bNAbs for HIV prevention: extended-release VRC01, AMP study, 10E8 safety signal and pan-clade challenges
13 November 2018. Related: Conference reports, PK and drug interactions, HIV prevention and transmission.
Simon Collins, HIV i-Base
The R4P2018 conference included a wealth of studies looking at broadly neutralising monoclonal antibody (bNAbs) for HIV prevention.
A selection of these studies reported below shows the complexities of this research which is important given large-scale studies are already ongoing.
New data on a long-acting variant of the bNAb VRC01 that requires less frequent infusions was included in several presentations.
This extended release formulation, VRC01-LS, has a two amino acid change that showed more durable protection against repeated SHIV challenges in animal studies.
A talk by Ann Marie Carias from Northwestern University looked to explain the complicated distribution of IV antibodies and the mechanism for the longer half-life of the new molecule.
PK data from VRC01-LS was presented using deconvolution (DV), light sheet microscopy (LSM) and and correlative positron emission tomography (PET) imaging was used to map antibody accumulation of VRC01 and VRC01-LS systemically and in cells and mucosal tissue in rhesus macaques.
Two hours after administration, both VRC01 and VRC01-LS were initially concentrated in the liver, but VRC01-LS accumulation was then more prominent in the transverse colon. At 72 hours, VRC01 is detected in the small intestines while VRC01-LS is largely accumulated in the lungs and large intestines. Importantly, accumulation at one site reduced distribution at other sites.
Carias also reported that antibody distribution varied between different tissue and cellular levels. For example, results at mucosal sites with squamous epithelium (vagina, oral cavity, inner foreskin) were distinct from sites with columnar epithelium (gut, rectum, upper FRT).
VRC01-LS remained longer than VRC01, including in brain tissue, apparently due to endosomal recycling within endothelial cells.
An earlier talk on using VRC01 to protect infants from transmission during breastfeeding also included a PK slide for the VRC01-LS formulation. [2]
Although the babies in these studies are already expected to have very low risk from HIV transmission, the intervention might be important in situations of higher risk, for example, when HIV is diagnosed very late in the pregnancy and before ART reduces viral load.
A second session on using bNAbs, later the same day, included a presentation from Lynn Morris from the National Institute for Communicable Diseases, South Africa, on the ongoing phase 2b efficacy AMP studies using VRC01 to prevent HIV infection. [3]
These two studies – HVTN703/HPTN 085 in gay men and transgender women in North and South America and HVTN704/HPTN 081 in African women – are now fully enrolled.
VRC01 is given as either a high or low dose (30 vs 10 mg/kg) by IV infusion every two months which results in highest antibody levels at the beginning of each dosing period that gradually drop so that protection also becomes more limited by the time of the next dose.
HIV sub-type is also important. Predicted coverage in the high dose groups includes >90% coverage (based on IC80) for both mid-cycle and trough concentrations for subtype B and ~75% for subtype C. In the low dose arm, this coverage remains high for mid-cycle levels but drops to only 82% protection at the trough level for clade B. For sub-type C, mid-cycle protection is only 73% and end-of-cycle trough levels drop to only 58% predicted coverage. See Table 1.
Table 1: Predicted coverage of VRC01 for HIV prevention based on in vitro neutralisation levels
% breadth coverage (IC80) |
||
Clade B | Clade C | |
High dose (30 mg/kg) | ||
Midpoint (30 ug/mL) | 93 | 75 |
Trough (16 ug/mL) | 93 | 73 |
Low dose (10 mg/kg) | ||
Midpoint (16 ug/mL) | 93 | 73 |
Trough (4 ug/mL) | 82 | 58 |
Although using monotherapy with a single bNAb is already expected to lead to breakthrough infections due to limited potency and breadth of coverage, with perhaps important differences based on HIV clade, the AMP study plans to investigate mechanisms of protection and failure.
The presentation also included details about patterns of drug resistance to VRC01 (at positions 456, 459, 270 and others) and the impact on drug sensitivity. This might lead to a genotypic predictive score that might replace the current need for neutralisation sensitivity screening at baseline.
An update on current enrollment in the AMP studies was presented by Sri Edupugantifrom Emory Vaccine Research Center in an excellent satellite session organised by the HIV Prevention Trials NetworkandHIV Vaccine Trials Network. [4, 5]
Also related, the following day, Jeffrey Schneider from Northwestern University, gave a talk showing that the VRC01 takes approximately a week to achieve steady-state in vaginal tissue in animal models, with gradual trafficking from plasma to tissue. [6]
Distribution to rectal tissue appears to be take a similar time for steady state levels, but delivered by cellular rather than vascular mechanism. Clarified tissue from 27 organs showed differential distribution through different transport mechanisms, again showed in impressive 3D imaging.
Several pipeline combinations of dual and triple antibodies are already being studied including VRC07 + PGDM1400 + PGT 121 in HVTN130/HPTN 089. A tri-specific engineered molecule with three specificities on one antibody (VRC01/PGDM1400/10E8) is also being studied in HVTN129/HPTN 088.
The difficulties of pan-clade activity even with combination antibodies is an important limitation to their efficacy for prevention on both an individual and population level.
Bette Korber from the Los Alamos National Laboratory reviewed the challenges of combining antibodies for global HIV prevention emphasising the differences by clade in the same HVTN and HPTN satellite session and related paper. [7] The modelling in a related paper suggests that nearly complete neutralisation of a given virus is needed for in vivo protection (~98% neutralisation for 50% relative protection) and that the inclusion of 10E8 is likely important to provide cross-clade protection in African studies. [8]
Korber outlined the importance of avoiding virtual monotherapy and that pan-clade coverage requires two, three or four bNAbs to ensure two or more active molecules. The talk emphasised that global studies needed to select antibody combination based on clade prevalence in the countries where the research is being conducted, with a comment that while AMP studies will provide important results, the clinical benefits are likely to be less than optimal.
However, while the safety and tolerability of bNAbs are generally good, grade 3 skin erythema was reported to 10E8 study in 7/8 participants in an early study. Reactions occurred two days after receiving dual 10E8LS and VRC07 infusion (separately to each side of the stomach). These were associated with mild tenderness and fever (both transient) and confirmed by biopsy as panniculitis with lymphocytic inflammation (all cases resolved). This has been sufficient to put further clinical development of 10E8 on hold, although the implications for the triple and trispecific studies were not provided. [9]
comment
Although the longer half-life of VRC01-LS improves dosing, it is unclear whether it would overcome the vulnerability from use as single antibody monotherapy by sustaining higher drug levels – though this seems unlikely.
From an advocacy perspective, these presentations suggests the importance of encouraging study participants in the ongoing phase 2b Antibody Mediated Protection (AMP) HIV prevention studies to accept opportunity to also use oral PrEP, at least in countries where this is available. The data on time to steady-state is also important for these participants.
Results from the pivotal proof of concept AMP studies are expected within two years.
Reference
- Carias AM et al. Imaging the distribution of I.V.-injected VRC01 and VRC01-LS in the in vivo rhesus macaque model. R4P2018, 21-25 October 2018. Oral abstract OA08.06.
https://www.professionalabstracts.com/hivr4p2018/iplanner/#/presentation/326 (abstract)
http://webcasts.hivr4p.org/console/player/40357 (webcast) - Cunningham C et al. Safety and pharmacokinetics of multiple doses of a potent anti-HIV monoclonal antibody VRC01 in HIV-exposed newborns. R4P2018, 21-25 October 2018. Oral abstract OA08.05.
https://www.professionalabstracts.com/hivr4p2018/iplanner/#/presentation/256 (abstract)
http://webcasts.hivr4p.org/console/player/40356 (webcast) - Morris L et al. Antibody mediated protection (AMP): where are we? which antibodies to use and how will we know if it´s working? R4P2018, 21-25 October 2018. Oral abstract SY01.02.
https://www.professionalabstracts.com/hivr4p2018/iplanner/#/presentation/42 (abstract)
http://webcasts.hivr4p.org/console/player/40359 (webcast) - Edupuganti S et al. Where are we in AMP Trial? R4P2018, 21-25 October 2018. Satellite session.
http://webcasts.hivr4p.org/console/player/40528 (webcast) - HIV Vaccine Trials Network and HIV Prevention Trials Network. State of the art of HIV bNAbs for prevention of HIV infection. R4P2018, 21-25 October 2018. Satellite session SA04.
http://www.professionalabstracts.com/hivr4p2018/iPlanner/#/grid (abstract) - Schneider J et al. Tracking Cy5-conjugated VRC01 following IV injection in the rhesus macaque reveals that tissue distribution can take 1 week to achieve steady state. R4P2018, 21-25 October 2018. Oral abstract O9.05.
https://www.professionalabstracts.com/hivr4p2018/iplanner/#/presentation/325 (abstract)
http://webcasts.hivr4p.org/console/player/40383 (webcast) - Korber B et al. Modelling coverage with combination monoclonals: the 2 vs. 3 issue. HVTN and HPTN satellite session. 21 October, 4.00 pm.
http://webcasts.hivr4p.org/console/player/40530 (webcast) - Wagh K et al. Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections. PLoS Pathogens (2018). DOI: 10.1371/journal.ppat.1006860.
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006860 - Koup R. Review of bNAbs in clinical development. R4P2018, 21-25 October 2018. HVTN and HPTN satellite session. 21 October, 4.00 pm.
http://webcasts.hivr4p.org/console/player/40515 (webcast)