A brief history of passive immunization
In 1890, von Behring and Kitasato , working at the Institute of Hygiene in Berlin, reported that serum from rabbits that had been immunized with bacterial toxins protected nonimmune rabbits from infection. Their discovery led to the use of immune serum from horses and other animals to treat tetanus and diphtheria infections in humans and marked the start of the age of ‘serum therapy’. This treatment was hailed as the most important medical breakthrough of the nineteenth century, and the inventors received the first Nobel Prize in Physiology or Medicine in 1901 . For approximately 40 years, serum therapy was used as front-line treatment for a number of major human bacterial and viral infections, including tetanus, diphtheria, pneumococcus, meningococcus, influenza, measles, and polio. Following the introduction of potent antibacterial drugs, antibody therapy was restricted to a smaller number of selected treatments for snake venoms, bacterial toxins, and some viral infections . However, in recent years, passive immunization has experienced a renaissance with the use of monoclonal antibodies (mAbs) to treat a number of cancers, as well as autoimmune and infectious diseases.
The early days of passive immunization with animal immune sera had been hampered by limited availability of quality antibodies, high cost, and frequent adverse reactions to serum components. In the 1940's, Cohn significantly advanced the field through the introduction of a procedure to purify immunoglobulins from blood, which, with further improvements, led to the use of potent polyclonal ‘immunoglobulin’ formulations for the prophylaxis and treatment of several viral diseases, including measles, polio, and infectious hepatitis , and for the protection of high-risk newborns unable to receive colostrum . These products produced fewer side-effects, but supplies were limited and expensive. In 1975, the field of passive immunization was revolutionized with the discovery of a technique to make mAbs by Kohler and Milstein , and in 2003, by transformative technology which introduced the capability of cloning heavy and light chain immunoglobulin genes amplified from single human B cells and their expression in bacteria, and later in other expression systems as described below [6,7]. This capability accelerated the discovery of new human antibodies, especially when coupled with rapid manufacturing platforms, and made possible their production on a large scale for clinical applications . By the end of 2014, 47 mAb products had been approved for clinical use, and it is projected that 70 mAb products will be on the market by 2020 with combined sales of $125 billion .
Use of anti-HIV monoclonal antibodies to prevent the sexual transmission of HIV
Most HIV transmission events occur across genital or rectal mucosal surfaces following sexual intercourse with an HIV-infected partner [10,11]. With the introduction of new intervention strategies, such as male circumcision and treatment-as-prevention, the global HIV incidence has dropped from its peak in 1997 of 3.5 million new infections/year, to 2.1 million/year , but this rate is still unacceptably high. A vaccine may be the ultimate goal for HIV prevention, but this approach has remained elusive. mAbs are currently being explored for HIV therapy and prevention. Approximately, one-third of HIV-infected individuals make HIV neutralizing-antibodies , and B cells from these individuals were used to isolate first generation HIV-neutralizing mAbs. These identified conserved epitopes shared between HIV subtypes and isolates; however, they had limited breadth and/or potency against global isolates and were only partially effective in simian/human immunodeficiency virus-challenge models. Subsequently, large cohorts of HIV-infected individuals were screened for highly effective neutralizing antibodies, and high throughput single B-cell receptor amplification techniques and novel soluble trimeric envelopes were employed to produce a new generation of extremely potent broadly neutralizing anti-HIV antibodies (bNAbs) and are active across multiple HIV clades . These second generation mAbs are 10 to 100-fold more potent than the first generation antibodies, and bind to various epitopes on the viral surface (Table 1) which enables the administration of combinations of distinct mAbs to reduce HIV immune escape. Unfortunately, potent HIV neutralization activity is associated with a high degree of somatic hypermutation, making the production of bNAbs through vaccination a challenge . Nonneutralizing HIV mAbs have also been described that may block HIV infection through other antiviral effector functions such as Fc-mediated functional assays (described below). Interest in nonneutralizing anti-HIV antibodies arose when data from the recent RV144 Thai vaccine trial showed that nonneutralizing antibodies were associated with protection in vaccinated study participants . However, to date nonneutralizing mAbs have been less effective than bNAbs in protecting against SHIV infection in vaginal and rectal transmission models [17–19].
Parenteral monoclonal antibody administration
Preclinical studies in animal models
Some of the first studies to demonstrate protective effects of HIV mAbs were conducted in the humanized mouse HIV-infection model [20–22]. Following the introduction of the chimeric HIV/SIV (SHIV) virus challenge model, nonhuman primates (NHP) have been extensively used to test the ability of anti-HIV bNAbs to prevent SHIV infection via the vaginal or rectal routes (Table 2[17,18,23–37]). The earliest NHP studies used intravenous (i.v.) infusion of first-generation bNAbs (e.g. 2G12, b12, 2F5); these mAbs required a high dose (≥25 mg/kg) to achieve protection against a single high-dose SHIV vaginal challenge, even with Tier 1 (neutralization sensitive) strains [24,26,34]. Passive immunization of various combinations of these bNAbs also protected neonatal macaques against high-dose i.v. or oral challenge with SHIVs, providing further proof-of-concept that mAbs can prevent HIV infection . The introduction of more potent cross-clade bNAbs and Tier 2 (neutralization resistant) SHIV strains have provided a more realistic picture of the potential of passive immunization with HIV antibodies. Second-generation bNAbs (particularly the PG, PGT, and VRC series) require lower doses (≤1 mg/kg) for protection in passive immunization studies than first-generation bNAbs; furthermore, they have demonstrated efficacy against both vaginal and rectal SHIV challenges with Tier 2 SHIV [32,35]. Engineering of bNAbs to enhance neutralization efficacy, Fc function and serum half-life has led to increased protection in some studies [29,36]. This research has paved the way for clinical trials of parenteral bNAb administration in humans to prevent HIV transmission.
Three Phase 1 clinical trials have been conducted to determine the safety, tolerability, and serum antibody pharmacokinetics in adults receiving i.v. infusions of the bNAb VRC01 with and without supplemental subcutaneous injections of antibody. VRC601 and 602 were dose escalation and pharmacokinetics studies of i.v. vs. subcutaneous administration of VRC01 in HIV-infected and uninfected study participants, respectively [39,40]. HIV Vaccine Trials Network (HVTN)104 was a larger phase 1 trial evaluating the safety of multiple doses of VRC01 administered over 6 months in regimens hypothesized to result in drug levels corresponding to protection against HIV. The study recruited a total of 88 healthy HIV-uninfected volunteers (44 men, 43 women, and 1 transgender person). The bNAb infusions and injections were well tolerated and no severe adverse events were reported. Pharmacokinetics results showed that: after a 40 mg/kg i.v. loading dose, VRC01 levels in blood were maintained at more than 10 μg/ml for 6 months through biweekly 5 mg/kg subcutaneous injections; 20 mg/kg VRC01 given i.v. monthly after a 40 mg/kg loading dose maintained blood levels more than 40 μg/ml; bimonthly VRC01 administered i.v. at 10, 30, or 40 mg/kg resulted in peak concentrations between 80 and more than 400 μg/ml and nadirs between 12 and more than 20 μg/ml. All three of these protocols maintained antibody titers well above the minimum effective HIV neutralization concentration of VRC01 (IC50 = 1 μg/ml). Potentially effective antibody titers were sustained from 53 to 81 days after mAb dosing was terminated . Furthermore, preliminary data indicate that the infused antibody enters vaginal and rectal mucosal tissues at levels conferring protection in ex-vivo HIV challenge studies .
Two large phase 2B clinical trials, referred to as the antibody-mediated prevention (AMP) study (www.ampstudy.org), have been initiated to evaluate the efficacy of the VRC01 bNAbs in reducing acquisition of HIV-1 infection in high-risk populations . HVTN704/HIV Prevention Trials Network (HPTN)085 will test parenteral administration of VRC01 in 2700 MSM and transgender people in the Americas, and HVTN703/HPTN081 will use the same approach in 1500 heterosexual women at risk for HIV acquisition in Sub-Saharan Africa. The mAb will be infused i.v. at doses of either 10 or 30 mg/kg bimonthly for a total of eight infusions, and participants will be tested for HIV infection through 80 weeks after initiation of mAb treatment. It is hoped that data from this study will provide additional information on safety, tolerability, and efficacy of VRC01 i.v. infusion, as well as antibody concentrations needed for protection against HIV. Furthermore, if this approach demonstrates protection against HIV acquisition, it may be used to protect vulnerable populations going forward. Other potent bNAbs are under study which could result in combination prophylactic regimens using several bNAbs at the same time to inhibit HIV binding via complementary mechanisms of action . One particularly potent bNAb, 3BNC117, has been shown to suppress HIV rebound after treatment interruption in chronically infected patients . Other refinements include the development of bispecific antibodies that could enhance the breadth and potency of protection against diverse HIV strains .
In the near term, the AMP studies will be pivotal for the assessment of the role of systemic bNAb infusions for HIV immunoprophylaxis, and the findings will inform future efficacy trials of this approach using other bNAbs alone or in combination. If VRC01 infusions are found to protect against HIV acquisition, this will facilitate moving quickly forward to study other bNAbs that have favorable characteristics, for example, longer half-lives, and/or the ability to neutralize a broader array of HIV strains . Analyses of viral isolates from individuals in the AMP trials who received either 30 or 10 mg/kg of VRC01 who became HIV infected will help to inform future dosing regimens of VRC01 and other bNAbs, and provide insights into optimal systemic antibody concentrations needed for protection against HIV acquisition. The pharmacokinetics of the dosing regimens used in the AMP studies has been thoroughly delineated in HVTN 104 , so it will be feasible to correlate expected antibody concentrations with HIV protection once the AMP data are available. The findings from the AMP studies can be correlated with earlier work with NHP, and will allow for enhanced appreciation of the extent to which bNAb protection in the nonhuman primate model correlates with anti-HIV protection in humans. HVTN 104 and the AMP studies have included mucosal sampling substudies, which will be informative for the determination of bNAb levels necessary for mucosal protection , which should facilitate the development of mucosal antibody approaches, including preventive HIV vaccines, vectored immunoprophylaxis, and topical mAb administration.
Topical monoclonal antibody administration
Topical administration of mAbs directly to sites of mucosal HIV transmission in the genital tract or rectum is another promising approach for HIV prevention. Topical mAb-based microbicides potentially offer several advantages including: use of synergistic mAb combinations, ease of application, delivery of concentrated product directly to site where needed, reversibility, few if any side-effects, and cost effectiveness.
Preclinical studies in animal models
Several studies have demonstrated that topical administration of anti-HIV mAbs can protect macaques from SHIV mucosal challenge (Table 3[17–19,47–50]). mAbs have been administered vaginally [18,19,48,50] or rectally [17,49], followed by high dose or repeated low-dose SHIV challenges to the site shortly after mAb delivery. The half-life of mAbs in mucosal secretions after topical delivery of 5–20 mg mAb was about 4 h; animals were protected to varying degrees against the SHIV challenges, and no side-effects were noted. Efficacy of topically administered mAbs has also been demonstrated in the humanized mouse model .
mAb-based vaginal microbicides have been evaluated for safety in at least three phase 1 clinical trials. A vaginal microbicide containing a combination of 4E10, 2F5, and 2G12 (MABGEL), developed by the European Microbicides Programme, was recently tested for safety and pharmacokinetics . The mAbs were produced in Chinese hamster ovary (CHO) cells as human immunoglobulin G 1 (IgG), were formulated at 20 mg/ml (high dose) or 10 mg/ml (low dose) in gel, and 2.5 ml of gel was administered vaginally to women daily for 12 days. None of the women reported serious adverse events, and effective concentrations of mAbs could be observed in cervicovaginal secretions up to 8 h posttreatment. Furthermore, there was no evidence of systemic absorption of the mAbs. Another European consortium, recently, conducted a first-in-human, double-blind, placebo-controlled phase 1 clinical trial with a plant-derived human HIV bNAb, 2G12, documenting the safety of a single vaginal administration of this mAb . Our team of US scientists is developing mAb-based vaginal microbicides using a transient expression system in Nicotiana (tobacco plants) . A prototype vaginal microbicide, called MB66, containing the HIV bNAb VRC01 and a mAb specific for the herpes simplex virus (HSV) type 2, called HSV-8 , has been formulated into gels and films and tested for efficacy and stability in vitro and in vivo. MB66 film is currently undergoing evaluation in a phase 1 clinical trial. Segment A of the study, a single dose of MB66 film in eight women, was recently completed with no serious adverse events; Segment B, seven daily vaginal doses of MB66 or placebo film in 15 women/group, is currently underway. The next generation MB66 microbicide may contain additional mAbs, such as more potent bNAbs and mAbs that block cell-associated HIV transmission, to improve efficacy. In addition, mAbs that agglutinate sperm may be added to provide contraceptive protection . A prototype MB66 vaginal ring has been developed and tested in macaques . Sustained release of mAbs from a vaginal ring could improve user compliance, overcoming the significant disadvantage of poor adherence to study protocols that has plagued other vaginal microbicide trials .
Production and engineering of anti-HIV monoclonal antibodies
Engineering monoclonal antibodies for enhanced performance in the mucosal environment
Recent research indicates that passive immunization with anti-HIV mAbs may be a viable approach for HIV prevention and therapy. Nontraditional antibodies such as secretory immunoglobulin A (s-IgA), and mAbs engineered with Fab or Fc modifications to improve function may be significantly more efficacious and cost-effective, further enhancing the feasibility of this approach in the future.
Engineering mAb isotype
Most mAbs are manufactured as IgG1, which is the most abundant immunoglobulin subclass in blood . However, polymeric s-IgA is the predominant immunoglobulin type in most mucosal secretions , and has structural characteristics that enhance its presence, stability and function at mucosal sites .
It is possible to manufacture IgA, dimeric IgA and s-IgA mAbs, but this is currently an industrialization challenge . However, several studies provide evidence that IgA mAbs may provide superior protection in the mucosal environment, indicating that it may be worthwhile to produce IgA mAbs for passive mucosal protection.
- Dimeric and secretory forms of IgA have double the number of available antigen-binding sites as IgG, and multiple antigen-binding sites are crucial for the formation of viral aggregates . Furthermore, the flexibility of diametrically opposed F(ab’) portions of dIgA with a higher extension span overcomes steric hindrance when accessing vulnerable epitopes on the viral envelope .
- IgA1 subclass antibodies have a more flexible hinge region and a broader reach than IgG and IgA2 subclass antibodies (16.3 vs. 10.2 nm). In a recent study, the dIgA1 form of HCGN194 captured approximately twice as many virions as dIgA2 in a virion capture assay, and inhibited the transcytosis of cell-free SHIV across an epithelial monolayer in vitro, whereas IgA2 and IgG mAbs did not .
- s-IgA is particularly suited to function in the mucosal environment because of resistance to protease digestion and its ability to anchor onto the apical side of epithelial tissues by interacting with mucins [49,65].
- Association of the polymeric immune globulin receptor with HIV-bound IgA mAbs mediates HIV virion excretion from polarized epithelial cells suggesting a possible mechanism of viral efflux and subsequent reduction in viral load from mucosal epithelia .
- Evidence for superior protection by IgA anti-HIV antibodies has been recently reported: a neutralizing monoclonal dIgA1 provided better protection than IgG in a SHIV rectal challenge study , in-vitro studies showed intracellular abrogation of HIV replication/transcytosis by HIV-specific IgA mAbs , and vaginal transmission of HIV-1 in humanized mice was inhibited by polymeric recombinant forms of IgA but not monomeric IgG mAbs .
Despite considerable evidence favoring IgA for mucosal protection, contrary evidence also exists. A recent study that compared the protective effects of a number of neutralizing and nonneutralizing mAbs of IgG vs. IgA2 isotypes in both in-vitro and in-vivo NHP studies did not find an advantage to the use of IgA mAbs for protection against HIV and SHIV infection . Furthermore, the RV144 HIV vaccine trial showed an inverse relationship between the presence of IgA HIV antibodies in serum and protection in vaccine recipients ; in-vitro experiments using serum from vaccinated study participants indicated that HIV Env-specific IgA antibodies competed for Env-binding sites with vaccine-elicited IgG antibodies and diminished their antibody-dependent cellular cytotoxicity (ADCC) antiviral effector function . In light of this evidence, Sholukh et al. administered both IgG and IgA isotype HIV-specific mAbs to NHP to determine if the dIgA2 mAbs compete with IgG mAbs to affect protection in a rectal SHIV challenge experiment; they found that instead of competing, IgG and dIgA2 mAbs worked synergistically to completely protect macaques from rectal SHIV challenge . Clearly, this is an important research area that calls for further investigation.
A variety of approaches for enhancing the function of anti-HIV mAbs have been devised through engineering of the Fab region. Passive immunization has demonstrated a strong correlation between anti-HIV mAb neutralizing potency, a property of the Fab region, and protection against SHIV mucosal challenge in vivo. VRC07–523, a clonal relative of VRC01 engineered to have increased neutralization potency, was five times more effective in a SHIV mucosal challenge study . Antibody valence is another important feature. Additional F(ab’) fragments provide increased possible orientations for maximal ligation and crosslinking of HIV-1 envelope spikes . In addition, bispecific antibodies have been engineered that demonstrate extremely potent and broadly neutralizing activity because of their ability to bind to more than one HIV Env epitope , and chimeric molecules such as one consisting of a PG16 antibody heavy chain and C-C chemokine receptor (CCR)5-like peptide have also been shown to be highly effective at neutralizing HIV .
Engineering of the immunoglobulin Fc region provides another approach to potentially enhance mAb protective functions. There are at least four Fc-mediated antibody activities that are important in regulating HIV infection (Fig. 1). The Fc region can activate complement, leading to the enzymatic destruction of virions or infected cells . ADCC is another principal Fc-mediated protective immune effector mechanism. Classic experiments illustrated killing of HIV antigen coated or infected cells by immune cells that had captured antibodies from immune serum from HIV-infected individuals [74,75], and this ADCC mechanism has been recapitulated in a number of studies using mAbs instead of immune serum [76–78]. Antibody-dependent cellular phagocytosis, another Fc-mediated antibody function, similar to ADCC but involving phagocytosis of infected cells and immune complexes, has also been demonstrated for HIV antigen-coated beads in vitro, and is associated with improved clinical outcomes in chronically infected HIV patients . Antibody-dependent cell-mediated viral inhibition is an Fc receptor-mediated effector function that mediates viral reduction not only through cytotoxicity but also by inhibition with antiviral factors such as cytokines .
Passive immunization studies have implicated the Fc region in protection against HIV/SHIV challenge in vivo. Fab fragments of the 2F5 anti-HIV mAb were not protective against vaginal SHIV challenge, whereas whole mAbs (with Fc region) were protective . Furthermore, b12 mAbs with diminished Fc function because of the LALA mutation were less protective than unmodified mAbs [24,25]. On the other hand, HIV mAbs engineered for enhanced Fc function have been more protective in SHIV mucosal challenge studies [29,33]. Various engineering approaches have been used to modify the Fc region of mAbs for enhanced function:
- There is a direct link between Fc glycosylation patterns and mAb effector function [79,82]. IgG molecules with Fc glycans lacking the core fucose residue display an increased affinity for Fcγ RIIIa and enhanced ADCC [82,83]. Nonfucosylated glycan forms on antibodies from elite controllers were shown to minimize viral load during chronic HIV-1 infection through antibody-dependent cell-mediated viral inhibition , and nonfucosylated HIV bNAbs have been made that demonstrate higher affinity for Fcγ RIIIa receptors and enhanced ADCC activity . Furthermore, Fc glycosylation also affects antibody interactions with mucins; antibodies with shorter glycan profiles preferentially associated with MUC16 and captured more virions . These data suggest that modification of Fc glycosylation could improve antibody function in the mucosal environment. However, one in-vivo SHIV vaginal challenge experiment was conducted comparing nonfucosylated b12 mAb to normally glycosylated b12, and the results were inconclusive .
- Another approach has been to modify the protein structure of the Fc region. GASDALIE is an Fc domain variant that enhances FcRγ binding and function . GASDALIE-modified anti-HIV bNAbs demonstrated enhanced protection against HIV infection in the humanized mouse model .
- The neonatal Fc receptor (FcRn) is another receptor of interest in designing mAbs with enhanced circulation time in blood and improved function at the mucosal surface. This receptor is expressed by mucosal epithelial cells, and is especially abundant in the placenta and newborn intestine, where it directs the polarized uptake of maternal IgG antibodies for fetal immune protection . mAbs engineered with point mutations that alter the binding of IgG to FcRn for greater stability have been shown to have a prolonged half-life in blood [89,90]; this activity could extend to the mucosa as Fc-engineered mAbs with enhanced FcRn function showed enhanced protection against SHIV vaginal challenge in animal studies .
Overview of monoclonal antibody production platforms
Mammalian cell platforms and alternative systems are rapidly being developed and optimized for more efficient mAb production, and promise to deliver clinical grade mAbs at reduced cost in the future (Fig. 2). Evaluation of various technologies and production options is best accomplished early in product development. Ideally, this occurs after product feasibility is established but well before product-related process development is initiated. Cost analysis for production and processing needs to be applicable to the complete platform process from initiation to harvest and downstream processing. The employed analytical methods are applicable to a variety of users and organizations and contain standardized and relevant cost data .
Understanding the cost implications of new technologies that may include continuous processes and modular facilities can be difficult. This evaluation at different production scales adds to the complexity. One example is mAb expression in mammalian cells. The production levels have increased dramatically in the last two decades and now concentrations of 3–5 g/l are not uncommon . During the past 10 years, an industry-wide emphasis on upstream process optimization has resulted in up to 100-fold increases in productivity. Based on current rates of optimization, it would not be surprising to witness further increases in the range of 10–15 g/l. Owing to the success of upstream process optimization, attention has shifted toward new or improved technologies that will augment the productivity of the downstream purification process. In particular, single use systems that have high throughput and minimize expensive chromatography resin turnover are being developed. Examples include continuous, multicolumn fed streams using disposable columns (such as simulated moving-bed chromatography)  as well as novel membrane chromatography technologies . Single use technologies offer the advantages of low capital costs. This can ultimately reduce the initial investment as well as distribute cost expenditures across the entire lifetime of the product . In this scenario, the increased cost burden of consumables results in an enhanced response rate when market demand changes. This flexibility is now increasingly important as drug pipelines transition from traditional mAbs with average demands of 250 kg/year to more heterogeneous product capabilities such as fusion proteins, nanobodies, bispecifics, and other emerging antibody structures, with production rates ranging up to 500 kg/year.
Mammalian cell mAb production systems
The prevalent stably transformed mammalian cell lines for recombinant mAb production are CHO, NS0, Sp2/0, HEK293, and PER.C6 . The majority (∼70%) of mAbs approved for human therapy are produced in CHO, although NS0 and Sp2/0 have also been used for clinical mAb production . The primary importance of mammalian cells compared with microbial or plant production systems lies in the mammalian posttranslational modifications such as glycosylation . Despite an excellent safety and efficacy record, the use of mammalian cells for recombinant mAb expression does have some drawbacks, including a relatively slow growth rate, potential risk of viral contamination, and complex manufacturing process. Furthermore, the current standard production process is expensive, cumbersome, and time consuming .
Alternative mAb production systems
In the interest of cost-savings and potential increased scale of production, numerous transgenic technologies have been explored during the last two decades. These transgenic systems have involved yeast, bacteria, insects, animals, and plants . Challenges for these transgenic platforms include immunogenic glycosylation, a susceptibility to viral pathogen copropagation, developmental instability, complex genetics, environmental containment concerns, and most significantly, prolonged development times. One or more of these deficiencies is associated with every transgenic system, including current mammalian cell-based techniques. In addition, major GMP challenges for large-scale production can also contribute to significantly longer development times and unfavorable economics. For global health indications, the existing mammalian manufacturing platform for antibodies is viable, but emerging platforms like yeast/fungus, plants, and transient mammalian transfection could potentially play a complementary role when cost, scale, and speed are critical factors.
Gaps, challenges, and conclusion
- Recent mAb HIV protection studies have measured antibody levels in female genital tract and rectal tissue to correlate antibody titers with protection. The male genital tract has not been studied but also requires protection from female-to-male HIV transmission. It is unknown whether systemically administered mAbs reach transmission sites in the male genital tract (foreskin and urethra), and whether mAbs can effectively be administered topically to the male genital tract.
- Infectious virus was detected in draining lymph nodes and gastrointestinal tissues from macaques that had been infused with protective levels of bNAbs and then challenged vaginally with SHIV . This indicates that protective mAb titers must be sustained in tissues distal from the site of viral entry. mAb titers have not been monitored at these sites, and implications of this finding for topical mAb-based microbicides are unknown.
- More studies are needed to identify synergistic combinations of bNAbs to maximize efficacy against a wide range of HIV strains and to minimize viral immune escape.
- There is a growing interest in the use of mAbs to block cell-associated HIV transmission . HIV-infected cells are present in genital secretions of HIV-infected men and women, and could play a role in the sexual transmission of HIV . Cell–cell HIV transmission is 10 to more than 1000-fold more efficient than cell-free transmission in vitro, and since cell-cell viral transmission entails transfer of HIV though specialized intercellular synapses, the virions are partially protected from environmental agents including antibodies [104,105]. A number of studies have ranked existing bNAbs for their ability to block cell–cell HIV transmission ; the outcome of these studies has varied depending on the timing and concentration of antibodies and the model systems used. More research is needed with improved mucosal transmission model systems to identify anti-HIV mAbs that effectively block cell-associated HIV transmission for addition to HIV-prevention mAb cocktails. Such antibodies could prevent early events in HIV acquisition such as spreading of virus from HIV-infected cells in genital secretions, and between cells in the genital mucosal epithelium [103,106].
- mAb-based prevention methods may never enter the mainstream because of cost considerations. Existing mammalian cell manufacturing platforms are very costly for clinical grade mAb production. Emerging platforms such as yeast/fungus, plants, and transient mammalian transfection may prove advantageous when cost, scale, and speed are critical factors. Use of potent mAbs engineered for enhanced function and half-life could also reduce costs.
The review is based on information presented at the workshop ‘Systemic and Topical Delivery of Anti-HIV Monoclonal Antibodies to Prevent HIV Transmission’ held on 17 October2016 in conjunction with the HIV Research For Prevention (R4P) Meeting in Chicago, Illinois, USA. All authors contributed substantively to the writing of this article.
Supported by NIH Grant U19 AI096398 (DA).
Conflicts of interest
KJW and LZ own Mapp, a company that intends to commercialize antibody-based products. None of the other authors have conflicts of interest.
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