Zinlirvimab (10-1074-LS): A Comprehensive Analysis of a Long-Acting Broadly Neutralizing Antibody for HIV Treatment and Prevention

Section 1: Executive Summary & Overview of Zinlirvimab (10-1074-LS)

Introduction and Nomenclature

10-1074-LS is an investigational human monoclonal antibody being developed for the treatment and prevention of Human Immunodeficiency Virus Type 1 (HIV-1) infection. It represents a significant advancement in the field of passive immunotherapy, belonging to a class of molecules known as broadly neutralizing antibodies (bNAbs).[1] Originally discovered by researchers at The Rockefeller University, the antibody and its long-acting variant have been licensed for clinical development by Gilead Sciences, Inc..[3] In this context, it is identified by several names: the research designation 10-1074-LS, the generic name zinlirvimab, and the Gilead development code GS-2872.[2] The "-LS" suffix denotes a critical modification engineered to extend its biological half-life, a feature central to its therapeutic strategy.

Classification and Therapeutic Rationale

Zinlirvimab is classified as a human IgG1 monoclonal antibody designed to neutralize a wide range of genetically diverse HIV-1 strains.[5] The development of bNAbs like zinlirvimab is driven by a compelling therapeutic rationale: to overcome the limitations of conventional antiretroviral therapy (ART). The current standard of care for HIV involves lifelong adherence to daily oral medication regimens.[8] While highly effective at suppressing viral replication, this approach presents considerable challenges, including treatment fatigue, cumulative long-term toxicities, and the persistent burden of daily adherence, which can compromise treatment success.[1] Zinlirvimab, engineered for infrequent administration, offers a potential paradigm shift. By maintaining therapeutic concentrations for months after a single dose, it aims to replace daily pills with a regimen administered semi-annually, thereby improving quality of life, simplifying treatment, and potentially enhancing population-level viral suppression by mitigating adherence issues.[1]

Mechanism and Development Strategy

The mechanism of action of zinlirvimab is highly specific; it targets a conserved carbohydrate-dependent epitope located at the base of the third variable loop (V3) of the HIV-1 envelope (Env) glycoprotein.[1] By binding to this critical site, the antibody blocks the virus from entering and infecting healthy host cells, primarily CD4+ T lymphocytes.[2] Recognizing the high genetic plasticity of HIV-1 and the risk of viral escape from a single immunological pressure point, the clinical development of zinlirvimab has been almost exclusively pursued through combination therapy. Its primary partner in numerous studies is teropavimab (3BNC117-LS), another long-acting bNAb that targets a different, non-overlapping epitope—the CD4 binding site.[3] This dual-bNAb strategy aims to provide broader coverage against diverse viral strains and create a higher barrier to the development of resistance.[10] More recently, and with greater clinical success, zinlirvimab has been combined with the long-acting HIV-1 capsid inhibitor lenacapavir, creating a multi-mechanistic regimen with the potential for twice-yearly administration.[2]

Synopsis of Clinical Status

Zinlirvimab is an investigational agent and has not been approved for any use by the U.S. Food and Drug Administration (FDA) or any other global regulatory authority.[15] It is currently in late-stage clinical development, with pivotal Phase 2 and 3 trials evaluating its efficacy and safety for both HIV treatment and prevention.[2] A significant milestone was achieved in January 2025, when the FDA granted Breakthrough Therapy Designation to the combination regimen of zinlirvimab, teropavimab, and lenacapavir for the treatment of HIV.[16] This designation is reserved for therapies that may demonstrate substantial improvement over available treatments and is intended to expedite their development and review, signaling strong regulatory confidence in the regimen's potential to address a significant unmet need in HIV care.

Section 2: Molecular Profile, Structural Biology, and Mechanism of Action

Target Specificity and Epitope

Zinlirvimab's potent anti-HIV activity is derived from its precise targeting of a highly conserved region on the viral envelope known as the V3 glycan supersite.[1] This epitope is located at the base of the V3 loop of the gp120 surface protein, a structure essential for viral entry into host cells.[3] The binding of zinlirvimab is complex and bimodal, depending on interactions with both a specific N-linked glycan and the underlying protein backbone of the Env trimer.[18] This targeting mechanism is distinct from that of other well-characterized bNAbs. For instance, its frequent clinical partner, teropavimab (3BNC117-LS), and the extensively studied VRC01 antibody both target the CD4 binding site (CD4bs), the region of gp120 that directly engages the primary host cell receptor.[3] By targeting a non-overlapping epitope, zinlirvimab provides a complementary mechanism of neutralization, forming the scientific basis for its use in combination regimens designed to achieve synergistic antiviral activity and suppress a broader range of viral quasispecies.

Structural Biology and Binding Dynamics (PDB: 4FQ2)

The crystal structure of the 10-1074 antigen-binding fragment (Fab), resolved to 1.90 Å, provides critical atomic-level detail into its unique mechanism of neutralization.[20] The structure reveals that the antibody's specificity is largely dictated by a deep cleft formed at the interface of its heavy chain complementarity-determining regions 2 and 3 (CDRH2 and CDRH3).[20] This cleft is exquisitely shaped to accommodate the N-linked glycan typically found at asparagine position 332 (N332) of the HIV-1 Env protein.[18]

Unlike antibodies that bind solely to carbohydrates or protein surfaces, 10-1074 achieves its high potency by simultaneously engaging both. It penetrates the dense "glycan shield" that protects the virus from immune recognition, using the N332 glycan as an anchor point to gain access to the underlying and highly conserved protein motif, 324G(D/N)IR327.[18] This dual-recognition strategy, where the antibody leverages a variable glycan to bind a conserved protein element, is a sophisticated evolutionary adaptation that allows it to neutralize a wide array of HIV-1 strains despite significant sequence diversity in the V3 loop itself.[20] Swapping key glycan-contacting residues between 10-1074 and related antibodies has experimentally confirmed the critical importance of this interaction for potent neutralization.[20]

The 'LS' Modification: Engineering for Extended Bioavailability

The transformation of 10-1074 into a viable long-acting therapeutic agent is entirely dependent on the "LS" modification. This is not merely an incremental improvement but rather the foundational engineering that enables the entire clinical strategy of infrequent dosing. The current standard of HIV care, while effective, is predicated on the lifelong burden of daily medication, a major contributor to treatment non-adherence and long-term health complications.[1] The LS modification directly addresses this fundamental challenge by fundamentally altering the antibody's pharmacology to permit dosing intervals of months, rather than days or weeks.

Molecular Basis

The LS modification consists of two specific amino acid substitutions introduced into the gene encoding the crystallizable fragment (Fc) domain of the antibody: Methionine at position 428 is replaced by Leucine (), and Asparagine at position 434 is replaced by Serine ().[4] These changes are located in the region of the Fc domain that interacts with a key cellular receptor responsible for regulating antibody lifespan.

Pharmacokinetic Mechanism

The primary mechanism by which the LS modification extends bioavailability involves the neonatal Fc receptor (FcRN).[4] FcRN is expressed on the surface of endothelial cells and plays a crucial role in preventing the degradation of immunoglobulin G (IgG). Antibodies in circulation are taken up by endothelial cells into endosomes. Inside the acidic environment of the endosome, FcRN binds to the Fc domain of IgG, rescuing it from the lysosomal degradation pathway and recycling it back to the cell surface, where it is released back into circulation. The M428L/N434S substitutions significantly enhance the binding affinity of the antibody's Fc domain for FcRN, particularly at the acidic pH of the endosome.[4] This stronger interaction leads to more efficient rescue and recycling, thereby dramatically slowing the antibody's clearance from the body.

Quantifiable Impact

The clinical impact of this molecular engineering is profound and has been quantified in human studies. A cross-protocol analysis comparing five pairs of parental bNAbs with their LS-modified variants revealed substantial pharmacokinetic improvements. Across the board, the LS variants demonstrated a 2.7- to 4.1-fold increase in elimination half-life and a 4.1- to 9.5-fold increase in dose-normalized area-under-the-curve (AUC), a measure of total drug exposure.[6] For 10-1074 specifically, the half-life in HIV-uninfected individuals was extended from a mean of 24.0 days for the parental antibody to approximately 80 days for the 10-1074-LS variant.[7] This nearly four-fold increase in half-life is what makes dosing schedules of every three or even six months pharmacokinetically feasible, directly enabling the development of the twice-yearly regimens currently in late-stage trials.[10] Without the LS modification, the antibody's persistence would be insufficient to maintain therapeutic concentrations over such extended periods, rendering the long-acting paradigm non-viable.

Section 3: Preclinical Development and Proof-of-Concept

The preclinical evaluation of zinlirvimab and its parental antibody provided a remarkably accurate blueprint for the subsequent clinical development strategy. These foundational studies in laboratory and animal models not only confirmed the antibody's potential but also presciently identified the primary challenges that would need to be addressed in human trials, namely the necessity of combination therapy to overcome viral escape.

In Vitro Neutralization Profile and Synergy

Initial in vitro characterization established 10-1074-LS as a potent neutralizing agent. When tested against a panel of primary HIV-1 isolates from Africa (representing Clades A, C, and D), it demonstrated a geometric mean 50% inhibitory concentration () of 2.55 µg/mL.[11] However, its breadth as a single agent was limited, neutralizing only 52% of the viruses in this panel at a concentration below 10 µg/mL.[11] This observation immediately highlighted a potential limitation for monotherapy.

In contrast, preclinical data strongly supported a combination approach. The neutralization breadth of 10-1074-LS and its partner, 3BNC117-LS, was shown to be highly synergistic. Against a panel of Clade C primary isolates, the individual antibodies neutralized 61% and 56% of viruses, respectively; when combined, their effective breadth increased to 81%.[10] This effect was even more pronounced against a multi-clade panel of pseudoviruses, where the combination neutralized 93% of strains, a significant improvement over the 80% and 59% achieved by 10-1074 and 3BNC117 alone, respectively.[10] These in vitro synergy data provided the foundational rationale for the co-development of these two antibodies as a clinical pair.

In Vivo Efficacy in Non-Human Primate (NHP) Models

Studies in non-human primate models, typically using simian-human immunodeficiency virus (SHIV), served as the critical in vivo proof-of-concept for zinlirvimab's utility in both prevention and treatment.

Prophylaxis Studies

The potential of 10-1074-LS for pre-exposure prophylaxis (PrEP) was robustly demonstrated in macaques. In one pivotal study, a single intravenous infusion of 10-1074-LS provided complete protection against repeated low-dose SHIV challenges for a remarkable duration of up to 8.5 months (37 weeks).[21] Another study showed that a single 20 mg/kg infusion could protect macaques from weekly intrarectal SHIV challenges for up to 23 weeks.[23] These results confirmed that maintaining a sufficient circulating concentration of the antibody was highly effective at preventing infection, providing strong justification for initiating human PrEP trials. Further exploring alternative delivery methods, a novel study evaluated a topical microbicide gel containing 10-1074. When applied vaginally prior to challenge with cell-associated SHIV, the gel protected five out of six macaques, yielding a calculated protection efficacy of 83.3% and suggesting potential utility as a female-controlled prevention method.[24]

Treatment and Viral Escape

In stark contrast to the success in prophylaxis, NHP studies evaluating 10-1074 as a treatment for established infection revealed a critical vulnerability. Administration of the antibody as monotherapy to infected animals resulted in an initial, transient decline in viremia. However, this suppression was short-lived, as the virus rapidly rebounded due to the selection and outgrowth of pre-existing or newly generated escape mutations that rendered it resistant to the antibody.[23]

This dichotomy in preclinical outcomes—potent and durable efficacy in preventing infection versus transient efficacy in treating established infection—was not a failure but a crucial finding. It accurately predicted the strategic imperatives for clinical development. The success in prophylaxis demonstrated the molecule's inherent power to neutralize the virus, supporting its evaluation for PrEP. Simultaneously, the failure of monotherapy due to viral escape made it unequivocally clear that for any therapeutic application, combination regimens would be non-negotiable. This finding directly shaped the entire clinical program, steering it away from monotherapy and towards dual-bNAb combinations and, ultimately, the more robust triple-combination regimen with the capsid inhibitor lenacapavir, which provides a different mechanism of action to suppress viral replication and prevent the emergence of resistance.

Section 4: Clinical Development Program: Foundational and Combination Studies

The clinical development of zinlirvimab has followed a logical and methodical progression, from initial safety and pharmacokinetic assessments to complex, multi-agent trials aimed at establishing a new paradigm for long-acting HIV therapy and exploring its potential role in cure strategies.

Phase 1 First-in-Human Trials (e.g., NCT03554408)

The first-in-human study of 10-1074-LS, NCT03554408, was a Phase 1 dose-escalation trial designed to establish its fundamental safety, tolerability, and pharmacokinetic (PK) profile.[25] The study enrolled both HIV-uninfected and virologically suppressed HIV-infected individuals. It systematically evaluated single intravenous (IV) infusions at escalating doses (3, 10, and 30 mg/kg) as well as subcutaneous (SC) administration. Crucially, the trial also included arms that evaluated 10-1074-LS in combination with its partner bNAb, 3BNC117-LS.[25] This foundational study successfully established the initial safety parameters and defined the therapeutic dosing range, confirming that the antibody was well-tolerated and exhibited the expected long-acting PK profile, thereby enabling its advancement into more complex efficacy studies.

The Cornerstone Combination: Zinlirvimab and Teropavimab (e.g., NCT05079451)

Building on the preclinical synergy data, a significant portion of the clinical program has focused on the dual bNAb combination of zinlirvimab and teropavimab (3BNC117-LS). Studies such as NCT05079451 were designed to assess the direct antiretroviral activity of this combination.[26] A common design for these trials is the Monitored Analytical Treatment Interruption (ATI). In this model, participants who are virologically suppressed on standard ART receive infusions of the bNAbs and then, under careful medical supervision, discontinue their daily oral medications.[12] The primary endpoint is the time to viral rebound. These ATI studies serve as the most direct method for evaluating the ability of the antibodies to control viral replication originating from the latent HIV reservoir in the absence of other antiretroviral drugs.

The Long-Acting Frontier: Combination with Capsid Inhibitor Lenacapavir (NCT04811040, NCT05729568)

The most advanced and commercially promising application of zinlirvimab is within a triple-combination, long-acting regimen sponsored by Gilead Sciences. This program combines zinlirvimab and teropavimab with lenacapavir, a first-in-class, long-acting HIV-1 capsid inhibitor, with the goal of creating a complete ART regimen that can be administered just twice a year.

Phase 1b (NCT04811040)

This trial served as the critical proof-of-concept for the triple combination, referred to as the LTZ regimen (Lenacapavir + Teropavimab + Zinlirvimab).[2] The study enrolled virologically suppressed adults with HIV who were confirmed to have virus susceptible to both bNAbs. After switching from their daily oral ART to the LTZ regimen, 90% (18 out of 20) of participants successfully maintained virologic suppression (defined as HIV-1 RNA <50 copies/mL) through 26 weeks.[14] The regimen was generally well-tolerated, with no serious adverse events reported.[14] These highly positive results provided the first clinical validation of the twice-yearly treatment strategy and prompted its rapid advancement into Phase 2.

Phase 2 (NCT05729568)

This larger, randomized, open-label Phase 2 study was designed to confirm the efficacy and safety of the LTZ regimen against the current standard of care.[29] Virologically suppressed participants were randomized to either switch to the twice-yearly injectable LTZ regimen or continue their baseline daily oral ART. The study successfully met its primary endpoint, demonstrating non-inferiority. At Week 26, 96% (51 of 53) of participants in the LTZ arm remained virologically suppressed, a rate equivalent to the 96% (26 of 27) observed in the standard of care arm.[16] This pivotal result confirmed the high efficacy of the regimen and provided the robust data needed to support its progression into Phase 3 trials and its eventual submission for regulatory approval.

Pediatric Applications (NCT03707977 - The Tatelo Study)

Recognizing that children represent a distinct population with unique pharmacological needs, the Tatelo study was conducted to evaluate bNAb therapy in young, virally suppressed children with HIV in Botswana.[1] This Phase 1/2 trial evaluated the parental 10-1074 antibody in combination with another long-acting bNAb, VRC01LS. The infusions were found to be safe and well-tolerated in this vulnerable population.[1] However, the study yielded a critical pharmacokinetic finding: the elimination half-life of 10-1074 was significantly shorter in these young children (median 19 days) compared to what has been observed in adults (24 days for the parental antibody).[1] This result underscores the principle that adult dosing and PK data cannot be directly extrapolated to pediatric populations and highlights the absolute necessity of conducting dedicated pediatric studies to establish safe and effective dosing regimens for children.

Exploratory Combinations for HIV Cure Research (NCT05245292)

Beyond viral suppression, zinlirvimab is also being investigated as a key component of HIV cure-directed strategies. The Phase 1 trial NCT05245292 is exploring an innovative "kick and kill" approach.[31] In this study, the dual bNAb combination of 3BNC117-LS and 10-1074-LS is administered along with N-803, an IL-15 superagonist complex. The therapeutic hypothesis is that N-803 will act as a latency-reversing agent (the "kick"), reactivating dormant, latently infected cells and forcing them to express viral proteins on their surface. This would make them visible to the immune system and susceptible to elimination by the infused bNAbs and other Fc-mediated effector functions (the "kill").[10] This trial positions zinlirvimab not just as a tool for treatment (suppression) but as a potential instrument for the far more ambitious goal of reservoir reduction and eventual eradication.

Section 5: Comprehensive Efficacy, Safety, and Clinical Trial Overview

Efficacy in Maintaining Virologic Suppression

The clinical efficacy of zinlirvimab has evolved significantly with the refinement of its therapeutic application. Early studies of the parental 10-1074 antibody as monotherapy in viremic individuals demonstrated its potent antiviral activity, achieving a mean viral load reduction of 1.52  copies/mL.[7] However, this effect was transient due to the rapid emergence of viral resistance, a finding that underscored the limitations of single-agent therapy.[7]

Subsequent development focused on combination regimens in virologically suppressed individuals undergoing analytical treatment interruption (ATI). These second-generation strategies, pairing zinlirvimab with teropavimab, demonstrated a significant extension in the time to viral rebound compared to placebo.[2] In one such study combining 10-1074 with VRC01LS, 44% of participants who stopped their daily ART maintained viral suppression through 24 weeks of bNAb-only treatment.[2]

The most compelling efficacy data to date have emerged from the triple-combination regimen with lenacapavir (LTZ). The Phase 1b proof-of-concept study showed that 90% of participants maintained virologic suppression for at least 26 weeks on this twice-yearly regimen.[14] This high level of efficacy was confirmed in the larger Phase 2 trial (NCT05729568), where 96% of participants switching to the LTZ regimen remained suppressed at Week 26, establishing non-inferiority to continuous daily oral ART.[16] These results represent a major breakthrough, demonstrating for the first time that a twice-yearly regimen can match the efficacy of the current gold standard of daily therapy.

Consolidated Safety and Tolerability Profile

Across its extensive clinical development program, zinlirvimab, both alone and in combination, has demonstrated a highly favorable safety and tolerability profile. In the foundational Phase 1 trials, single infusions of 10-1074-LS were well-tolerated in both HIV-infected and uninfected participants.[7] The safety profile has remained consistently strong in more complex combination studies. In the pivotal LTZ trials, the regimen was generally well-tolerated.[14] The most commonly reported adverse events (AEs) were mild-to-moderate infusion-related reactions associated with the bNAbs or injection site reactions (e.g., erythema, cellulitis) related to the subcutaneous administration of lenacapavir.[14] Critically, across these key studies, there were no serious adverse events deemed related to the study drugs and no participants discontinued the regimen due to AEs, indicating excellent tolerability and supporting its potential for long-term use.[14]

Central Clinical Trial Summary Table

The following table consolidates the key details of the most significant clinical trials that have defined the development trajectory of zinlirvimab (10-1074-LS).

Clinical Trial ID	Phase	Intervention(s)	Patient Population	Primary Objective(s)	Key Reported Outcomes & Significance
NCT03554408	1	10-1074-LS +/- 3BNC117-LS	HIV-infected & uninfected adults	Safety, PK, tolerability	Established initial safety and PK profile for IV and SC routes, enabling further development. 25
NCT05079451	1	3BNC117-LS + 10-1074-LS	Virologically suppressed adults	Safety, prevention of viral relapse during ATI	Assessed the dual bNAb regimen's ability to control viremia off ART, a key test of antiretroviral potency. 26
NCT03707797 (Tatelo)	1/2	10-1074 + VRC01LS	Virally suppressed children	Safety, PK, dose-finding	Demonstrated good safety but a shorter half-life in children, highlighting the need for pediatric-specific dosing. 1
NCT04811040	1b	Lenacapavir + Teropavimab + Zinlirvimab	Virologically suppressed adults	Safety, efficacy	Proof-of-concept for the LTZ regimen; 90% maintained suppression at 26 weeks, validating the twice-yearly strategy. 2
NCT05729568	2	Lenacapavir + Teropavimab + Zinlirvimab	Virologically suppressed adults	Efficacy vs. baseline ART	Confirmed high efficacy (96% suppressed at 26 weeks), demonstrating non-inferiority to daily oral ART and supporting Phase 3 progression. 16
NCT05245292	1	3BNC117-LS + 10-1074-LS + N-803	Virologically suppressed adults	Safety, antiretroviral activity during ATI	Explores zinlirvimab's role in a "kick and kill" HIV cure strategy, pushing its application beyond simple viral suppression. 31

Section 6: The Challenge of Viral Resistance

While zinlirvimab has demonstrated potent activity, its clinical efficacy is fundamentally constrained by the genetic diversity of HIV-1 and its capacity to develop resistance. This challenge manifests in two distinct forms: emergent resistance under therapeutic pressure and, more problematically, pre-existing baseline resistance in untreated populations.

Mechanisms of Resistance

Resistance to 10-1074 is primarily mediated by specific mutations within or near its target epitope on the HIV-1 Env protein. The antibody's binding is critically dependent on the presence of an N-linked glycan at position 332.[18] Therefore, the most common and effective resistance mechanism involves mutations that disrupt this key interaction. This typically occurs through alterations to the potential N-glycosylation site (PNGS) sequon (a sequence of N-x-S/T, where x is any amino acid except Proline). A mutation that eliminates this sequon prevents the attachment of the glycan, thereby abolishing the primary anchor point for the antibody and rendering the virus resistant.[18]

Emergent Resistance in Clinical Trials

The phenomenon of emergent resistance was clearly demonstrated in early clinical trials that tested 10-1074 as monotherapy in individuals with active viral replication. In these studies, while the antibody infusion led to a rapid initial decline in viremia, this suppression was consistently followed by viral rebound within weeks.[7] Virologic analysis of the rebounding virus revealed the selection and outgrowth of multiple independent viral lineages containing escape mutations that conferred resistance to 10-1074.[7] This predictable outcome provided definitive evidence that monotherapy was not a viable treatment strategy and was the primary driver for the mandatory use of combination therapy in all subsequent therapeutic trials.

Pre-existing (Baseline) Resistance

A more formidable challenge for the broad clinical implementation of zinlirvimab is the presence of resistance-associated mutations in bNAb-naïve individuals. The initial promise of a long-acting therapy that could be used universally is tempered by the reality that a significant fraction of the HIV-infected population may already harbor virus that is inherently resistant. A study analyzing proviral DNA from a UK cohort of individuals with primary HIV infection found that 29% of participants had at least one viral sequence containing known 10-1074 resistance mutations.[18] Of these, 95% were mutations that directly interfered with the critical N332 glycan binding site.[18] The prevalence of these resistance mutations was also found to vary significantly by HIV-1 subtype, with the highest rates observed in non-B clades like CRF01-AE.[18]

This high prevalence of pre-existing resistance acts as a critical gatekeeper to the clinical use of zinlirvimab. It transforms the agent from a potential one-size-fits-all solution into a personalized medicine that requires a companion diagnostic. To avoid prescribing an ineffective therapy, clinicians must first screen a patient's virus for susceptibility. This necessity is explicitly reflected in the stringent inclusion criteria of all major clinical trials for zinlirvimab-containing regimens, which mandate baseline sensitivity screening using a sophisticated phenotypic assay, such as the Monogram PhenoSense assay.[26] While this ensures that only appropriate candidates are treated, it also introduces significant logistical and economic hurdles to implementation. The requirement for expensive, specialized laboratory testing may limit access, particularly in resource-constrained settings where the burden of HIV is highest. Therefore, the ultimate public health impact of zinlirvimab will be determined not only by its clinical efficacy but also by the accessibility and affordability of the resistance screening required for its safe and effective use.

Section 7: Strategic Analysis and Future Outlook

Development and Regulatory Trajectory

The journey of zinlirvimab from an academic discovery to a late-stage clinical asset illustrates a successful model of public-private partnership in drug development. Discovered and characterized at The Rockefeller University, its potential was recognized and advanced through licensing to Gilead Sciences, a company with deep expertise and commercial infrastructure in HIV therapeutics.[2] Gilead's stewardship has propelled the molecule through a comprehensive clinical program, culminating in the highly successful Phase 2 trial of the twice-yearly LTZ regimen.[16]

The regulatory path for this regimen appears promising. The FDA's decision to grant it Breakthrough Therapy Designation in January 2025 is a significant endorsement of its potential to offer a substantial improvement over existing therapies.[16] This designation could facilitate a more rapid review process following the completion of Phase 3 trials and submission of a Biologics License Application (BLA). As of now, zinlirvimab remains an investigational compound and is not approved for any indication by the FDA or other regulatory bodies.[15]

Positioning within the HIV Treatment and Prevention Paradigm

Should it gain approval, a zinlirvimab-based regimen would enter a dynamic but well-defined HIV market, where its primary value proposition is a dramatic reduction in dosing frequency.

Comparison to Standard of Care (SoC)

The current standard of care for the vast majority of people living with HIV is a daily, single-tablet oral ART regimen.[8] These regimens are highly effective, safe, and convenient. However, their success is contingent on lifelong, near-perfect adherence. The twice-yearly LTZ regimen directly addresses the primary unmet need of adherence burden. By uncoupling treatment success from daily patient behavior, it has the potential to improve long-term outcomes, reduce the risk of virologic failure, and significantly enhance patient quality of life.

Comparison to Other Long-Acting Agents

The primary competitor in the long-acting injectable space is the combination of cabotegravir and rilpivirine (Cabenuva), which is administered either monthly or every two months. While Cabenuva represents a significant step forward from daily pills, a twice-yearly regimen would offer a clear and substantial advantage in convenience, reducing the number of required clinic visits and injections from six or twelve per year to just two. This could be a decisive factor for both patient preference and healthcare system efficiency.

Future Applications and Unanswered Questions

The clinical utility of zinlirvimab extends across the spectrum of HIV medicine, from treatment and prevention to cure research.

• Treatment: The most immediate and well-defined role for zinlirvimab is as a core component of a twice-yearly maintenance therapy for virologically suppressed individuals with susceptible virus.[10]
• Prevention (PrEP): Its potent neutralizing activity and exceptionally long half-life make it an attractive candidate for HIV PrEP.[4] A semi-annual injection for prevention could offer a highly effective and convenient alternative to daily oral PrEP or the bimonthly injectable cabotegravir, potentially increasing uptake and adherence in key populations.
• Cure Research: As demonstrated in trials combining it with latency-reversing agents, zinlirvimab is a valuable tool for exploring "kick and kill" and other strategies aimed at reducing or eliminating the latent HIV reservoir.[10] Its ability to mediate Fc effector functions may be crucial for clearing reactivated infected cells.

Concluding Remarks

Zinlirvimab (10-1074-LS) stands as a leading example of the next generation of HIV therapeutics. Through sophisticated antibody engineering, specifically the half-life-extending LS modification, it has been transformed into a cornerstone for potentially revolutionary long-acting treatment regimens. Its clinical development program, particularly in combination with teropavimab and the capsid inhibitor lenacapavir, has yielded impressive efficacy and safety data, demonstrating that a twice-yearly therapy can match the virologic control of daily oral medication. The significant challenge of pre-existing viral resistance necessitates a personalized medicine approach, requiring careful patient selection through susceptibility screening. Nevertheless, for the large proportion of individuals with susceptible virus, zinlirvimab-based regimens have the potential to fundamentally redefine the standard of care, offering a future where the management of HIV is unburdened from the demands of daily therapy.

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