Tandem bispecific broadly neutralizing antibody — a novel approach to HIV-1 treatment

The last decade has led to a significant advance in our knowledge of HIV-1 latency and immunity. However, we are still not close to finding a cure for HIV-1. Although combination antiretroviral therapy (cART) has led to increased survival, almost close to that of the general population, it is still not curative. In the current issue of the JCI, Wu et al. studied the prophylactic and therapeutic potential of an engineered tandem bispecific broadly neutralizing antibody (bs-bnAb), BiIA-SG. This bnAb’s breadth and potency were highly effective in protection and treatment settings, as measured by complete viremia control following direct infusion, as well as elimination of infected cells and delay in viral rebound when delivered with a recombinant vector. These observations underscore the need for the clinical development of BiIA-SG for the prevention of HIV-1.

Human immunodeficiency virus 1 (HIV-1) is a major global health issue. Each year there are 40,000 new cases of HIV infection among Americans and as many as 2 million new cases worldwide. Strategies toward finding a cure for HIV-1 are hampered by the fact that HIV-1 is extraordinarily variable. This diversity poses a major obstacle to the development of an AIDS vaccine. The genetic diversity of HIV-1 isolates can reach up to 20% for envelope polyprotein (Env) sequences (1). Although the influenza vaccine is promoted as a model system for HIV, the diversity of HIV is greater than that seen in influenza (2), and the variability issues in the design of an influenza vaccine are fundamentally distinct from those for an HIV vaccine. Design of an HIV vaccine constitutes a significant hurdle that must be overcome. A vaccine can induce or leverage, respectively, humoral and cellular immune responses capable of recognizing the different circulating HIV subtypes.

Combination antiretroviral therapy (cART) has been very effective in controlling HIV-1 replication and suppression of HIV-1 to undetectable levels in the peripheral blood of patients for long periods of time. However, the infectious virus still persists in reservoirs and results in the replication competence of integrated HIV-1 genomes in small subsets of latently infected memory CD4⁺ T cell populations, called viral sanctuaries. This leads to a viral rebound within a few weeks of cessation of cART. Targeting the reservoirs has not been successful. Curative strategies targeted toward the activation of dormant virus that would lead to its destruction via host immune or viral cytopathic effects have had limited success.

It has recently been demonstrated that virus diversity in infected individuals arises because of the pressure exerted by the immune system and the ability of HIV-1 to mutate, leading in turn to the ability of the immune response to develop broadly neutralizing antibodies (bnAbs) (3–5). It is now well known that bnAbs target the glycosylated structure of the HIV-1 envelope present on the viral membrane, referred to as the closed trimeric structure of the gp120/gp41 complex. This closed state is the most infectious among the different conformational states of the envelope present on HIV-1 virions (6, 7). Similar structures can also be exposed on the membrane of the infected cells at the time of virus budding (8).

Over the years, several studies have exploited the ability of bnAbs to confer protection from infection, to control virus replication, and to reduce the size of the latently infected cells’ reservoir (review in ref. 9). The original passive protection studies in animal models indicated that monoclonal Ab (mAb) combinations are usually more effective in preventing simian human immunodeficiency virus (SHIV) infection in nonhuman primates (10–13). More recently, bnAb combinations have also been tested for their potential activity in reducing viremia, viral rebound in animal models, and in exploratory clinical trials. In the humanized mouse model, a combination of the CD4 binding site 3BNC117 (14), V3 glycan 10-1074 (15), and V1V2 glycan PG16 (16) bnAbs induced decreased viremia in approximately 50% of the mice, and substantially delayed virus rebound compared with animals treated with cART (17). Moreover, a decline in the level of cellular-associated DNA occurred only in the aviremic mice treated with the 3-mAb cocktail. Therefore, bnAbs can significantly impact both plasma viremia and the pool of latently infected cells through recognition of HIV-1 Env on the host cell membrane (17). Similar observations have been reported in the nonhuman primate model in which bnAbs successfully reduced the level of plasma viremia during chronic (18–20) and acute (21) SHIV infection. Additionally, bnAb combinations have been shown to reduce the size of the pool of latently infected cells (19, 21).

The efficacy of individual bnAb infusions was recently tested in human trials and appeared to have a beneficial effect on the control of plasma viremia (22). However, in 2 different regimens, resistant virus isolates were either observed before treatment and hampered the therapeutic effect of the bnAb (23), or appeared following infusion of the bnAbs during analytical treatment interruption (24). Taken together, these studies have thus far indicated that development of mAb-based molecules with several epitope specificities is a desirable goal to circumvent HIV-1 envelope sequence diversity and propensity to escape.

Wu and collaborators (25) decided to take a different approach to circumvent the diversity of HIV-1 envelopes. They based their molecule on 1 single gene–encoded tandem bs-bnAb, namely BiIA-SG, where 2 single-chain variable fragment (scFv) binding domains against the V3 glycan epitope recognized by the PGT128 mAb and the CD4 receptor recognized by the Hu5A8 mAb are simultaneously present (Figure 1). This represents a radically different approach compared with a predecessor of this molecule reported by Huang and collaborators (26) that included a single scFv for each anti–HIV-1 envelope broadly neutralizing monoclonal antibody (bnmAb) against the CD4 receptor. The aspects related to the new class of molecules discussed herein do not include obvious considerations on the pharmacokinetic, tissue distribution, and ability to induce anti–drug antibody responses, since these will have to be addressed in further dedicated studies.

Figure 1

Schematic diagram showing binding of the BiIA-SG antibody. (A) Engineered tandem bispecific bnAb BiIA-SG antibody with scFv domain(s) for binding to HIV-1 gp160 trimer (green VH/VL chain of PGT128) and to soluble CD4 (orange VH/VL chain of Hu5A8) via 20-mer linkers. Two possible interactions are predicted for the molecule: intraspike cross-linking (B) and interspike cross-linking (C). scFv, single-chain variable fragment; VH, heavy-chain variable region; VL, light-chain variable region.

As reported by Wu et al. (25), the neutralizing breadth and potency of the new BiIA-SG molecule are definitely higher than those of the original neutralizing PGT128 mAb, or the BiIA-DG with a single scFv domain. The authors suggest that the improved activity of the BiIA-SG may be due to the ability of the anti-CD4 arm to bring the PGT121 arm in proximity to the HIV-1 Env. In addition, this effect may also be due to the presence of 2 binding sites that favor the binding of the molecule to the targeted antigens. In developing a new class of therapeutics, this aspect could be relevant to improve the performance of bispecific molecules such as those based on the potent class of membrane proximal epitope region–specific (MPER-specific) mAbs that do need a simultaneous bivalent binding to the membrane lipid layer and to the HIV-1 envelope (27). It is interesting that a similar molecule was originally designed and characterized to include the MPER 10e8 specificity and was also developed into a trispecific molecule (28). Ultimately, it will be interesting to observe if this newly engineered molecule can address the need for the simultaneous recognition of 2 different regions of the HIV-1 envelope to broaden the breadth and prevent escape. These new molecules could represent the benchmark for comparison with the recently reported trispecific mAb-based molecules that are also aimed at increasing breadth and potency of anti–HIV-1 activity (29).

The authors also demonstrate that the BiIA-SG molecule is able to protect from infection and control virus rebound in the humanized mouse model for HIV-1 infection. Of note, the molecule, delivered as an adeno-associated virus construct, led to a reduction of P24⁺ T cells in the blood and spleen.

Additional information about the activity of BiIA-SG against the so-called sanctuary for HIV-1 in the latent reservoir will have to be obtained before designing studies to prevent the appearance of escape mutants and to reduce the virus reservoir in tissues such as lymph nodes, the GI tract, and the central nervous system. If the mechanism of action of the BiIA-SG is related to its broadly neutralizing function, it still remains to be determined how this molecule will perform against the circulating HIV-1 isolates, taking into account HIV-1 diversity and the dichotomy already observed between in vitro breadth of individual bnAbs and the presence of escape mutants (23, 24).

In addition to the neutralization activity, bnAbs can significantly impact both plasma viremia and the pool of latently infected cells through recognition of the HIV-1 Env on the host cell membrane (17) and engagement of Fcγ-R–bearing cells (30). Therefore, the possibility of further enhancing the activity of this promising class of immunotherapeutics needs to be explored by designing bnAbs that can engage Fcγ-R–bearing cells and facilitate the killing of latently infected cells.

This manuscript was supported by the Center For AIDS Research, Immunology Core, Duke University Medical Center (AI064518).

Address correspondence to: Guido Ferrari, Duke University Medical Center, 915 La Salle Street, SORF Building, Room 208, Durham, North Carolina 27710, USA. Phone: 919.684.2862; Email: gflmp@dm.duke.edu.

Conflict of interest: The author has declared that no conflict of interest exists.

Reference information: J Clin Invest. 2018;128(6):2189–2191. https://doi.org/10.1172/JCI121078.

See the related article at Tandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized mice.

1. Gaschen B, et al. Diversity considerations in HIV-1 vaccine selection. Science. 2002;296(5577):2354–2360.
   View this article via: PubMed CrossRef Google Scholar
2. Korber B, Gaschen B, Yusim K, Thakallapally R, Kesmir C, Detours V. Evolutionary and immunological implications of contemporary HIV-1 variation. Br Med Bull. 2001;58:19–42.
   View this article via: PubMed CrossRef Google Scholar
3. Liao HX, et al. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature. 2013;496(7446):469–476.
   View this article via: PubMed CrossRef Google Scholar
4. Gao F, et al. Cooperation of B cell lineages in induction of HIV-1-broadly neutralizing antibodies. Cell. 2014;158(3):481–491.
   View this article via: PubMed CrossRef Google Scholar
5. Moody MA, et al. Strain-specific V3 and CD4 binding site autologous HIV-1 neutralizing antibodies select neutralization-resistant viruses. Cell Host Microbe. 2015;18(3):354–362.
   View this article via: PubMed CrossRef Google Scholar
6. Poignard P, et al. Heterogeneity of envelope molecules expressed on primary human immunodeficiency virus type 1 particles as probed by the binding of neutralizing and nonneutralizing antibodies. J Virol. 2003;77(1):353–365.
   View this article via: PubMed CrossRef Google Scholar
7. Moore PL, et al. Nature of nonfunctional envelope proteins on the surface of human immunodeficiency virus type 1. J Virol. 2006;80(5):2515–2528.
   View this article via: PubMed CrossRef Google Scholar
8. Pollara J, Bonsignori M, Moody MA, Pazgier M, Haynes BF, Ferrari G. Epitope specificity of human immunodeficiency virus-1 antibody dependent cellular cytotoxicity [ADCC] responses. Curr HIV Res. 2013;11(5):378–387.
   View this article via: PubMed CrossRef Google Scholar
9. Margolis DM, Koup RA, Ferrari G. HIV antibodies for treatment of HIV infection. Immunol Rev. 2017;275(1):313–323.
   View this article via: PubMed CrossRef Google Scholar
10. Mascola JR, et al. Potent and synergistic neutralization of human immunodeficiency virus (HIV) type 1 primary isolates by hyperimmune anti-HIV immunoglobulin combined with monoclonal antibodies 2F5 and 2G12. J Virol. 1997;71(10):7198–7206.
    View this article via: PubMed Google Scholar
11. Hessell AJ, et al. Broadly neutralizing monoclonal antibodies 2F5 and 4E10 directed against the human immunodeficiency virus type 1 gp41 membrane-proximal external region protect against mucosal challenge by simian-human immunodeficiency virus SHIVBa-L. J Virol. 2010;84(3):1302–1313.
    View this article via: PubMed CrossRef Google Scholar
12. Pegu A, et al. Neutralizing antibodies to HIV-1 envelope protect more effectively in vivo than those to the CD4 receptor. Sci Transl Med. 2014;6(243):243ra88.
    View this article via: PubMed CrossRef Google Scholar
13. Sholukh AM, et al. Defense-in-depth by mucosally administered anti-HIV dimeric IgA2 and systemic IgG1 mAbs: complete protection of rhesus monkeys from mucosal SHIV challenge. Vaccine. 2015;33(17):2086–2095.
    View this article via: PubMed CrossRef Google Scholar
14. Scheid JF, et al. Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science. 2011;333(6049):1633–1637.
    View this article via: PubMed CrossRef Google Scholar
15. Mouquet H, et al. Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies. Proc Natl Acad Sci U S A. 2012;109(47):E3268–E3277.
    View this article via: PubMed CrossRef Google Scholar
16. Walker LM, et al. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science. 2009;326(5950):285–289.
    View this article via: PubMed CrossRef Google Scholar
17. Halper-Stromberg A, et al. Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell. 2014;158(5):989–999.
    View this article via: PubMed CrossRef Google Scholar
18. Shingai M, et al. Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature. 2013;503(7475):277–280.
    View this article via: PubMed CrossRef Google Scholar
19. Barouch DH, et al. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature. 2013;503(7475):224–228.
    View this article via: PubMed CrossRef Google Scholar
20. Shingai M, et al. Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques. J Exp Med. 2014;211(10):2061–2074.
    View this article via: PubMed CrossRef Google Scholar
21. Bolton DL, et al. Human immunodeficiency virus type 1 monoclonal antibodies suppress acute simian-human immunodeficiency virus viremia and limit seeding of cell-associated viral reservoirs. J Virol. 2016;90(3):1321–1332.
    View this article via: PubMed CrossRef Google Scholar
22. Caskey M, et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature. 2015;522(7557):487–491.
    View this article via: PubMed CrossRef Google Scholar
23. Lynch RM, et al. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci Transl Med. 2015;7(319):319ra206.
    View this article via: PubMed CrossRef Google Scholar
24. Scheid JF, et al. HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature. 2016;535(7613):556–560.
    View this article via: PubMed CrossRef Google Scholar
25. Wu X, et al. Tandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized mice. J Clin Invest. 2018;128(6):2239–2251.
    View this article via: JCI CrossRef PubMed Google Scholar
26. Huang Y, et al. Engineered bispecific antibodies with exquisite HIV-1-neutralizing activity. Cell. 2016;165(7):1621–1631.
    View this article via: PubMed CrossRef Google Scholar
27. Alam SM, et al. Role of HIV membrane in neutralization by two broadly neutralizing antibodies. Proc Natl Acad Sci U S A. 2009;106(48):20234–20239.
    View this article via: PubMed CrossRef Google Scholar
28. Steinhardt JJ, et al. Rational design of a trispecific antibody targeting the HIV-1 Env with elevated anti-viral activity. Nat Commun. 2018;9(1):877.
    View this article via: PubMed CrossRef Google Scholar
29. Xu L, et al. Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques. Science. 2017;358(6359):85–90.
    View this article via: PubMed CrossRef Google Scholar
30. Bournazos S, Klein F, Pietzsch J, Seaman MS, Nussenzweig MC, Ravetch JV. Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity. Cell. 2014;158(6):1243–1253.
    View this article via: PubMed CrossRef Google Scholar