlivimab) was well tolerated in selected people with virological suppression of HIV, with high efficacy for 6 months. These results are consistent with the conclusion that the combination of LEN + GS-5423 (telopavir) + GS-2872 (zinlivimab) provides long-acting treatment for HIV with twice-yearly dosing.

[0342] Example 2

[0343] Modeling to determine flat dosing that allows twice-yearly administration

[0344] In this example, we performed population PK (popPK) modeling and simulations to predict the PK profiles of GS-5423 (telopavir) and GS-2872 (zinrivimab) under weight-based dosing and flat dosing at different doses and compared them with target efficacy levels to determine the optimal dose range of GS-5423 and GS-2872 for every 6-month dosing in adults with HIV.

[0345] method

[0346] PK data for GS-5423 (telopavir; 3BNC117-LS; TAB) and GS-2872 (zinrivimab; 10-1074-LS; ZAB) were obtained from four clinical studies in viremic or virally suppressed PWH (TAB: n=34; ZAB: n=36) who received a single intravenous dose of TAB (30 mg / kg) and / or ZAB (10 mg / kg or 30 mg / kg) alone or in combination with or without LEN, including YCO-0946 (NCT03254277) and YCO-0971 (NCT03554408). TAB and ZAB serum concentrations were measured using the validated Mesa Scale Discovery-electrochemiluminescent immunoassay. A two-compartment population pharmacokinetic model was developed to describe the PK data of GS-5423 and GS-2872 after IV and SC administration in HIV- and HIV+ participants. See Joel S. Owen, Jill Fiedler-Kelly, "Introduction to Population Pharmacokinetic / Pharmacodynamic Analysis with Nonlinear Mixed Effects Models", Wiley; 1st edition, 2014 (ISBN: 9780470582299). PopPK models for TAB and ZAB were developed using nonlinear mixed effects modeling. Covariate analysis was performed on the PK parameters of GS-5423 and GS-2872 to determine significant covariates, including body weight, demographic effects, baseline characteristics, combination regimens, and disease status. A population PK model was simulated to predict the PK curves of GS-5423 and GS-2872 after IV administration of 30 mg / kg or 10 mg / kg body weight normalized dosing or equivalent flat doses every 6 months. Model simulations were performed to predict the concentrations of TAB and ZAB following flat and weight-based dosing. The distribution of body weight was assumed to be consistent with previous studies in HIV virologically suppressed adults on antiretroviral therapy (mean weight of 85 kg).

[0347] result

[0348] Simulations based on PK modeling of data from four clinical studies (including YCO-0946 and YCO-0971) showed that fixed doses of 2550 mg or 850 mg of GS-5423 or GS-2872 were expected to produce similar exposures to 30 mg / kg or 10 mg / kg body weight-based doses, respectively, without a meaningful increase in PK variability (Figures 3A to 3D). Therefore, given that GS-5423 and GS-2872 were well tolerated alone or in combination up to 30 mg / kg in the ongoing study 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 HIV-infected adults.

[0349] GS-5423 (TAB) and GS-2872 (ZAB) PK data in PWH are fully described by a two-compartment PopPK model. Increased body weight is associated with increased distribution volume and clearance of both TAB and ZAB. Compared with those PWH suppressed at baseline, PWH with viremia have a significant increase in the clearance of TAB and ZAB. Model simulations show that based on the weight distribution (mean weight is about 85kg) in the most recent 3 phase HIV studies of adult PWH, for both TAB and ZAB, a flat dose of 2550mg will result in exposure similar to 30mg / kg.

[0350] Previous studies of non-LS forms of each antibody in HIV+ participants who underwent analytical treatment interruption (Mendoza et al., Nature. (2018) 561(7724): 479-484 and Gaebler et al., Nature (2022) 606(7913): 368-374) showed that virological suppression was generally maintained when serum concentrations of both antibodies were above 10 μg / mL. Based on PK simulations, 1700 mg GS-5423 or 850 mg GS-2872 is expected to maintain concentrations above 10 μg / mL in 99%-100% of subjects until 6 months (26 weeks) after administration (Figures 4A to 4B, Table 3). Therefore, it is expected that the dose range of 1700 mg to 2550 mg GS-5423 and 850 mg to 2550 mg GS-2872 given IV every 6 months is an effective and safe dose range for both bNAbs.

[0351] Table 3

[0352] Predicted percentage of patients above 10 μg / mL at week 26 following IV administration of GS-5423 and GS-2872 every 6 months

[0353]

[0354] Example 3

[0355] Evaluation of the anti-HIV antibodies 3BNC117 / telopavir and 10-1074 / zinrivimab by PK-PD modeling Therapeutic concentrations and predicting duration of clearance in HIV cure studies

[0356] 3BNC117 and 10-1074 have been shown to induce a rapid decline in viremia in people with HIV, as well as delay the time to viral rebound in suppressed people with HIV during analysis of 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 potential of 3BNC117 / TAB and 10-1074 / ZAB in combination with immunomodulators to eliminate HIV reservoirs and induce long-term remission in HIV patients is being studied. However, due to their potent viral neutralization, insufficient duration of clearance before ATI may confound efficacy assessment of time to virological rebound in HIV cure studies. The aims of this study were to characterize the pharmacokinetic (PK) and PK-PD relationships of these bNAbs by pharmacokinetic-pharmacodynamic (PK-PD) viral dynamics modeling and to predict the required clearance length of TAB / ZAB in HIV cure studies in order to assess post-treatment viral control during ATI.

[0357] method

[0358] Population PK and PK-PD models were developed using a nonlinear mixed-effects modeling approach based on serum bNAb concentrations and / or viral dynamics data from 6 efficacy studies in people with HIV and 3 PK studies of 3BNC117 / TAB (GS-5423) and / or 10-1074 / ZAB (GS-2872) (Table 4).

[0359]

[0360] 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 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), where PK was measured using two methods. The PK data of bNAbs were modeled by a 2-compartment linear PK model. Covariates (demographics, disease state, combination therapy) were tested using stepwise forward addition (α = 0.01) and reverse elimination (α = 0.001) methods. The PK-PD model describes viral replication using a logistic growth function and viral elimination using first-order kinetics, and a nonlinear saturable (Emax) model is used to describe the relationship between bNAb concentration and viral elimination rate. Different viral populations sensitive or resistant to each bNAb are modeled to capture resistance selection mechanisms among 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 PK and viral rebound kinetics during ATI after washout periods of varying lengths following TAB / ZAB administration. NLME was used for modeling. R software was used for simulation and graphics.

[0361] result

[0362] PK Modeling. The PK data of 3BNC117, 10-1074, TAB, and ZAB were adequately described by a linear 2-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, were similar between HIV-free and suppressed individuals with HIV (62 and 79 days for TAB and ZAB, respectively), and were shorter in viremic individuals with HIV (46 and 55 days for TAB and ZAB, respectively) ( Figure 7 ).

[0363] PK-PD modeling. The PK-PD model fully describes the clinical responses of bNAb treatment with 3BNC117, 10-1074 alone at different doses and in combination, as well as with TAB and ZAB ( Figure 8 The model describes the timing of viral rebound during ATI after bNAb treatment with 3BNC117 alone or in combination with 10-1074 ( Fig. 9 ). Corresponding to 50% maximum efficacy (EC 50 The estimated mean serum concentrations of 5-6-nitropropene (P<0.05) were 25.4 μg / mL and 32.2 μg / mL, which corresponded to EC values ​​of 6.35 μg / mL and 8.06 μg / mL, respectively. 20 (Table 5).

[0364] Table 5 - Estimation of key PK-PD model parameters

[0365] parameter average value 95% CI %CV <![CDATA[EC 50,3BNC117或TAB ,μg / mL a ]]> 25.4 (19.6-32.9) 162 <![CDATA[EC 50,10-1074或ZAB ,μg / mL b ]]> 32.2 (10.1-102.8 79.5 <![CDATA[Virus replication rate constant, kg, day -1 > 0.441 (0.414-0.468) 24.5 <![CDATA[Virus elimination rate constant, k del,3BNC117或TAB , days -1 > 0.507 (0.476-0.538) - <![CDATA[Virus elimination rate constant, k del,10-1074或ZAB , days -1 > 0.799 (0.609-0.990) -

[0366] CI, confidence interval; CV, coefficient of variation EC 20 , the concentration that results in 20% of the maximal drug effect; EC 50 , concentration resulting in 50% maximal drug effect; PD, pharmacodynamics; PK, pharmacokinetic; TAB, telopavir; ZAB, zinurin. a Corresponds to a mean (95% CI) EC of 6.35 (4.90-8.22) μg / mL 20 value. b This corresponds to a mean (95% CI) EC20 value of 8.06 (2.53-25.7) μg / mL.

[0367] PK-PD stimulation. PK-PD simulations predicted that after a washout period of ≥48 weeks following single-dose intravenous administration of TAB and ZAB, viral neutralization by these bNAbs would have minimal impact on the time to viral rebound during ATI ( Fig.10 After single intravenous administration of 30 mg / kg TAB and 10 mg / kg ZAB, bNAb concentrations are predicted to fall below their in vivo EC50s at approximately similar times and to remain at similar levels relative to their EC50s thereafter, thus minimizing the risk of resistance arising from functional monotherapy with either bNAb. At week 48, bNAb concentrations were predicted to be below the EC50 in more than 90% of participants ( Fig.11 ).

[0368] Example 4

[0369] Telopavir (GS-5423) and ginsevimab (GS-2872) with the capsid inhibitor lenacapvir (LEN) Phase 2 Study of the Combination in Virologically Suppressed Adults with HIV-1 Infection

[0370] Study Design : GS-US-539-5939 (NCT05729568 on ClinicalTrials.gov) is a Phase 2, randomized, open-label, active-controlled, multicenter study to evaluate the safety and efficacy of a long-acting combination regimen of the capsid inhibitors lenacapvir (LEN), telopavir (GS-5423), and ginseloimumab (GS-2872). The study will include approximately 125 participants who are sensitive to both bNAbs according to protocol-defined criteria, who meet all eligibility criteria, and who will be randomized without stratification into treatment groups 1, 2, and 3 in a 2:2:1 ratio. A schematic diagram of the clinical trial study is available at Fig.12 Depicted in.

[0371] Participants will receive their last dose of baseline oral antiretroviral therapy (ART) on Day 1, and participants randomized to treatment groups 1 and 2 will interrupt their baseline ART regimen after the full study regimen (subcutaneous injection of LEN, oral LEN 600 mg, and intravenous (IV) infusion of GS-5423 and GS-2872) is administered on Day 1, and will self-administer oral LEN 600 mg on Day 2. Participants in treatment group 3 will continue their prescribed baseline oral ARV regimen until Week 52. Participants randomized to treatment groups 1 and 2 will receive trial medication (injectable LEN and IV infusion of GS-5423 and GS-2872) at Week 26. All participants in all treatment groups will return to the study center for follow-up at Weeks 4, 12, 24, 26, 38, 50, and 52.

[0372] At Week 52, participants in Treatment Groups 1 and 2 (with plasma levels of HIV RNA less than (<) 50 copies / mL) who receive the study regimen of LEN, GS 5423, GS-2872 and complete study follow-up until Week 52 will be enrolled in the study extension phase. Participants who choose not to participate or are not eligible for the extension phase will resume their baseline ART regimen (or an appropriate regimen selected by the investigator) and return for study follow-up 30, 90, and 180 days after Week 52. Participants randomized to Treatment Group 3 will receive the study regimen of LEN, GS-5423, and GS-2872 every 26 weeks, and this treatment group completes study follow-up until Week 52 throughout the randomized phase of the study with HIV-1 RNA plasma levels <50 copies / mL. Doses of GS-5423 and GS-2872 will be determined at the time of the primary analysis. Participants in treatment group 3 who reach week 52 prior to the primary analysis will receive the study regimen at the dose assigned to treatment group 2 until after completion of the primary analysis and dose selection (unless treatment group 2 is modified in response to the data monitoring committee (DMC)). Participants in treatment group 3 who do not receive the study regimen after week 52 will return for a 30-day follow-up visit.

[0373] An independent DMC will be convened to review safety and efficacy data at two planned interim analyses: after approximately the first 50% of enrolled participants complete the Week 12 and Week 26 visits or prematurely discontinue 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 interim DMC meeting may be convened to review the data.

[0374] Virological failure (VF) Participants who experience virological rebound (VR) as defined below will be considered to be in the setting of virological failure and may undergo resistance analysis.

[0375] Virological rebound : Participants who met the following criteria were considered to have VR:

[0376] Rebound of HIV-1 RNA ≥ 50 copies / mL at any visit after Day 1, which is subsequently confirmed at a subsequent scheduled or unscheduled visit, or

[0377] Any participant with HIV-1 RNA ≥ 50 copies / mL at the time of study drug discontinuation

[0378] If, prior to all participants reaching Week 26, the above-specified or interim DMC efficacy analysis (based on virologic failure (VF) defined as plasma levels of HIV-1 RNA greater than or equal to (≥) 50 copies / mL at Weeks 12 and 26 or virologic rebound crossing the futility boundary (i.e., lower limit of the 95% confidence interval (CI) for the treatment difference (treatment group 1 or treatment group 2 - stay baseline regimen (SBR)) for VF>0) is completed, the DMC may recommend discontinuing the lower dose group. The decision to discontinue a dose group will be made by the sponsor.

[0379] Target Group Adults with HIV-1 who were on ART, had demonstrated viral suppression (plasma levels of HIV-1 RNA <50 copies / mL) for at least 12 months prior to screening, and met protocol criteria for sensitivity to a bNAb.

[0380] Duration of intervention : Up to 52 weeks during the randomized phase and up to 104 weeks during the extension phase.

[0381] Table 6

[0382] Testing products, dosages and administration methods :

[0383]

[0384] *PO = oral; SC = subcutaneous; IV = intravenous

[0385] 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. The 95% CI was constructed using the unconditional exact method. The efficacy endpoints between treatment groups were compared 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 snapshot algorithm defined by the US FDA, will be analyzed using the same methods as for the primary efficacy endpoint.

[0386] The change in CD4+ T cell count from baseline will be summarized by treatment using descriptive statistics. The difference in the change in CD4+ T cell count from baseline will be compared between the two treatment groups.

[0387] 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 results and changes from baseline values ​​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.

[0388] Serum or plasma concentrations and PK parameters of GS-5423, GS-2872, and LEN (and metabolites, if applicable), as appropriate, will be listed and summarized by treatment group for each analysis using descriptive statistics.

[0389] Table 7

[0390] Goals and End Points

[0391]

[0392] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and those skilled in the art will propose various modifications or changes based on these embodiments and implementations, and include these modifications or changes within the spirit and authority of this application and the scope of the appended claims. All publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

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

2. The method of claim 1, wherein the first antibody and the second antibody comprise an Fc region comprising the following amino acids at the specified 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 (LS) at position 434; (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) Aspartic acid at position 309, histidine at position 311 and serine (DHS) at position 434.

3. The method according to any one of claims 1 to 2, wherein the first antibody competes with or comprises the VH region and VL region of an antibody selected from the group consisting of 10-1074-LS (GS-2872, Jinliweimab), 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, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1 and VRC29.03; and the second antibody competes with or comprises the VH region and VL region of an antibody selected from the group consisting of: 3BNC117-LS (GS-5423; telopavir), 3BNC117, GS-9723, 3BNC60, b12, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b0 1, 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. The method according to any one of claims 1 to 3, wherein the first antibody competes with or comprises the VH region and VL region of 10-1074, and the second antibody competes with or comprises the VH region and VL region of 3BNC117.

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

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

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

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

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

10. The method according to 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 about 550 mg to about 2900 mg, such as about 600 mg to about 2800 mg, such as about 650 mg to about 2700 mg, such as about 700 mg to about 2600 mg, such as about 850 mg to about 2550 mg.

11. The method according to any one of claims 1 to 10, wherein the first antibody is administered intravenously at a dose of 2550 mg and the second antibody is administered intravenously at a dose of 2550 mg.

12. The method according to any one of claims 1 to 10, wherein the first antibody is administered intravenously at a dose of 850 mg and the second antibody is administered intravenously at a dose of 1275 mg.

13. The method according to any one of claims 1 to 10, wherein the first antibody is administered intravenously at a dose of 850 mg and the second antibody is administered intravenously at a dose of 1700 mg.

14. The method of any one of claims 1 to 10, wherein the first antibody is administered intravenously at a dose of 850 mg and the second antibody is administered intravenously at a dose of 2550 mg.

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

16. The method of claim 15, wherein the one or more long-acting HIV drugs are selected from the group consisting of 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. The method of claim 16, wherein the one or more long-acting HIV drugs comprises a long-acting capsid inhibitor.

18. The method according to any one of claims 16 to 17, wherein the long-acting capsid inhibitor is selected from lenacapvir, VH4004280 and VH4011499.

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

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

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

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

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

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, etafovir, and GS-1614.

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 a prodrug of GS-1156, and combinations thereof.

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

27. The method of any one of claims 1 to 26, wherein the subject is heavily treated with therapy (HTE).

28. The method of any one of claims 1 to 27, wherein the subject is resistant or unresponsive 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. The method of any one of claims 1 to 30, wherein the subject is receiving antiretroviral therapy (ART).

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

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

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

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 has recently been infected with HIV.

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

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

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

40. A method of treating or preventing HIV in a human subject in need thereof, the method comprising: a) co-administering at a first time point (i) an effective amount of 10-1074-LS (Zinlivimab; GS-2872) and (ii) an effective amount of 3BNC117-LS (telopavir; (GS-5423)); and b) co-administering an effective amount of 10-1074-LS and an effective amount of 3BNC117-LS at a second time point at least about 24 weeks, such as at least about 25 weeks, such as at least about 26 weeks after the first time point.

41. The method of claim 40, wherein the 10-1074-LS and the 3BNC117-LS are co-administered every 6 months (Q6M).

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

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

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

45. The method according to any one of claims 40 to 44, wherein the 10-1074-LS and the 3BNC117-LS are co-administered twice within 1 year.

46. ​​The method of any one of claims 40 to 44, wherein the 10-1074-LS and the 3BNC117-LS are co-administered 4 times within 2 years.

47. The method of any one of claims 40 to 44, wherein the 10-1074-LS and the 3BNC117-LS are co-administered 6 times within 3 years.

48. The method of any one of claims 40 to 44, wherein the 10-1074-LS and the 3BNC117-LS are co-administered 8 times within 4 years.

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. The method according to 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 about 550 mg to about 2900 mg, such as about 600 mg to about 2800 mg, such as about 650 mg to about 2700 mg, such as about 700 mg to about 2600 mg, such as about 850 mg to about 2550 mg.

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

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

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

59. The method of claim 58, wherein the one or more long-acting HIV drugs are selected from the group consisting of 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. The method of claim 59, wherein the long-acting capsid inhibitor is selected from lenacapvir, VH4004280, and VH4011499.

61. The method of any one of claims 59 to 60, wherein the long-acting capsid inhibitor comprises lenacapvir.

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

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

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

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

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, etafovir, and GS-1614.

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 a prodrug of GS-1156, and combinations thereof.

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

69. The method of any one of claims 40 to 68, wherein the subject is heavily treated with therapy (HTE).

70. The method of any one of claims 40 to 69, wherein the subject is resistant or unresponsive 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. The method of any one of claims 40 to 70, wherein the subject is viremic.

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

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

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

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

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

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

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

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

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

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

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

83. The kit of claim 82, wherein the unit dose of the first antibody and the second antibody is independently in the range of about 500 mg to about 3000 mg, such as about 550 mg to about 2900 mg, such as about 600 mg to about 2800 mg, such as about 650 mg to about 2700 mg, such as about 700 mg to about 2600 mg, such as about 850 mg to about 2550 mg.

84. A kit comprising one or more unit doses of 3BNC117-LS (telopavir) and 10-1074-LS (zinliweimab), wherein the 3BNC117-LS (telopavir) and the 10-1074-LS (zinliweimab) are formulated for administration twice a year (e.g., once every 6 months (Q6M), once every 26 weeks (Q26W), once every 25 weeks (Q25W), or once every 24 weeks (Q24W)).

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, such as about 600 mg to about 2800 mg, such as about 650 mg to about 2700 mg, such as about 700 mg to about 2600 mg, such as about 850 mg to about 2550 mg.

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

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

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

89. The kit of claim 85, wherein the one or more unit doses of 10-1074-LS is 850 mg and the one or more unit doses of 3BNC117-LS is 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. 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. The kit of claim 91, wherein the one or more containers are selected from the group consisting of vials, ampoules, and pre-loaded syringes.

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

96. The method of any one of claims 94 to 95, wherein the long-acting capsid inhibitor comprises lenacapvir.

97. The kit of claim 96, wherein the unit dose of lenacapvir is in the range of 300 mg to 1000 mg.

98. The kit of any one of claims 96 to 97, wherein the lenacapvir is formulated for oral or subcutaneous administration.

99. The kit of any one of claims 94 to 98, wherein the long-acting INSTI is selected from bicagevir, 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, esxavirine, doravirine, and GS-5894.

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, etafovir, and GS-1614.

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 a prodrug of GS-1156, and combinations thereof.

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