bNAb research at CROI 2019: vaccine, prevention, treatment and cure…
Simon Collins, HIV i-Base
Over the last few years the potential role for broadly neutralising monoclonal antibodies (bNAbs) has included research looking at their use for prevention (as PrEP and to prevent vertical transmission), for treatment (based on direct antiviral effect) and as part of a strategy for a cure (by sustaining undetectable viral load off ART).
Several studies at CROI focused on bNAbs including an excellent opening plenary lecture by Michel Nussensweig from The Rockefeller University, New York looked at the discovery and development of HIV broadly neutralising antibodies. 
This talk included a history of the rapid developments in this field and the implications for developing an HIV vaccine. Although many of the current antibodies are relatively new compounds, it was known for many years that 5-10% of HIV positive people naturally develop broadly neutralising antibodies – although it is only recently that scientists have been able to isolate them in a laboratory. Also, that developing these responses are an unusual process – commonly taking 2-3 years in those who generate them.
The group at Rockefeller and collaborators looked at finding the B-lymphocytes that are producing bNAbs and developed new methods of antibody cloning. Together with other groups they discovered that the range of antibody responses was wider than previously realised and that there were also multiple possible binding sites on the HIV envelope protein (in addition to CD4 binding site). They also realised that HIV bNAbs are highly mutated as a result of multiple repeated interactions between the antibody system and the virus over time – and that a successful HIV vaccine might therefore need to mirror this multiple stage process which has now been achieved in a mouse model. Although this shows proof of concept in a simple constructed immune system this is very different to transfer to the complexity of the human immune system.
Also, although bNAbs are often very expensive (>$100,000), their effectiveness in cancer is highly relevant for HIV: they produce both direct targeting of the disease and the engagement of the immune system, where host immunity then eradicates the cancer.
3BNC117 and 10-1074
Two bNAbs are currently in more advanced development at Rockefeller University: 3BNC117 which targets the CD4 binding site and 10-1074 which targets the base of the V3 loop of the HIV envelope protein. Clinical experience includes results in more than 200 individuals without a signal of serious safety concerns.
The group are focusing on potential for multiple use – including passive protection; a type of PrEP, PEP, as an alternative antiviral treatment to ART in chronic infection and for HIV eradication.
In a macaque study that treated animals with bNAbs three days after infection, the researchers observed a a sustained period of undetectable HIV viral load and that rebounding viraemia as antibody levels faded after 50-100 days was lower than seen with seroconversion. Then, unusually, approximately half the animals (6/13) saw viraemia reduced to undetectable levels again without further bNAb exposure. 4/13 behaved like elite controllers and 3/13 behaved like control animals. 
Treating the 6/13 animals with anti CD8 antibodies made them all became viraemic – thought to be similar to a cancer-like response where the antibodies and virus produce complexes that immunised the patient, this showed that the viral control appeared to be mediated by CD8 cells.
The potential for bNAb compounds are graded based on breadth and potency but the half-lives of these compounds is also critical, as this determines how frequently the treatments need to be given, and can be extended by modifying the structure of the antibodies (for example by adapting to use the LS mutation).
In human studies, a single injection of either 3BNC117 or 10-1074, individually reduced mean viral load by about 1.5 log copies/mL (range: 0.8 to 2.5) that returned to baseline levels after four weeks, but with selected resistance. However, because each of these compounds uses a different binding site, viruses will not be cross-resistant.
In a phase 1b study combining both antibodies together in nine patients with HIV reservoirs sensitive to both 3BNC117 and 10-1074, extended the time for viral load rebound after stopping ART to approximately 15 weeks after the last treatment. This study involved giving the combined antibody three times and produced three different patterns of response.
In 4/9 participants, viral load rebounded with resistance to the antibody with the longer half-life (10-1074), once plasma concentrations of 3BNC117 fell below 10 ug/mL, leaving effect monotherapy. In 3/9 participants, viral load only rebounded after both antibodies had dropped to below detection. Finally, 2/9 participants remained undetectable for much longer: one rebounded after a year and the other is still virally suppressed. 
Both of these participants were treated within six months of infection, and they have generated strong immune response to nearly every antigen tested both in CD4 and CD8 responses.
Ongoing studies are now using long acting LS versions of these antibodies that, for example for 10-1074-LS, maintain levels above therapeutic cut-off of 10 ug/mL for more than three months using 1 mL subcutaneous dose and considerably longer (well past one year) using 3 mg/kg IV dose.
A UK study using these compounds is currently being planned.
bNAbs as prevention: penile tissue and IV exposure
In an oral abstract, David Garber from US CDC presented results from using a single subcutaneous injection of 10-1074 alone or in combination with 3BNC117 (10 mg each bNAb/kg) in a macaque study using bNAbs as PrEP. 
Although current PrEP research has focused on drug concentrations in rectal tissue or female genital tissue there are limited data on exposure via other routes. Although efficacy from penile exposure can be extrapolated from other sexual exposure studies (infections were not reported with good adherence). There are however very limited data on risk from shared drug use/injecting.
Both this exposure risks were used in a macaque study where single or dual bNAbs were used to produce passive immunisation against HIV as PrEP.
Macaques were then challenged with SHIV weekly via penile (prepuce pouch), distal urethra or IV routes.
In six animals given only 10-1074 there was a significant delay to infection compared to 10 placebo control animals, requiring a median of 15.5 (range 5 to 19) vs 2.5 (range 1 to 12) penile challenges, p=0.007).
In the dual bNAb study using IV exposure to SHIV, a median of 5 challenges (range 4 to 9) was needed in five active animals vs only a single challenge (range 1 to 1) in the two control animals, p=0.014.
Neither study reported any differences in viral kinetics between active and control groups after SHIV acquisition, when followed for approximately 11 weeks.
PK results reported breakthough infection linked to clearance levels of the antibodies. Protection in the dual bNAb group was driven by the longer half-life of 10-1074.
Early data on new trispecific bNAb
As discussed above, the limited breadth and potency of even the most promising bNAbs means that resistance can quickly develop if used as monotherapy and is also possible in dual bNAb combinations in people who have reduced sensitivity to one compound at baseline.
Preliminary results were shown for a trispecific bNAb in a joint development by the Vaccine Research Centre at NIAID and Sanofi where a single molecule could interact with three independent envelope regions: the CD4 binding site, MPER and the V1V2 glycan site. 
The combination compounds have some of the highest breadth and potencies compared to the global panel of other bNAbs. For example, this includes greater potency compared to VRC01, 10E8 and 3BNC117 and greater breadth compared to PGT121, 3BNC117 and 10-1074 etc with decreased viral escape compared to single bNAbs.
Antiviral activity of up to 3 log copies/mL was reported from an SHIV macaque study (data slides withdrawn from the webcast), with rebound reported when antibody levels fell below the minimum threshold. Human clinical studies are planned for later in 2019.
PGT121: phase 1 results in HIV positive people
Results from a phase 1 study using the bNAb PGT121 study were reported in detail in the last issue of HTB. 
In treatment-naive participants, a single infusion of PGT121 produced a median viral load reduction of –1.7 log copies/mL in participants with high baseline viral load, but breakthrough with bNAb resistance also occurred quickly when used as monotherapy.
In two people starting with low baseline viral load (<400 copies/mL) a single infusion dropped viral load to undetectable where it remained, without ART, for at least the next six months. 
VRC01 as PrEP in adults and PEP in neonates
A preconference workshop talk on was also given by Rosemarie Mason from NIAID on targeted isolation of monoclonal antibodies, including a review on the ongoing international phase 2b VRC01 antibody-mediated prevention (AMP) studies. These are double-blind placebo-controlled studies (with some allowance to use oral PrEP) that are due to have first results later this year. 
Elizabeth McFarland from University of Colerado and colleagues presented results from an open-label pharmacokinetic and safety study using the long-acting VRC01-LS sub-cutaneous formulation in 21 HIV-exposed newborns. 
Importantly, in this study with sites in the US, Zimbabwe and South Africa, both mothers and babies used ART to minimise risk of transmission.
Pharmacokinetic results showed protection bNAbs levels that were sufficient to cover breastfeeding period with no serious safety concenrs. There have been no HIV transmissions.
Research into bNAb includes the expectation that better, more potent compounds will be discovered over time, and that these will have broader coverage. These will in turn increase better bNAb combinations.
As cancer treatment, bNAbs are very expensive (commonly more than £100,000 a course for some indications), though they are significantly cheaper for more common uses (~£5000 for Crohns disease).
Although these compounds are usually high-cost medicines, this depends or both dose and number of people likely to use it, with little transparency for the process that companies use to set a drug price. Ultimately, drug price is an artifact of the political pressure to make treatment accessible.
The risk of developing resistance to bNAb monotherapy – is once levels of one bNAs fall below 10 ug/mL in the presence of significant viraemia – is an important safety concern that should be considered for future studies. Hopefully this risk will be overcome with second-generation long-acting formulations.
Some of the potential limitations for VRC01 monotherapy highlighted in the talk by Michel Nussenweig were known before enrolment of the AMP studies, so results from these PrEP trials are highly awaited.
Unless stated otherwise, all references are to the programme and abstracts of the Conference on Retroviruses and Opportunistic Infections (CROI), 4-7 March 2019, Seattle.
- Nussensweig M et al. Discovery and development of HIV broadly neutralizing antibodies. Opening session. Conference on Retroviruses and Opportunistic Infections (CROI), 4-7 March 2019, Seattle. Oral abstract 10.
- Nishimura Y et al. Early antibody therapy can induce long lasting immunity to SHIV. Nature 2017; 543(7646): 559–563. doi: 10.1038/nature21435
- Mendoza et al. Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature (561):479–484 (2018).
- Garber DA et al. Protection against penile or intravenous SHIV challenges by bNAb 10-1074 or 3BNC117. Conference on Retroviruses and Opportunistic Infections (CROI), 4-7 March 2019, Seattle. Oral abstract 100.
- Pegu A et al. Potent antiviral activity of trispecific broadly neutralizing HIV antibodies. Conference on Retroviruses and Opportunistic Infections (CROI), 4-7 March 2019, Seattle. Late breaker oral abstract 28 LB.
- Collins S. First phase 1 results from bNAb PGT121 in HIV positive people. HTB, 28 March 2019.
- Stephenson KE et al. Therapeutic activity of PGT121 monoclonal antibody in HIV-infected adults. Conference on Retroviruses and Opportunistic Infections (CROI), 4-7 March 2019, Seattle. Oral abstract 145.
- Mason RD. More colorful immunology: targeted isolation of monoclonal antibodies. CROI 2019 pre conference workshop. Abstract 5.
- McFarland E et al. Safety and pharmacokinetics of monoclonal antibody, VRC01LS, in HIV-exposed newborns. CROI 2019. Oral abstract 44.