Novel HIV-1 envelope proteins to induce neutralizing antibodies

Transcription

1 Novel HIV-1 envelope proteins to induce neutralizing antibodies Rogier Sanders Academic Medical Center, University of Amsterdam, Netherlands Weill Medical College of Cornell University, New York, U.S.A. Satellite session Future Perfect: Opportunities and Obstacles for HIV Vaccines 9th IAS Conference on HIV Science, Paris, France July 23 rd, 2017

2 Neutralizing antibodies protect from HIV acquisition Vaginal challenge experiments with SHIV in macaques Neutralizing Non-neutralizing in vitro neurtralization IC 50 (µg/ml) 10 2G12 2G12 VRC E8 VRC01 3BNC117 b12 3BNC PG9 PGT VRC01 PGT Spearman r = PGT121 p = in vivo protection IC 50 (µg/ml) Burton et al PNAS 108: Van Gils & Sanders Trends Microbiol. 22: > A goal for HIV: induce neutralizing antibodies (NAbs)

3 HIV is extremely variable Weiss RA Nat. Med. 9: > Goal for HIV: induce broadly neutralizing antibodies (bnabs)

4 The target for broadly neutralizing antibodies: The envelope trimer (Env) Only relevant target for broadly neutralizing antibodies (bnabs) Highly variable (~30% between different subtypes) Synthesized as a gp160 precursor protein, cleaved into gp120 and gp41 Three gp120s plus three gp41s form a trimer of heterodimers by non-covalent interactions Interactions with CD4 and CCR5/CXCR4 mediate viral entry N-linked glycosylation (sugar) comprises ~50% of mass external domains gp120 gp41 Cleavage gp140 termination ê SP C1 V1 V2 C2 V3 C3 V4 C4 V5 C5 HR1 HR2 TM CT <- gp120 gp41 ->

5 Novel Env immunogens based on 3 hypotheses Observation 1: non-native Env forms (gp120, uncleaved gp140) do not consistently induce neutralizing antibodies against primary (Tier-2) viruses Hypothesis 1: native-like Env trimer immunogens should induce Tier-2 neutralizing antibodies Lead immunogens: BG505 SOSIP.664 and ConM SOSIP.v5.2.8 Observation 2: In HIV-1 infected individuals broadly neutralizing antibodies do not emerge instantly in response to one antigen, but they are a product of co-evolution between the escaping virus and the chasing immune system Hypothesis 2: Immunization with lineage Env immunogens (sequential Env series) from individuals developing broadly neutralizing antibodies might induce similar antibodies Lead immunogens: CH505 gp120 series Observation 3: current Env vaccines generally do not engage the germline precursors of knownbroadly neutralizing antibodies Hypothesis 3: engineered germline-targeting Env immunogens that do engage these germline precursors might prime broadly neutralizing antibody responses Lead immunogens: eod-gt8 60-mer and BG505 SOSIP.v4.1-GT1.1

6 Native-like Env immunogens: BG505 SOSIP.664 Preclinical observations in vitro BG505 SOSIP.664 mimics the native trimer structure BG505 SOSIP.664 binds to most known broadly neutralizing antibodies including ones that require native-like quaternary trimer structure Sanders et al PLoS Path. 9:e Derking et al PLoS Path. 11: e Lee et al Science 351: Preclinical observations in vivo BG505 SOSIP.664 consistently induces neutralizing antibodies against the parental Tier-2 BG505 virus in rabbits and macaques Sanders et al Science 349: aac4223 De Taeye et al Cell : Pauthner et al Immunity 46: e6 Blue: JR-FL gp160 White: BG505 SOSIP PGT128 PGT122 PG9 2G12 PGT135 CH103 1NC9 PGT151 8ANC195 35O22

7 Native-like Env immunogens: BG505 SOSIP.664 Progress on cgmp manufacturing Stable CHO-cell line development at Catalent Pharma Stable CHO-cell clones Research & Master Cell Banks COMPLETED Process & Product Development at KBI Biopharma Upstream Process Development COMPLETED Downstream Process Development COMPLETED (Purification based on 2G12 bnab + SEC) Formulation Development COMPLETED Analytical Test Method (ATM) Development COMPLETED Process lock Confirmation run (50L) COMPLETED Demonstration Run (200L) COMPLETED ATM qualification/verification/validation COMPLETED cgmp Run (200L) BDS Release testing COMPLETED GMP-grade BG505 SOSIP.664 imaged after 1 month at RT DP fill-finish at Ajinomoto Althea, Inc. & Release testing COMPLETED Antu Dey, Al Cupo

8 Native-like Env immunogens: BG505 SOSIP.664 Clinical trial 1: dose-ranging (AS01b; GSK) Clinical trial 2: adjuvant screening (J. McElrath) Immunogen: BG505 SOSIP.664 Vaccinations (months) Goals: Evaluate the safety and immunogenicity of BG505 SOSIP.664 in healthy adults Evaluate whether the BG505 SOSIP.664 trimer can induce Tier-2 neutralizing antibody responses in humans Lead scientists Funders Manufacturer Moore/Sanders NIH (HIVRAD/HVTN) & BMGF (IAVI VxPDC) KBI Biopharma GMP finished Q Clinical trial start Q & Q Clinical sites Ragon Institute & FHCRC

9 Native-like Env immunogens: ConM SOSIP.v5.2.8 ConM: consensus of group M; should have less strain/clade specific antigenic determinants and might help to drive neutralization breadth. Preclinical observations in vitro ConM SOSIP.v5.2.8 mimics the native trimer structure ConM SOSIP.v5.2.8 binds to most known broadly neutralizing antibodies including ones that require native-like quaternary trimer structure Preclinical observations in vivo ConM SOSIP.v5.2.8 induces neutralizing antibodies against the parental ConM and related Tier-2 ConS virus in rabbits and macaques Unpublished results ConM SOSIP & JR-FL gp160 (5FUU.pdb) r.m.s.d. distance: Å neut titers neut titers ConM (Tier 1A) ConS (Tier 2) Trimer Negative neut titers neut titers NP NP Trimer Negative * * NP NP

10 Native-like Env immunogens: ConM SOSIP.v5.2.8 Progress on cgmp manufacturing Stable CHO-cell line development at Polymun (Austria) Stable CHO-K1-cell clones (based on Bacterial Artificial Chromosome (BAC) technology) Single cell cloning & Screening Research COMPLETED Process & Product Development at Polymun Upstream Process Development COMPLETED Downstream Process Development COMPLETED (Purification based on PGT145 bnab) cgmp Run COMPLETED Marker ConM SOSIP -DTT +DTT PNGaseF gp41 SDS PAGE Trimer [95 %] gp140 gp120 gp120 (deglyc.) 670 kd 157 kd 43 kd 12 kd Dietmar Katinger Philipp Mundsperger

11 Native-like Env immunogens: ConM SOSIP.v5.2.8 Clinical trial Immunogen: ConM SOSIP.v5.2.8; adjuvant: MPLA liposomes (Polymun) Vaccinations (months) v Goals: Evaluate the safety and immunogenicity of ConM SOSIP.v5.2.8 in healthy adults Evaluate whether ConM SOSIP.v5.2.8 can induce ConM and ConS neutralizing antibody responses in humans v Lead scientists Sanders/Shattock Funder EU (ERC & EAVI2020) Manufacturer Polymun GMP finished Q Clinical trial start Q12018 Clinical site Imperial College ERC-StG #681137

12 Lineage Env immunogens: CH505 gp120 series CH505 Env and CH103 Ab co-evolution leading to broad neutralization Env: CH505 T/F CH505 wk53 CH505 wk78 CH505 wk100 CH505 wk136 Env-Ab complex UCA CH103 lineage intermediate antibodies CH103 CH103 lineage antibodies CH505 Envs TF wk53 wk78 wk Binding titer (Log AUC) (Williams, Haynes, Verkoczy et al., Submitted) Courtesy of Bart Haynes

13 Lineage Env immunogens: CH505 gp120 series Preclinical observations in vitro Sequential CH505 gp120s show increased binding to CH103 broadly neutralizing antibody lineage variants Williams, Haynes, Verkoczy et al., submitted Preclinical observations in vivo Transmitted/Founder (TF) CH505 gp120 can initiate CH103 lineages in germline CH103 knock in mice Germline CH103 knock-in mice have Light Chain receptor editing that can be overcome by sequential immunizations The absence of gp41 in the construct may avoid immune diversion by microbiome-reactive, gp41 reactive B cells Williams, Verkoczy, Haynes et al., submitted Williams et al Science 349: aab1253 Courtesy of Bart Haynes

14 Lineage Env immunogens: CH505 gp120 series Clinical trial 1 (HVTN115A): dose-ranging with TF Clinical trial 2 (HVTN115B): lineage immunization TF Wk 53 Wk 78 Wk 100 Wk 100 Wk Vaccinations (months) Lead scientist Haynes Funder NIH (CHAVI-ID & DAIDS) Manufacturer KBI Biopharma GMP finished Q Clinical trial start Q4 2017, Q Clinical site Duke Univ. Goals: Evaluate the safety and immunogenicity of CH505 lineage immunogens in healthy adults Evaluate whether the CH505 lineage gp120s can induce CH103-like antibody responses in humans Courtesy of Bart Haynes

15 Germline-targeting immunogens: Hypothesis Not all naive B cells are created equal! Specifically select those germline antibody precursors that have the capacity to mature into broadly neutralizing antibodies non-neutralizing antibody germline antibody precursors Adapted frommedina-ramírez broadly neutralizing antibody

16 Germline-targeting immunogens: eod-gt8 60-mer Preclinical observations in vivo eod-gt8 60-mer primes VRC01-class precursors in germline VRC01 knock-in mice eod-gt8 can isolate VRC01-class precursors from human naïve B cells, frequency of 1 in 2.4 million. eod-gt8 60-mer primes VRC01-class precursors in Kymab Ig-locus transgenic mice that have only ~1 VRC01-class precursor per mouse. VRC01-class precursors primed by eod-gt8 60-mer can be boosted to produce antibodies with properties of partially mature VRC01-class broadly neutralizing antibodies Jardine et al Science 349:156-61; Dosenovic et al Cell 161: ; Jardine et al Science 351: ; Sok et al Science 353: ; Briney et al Cell 166(6): ; Tian et al Cell 166: VRC01-class Abs use: VH1-2 and 5AA L-CDR3 Germline-Targeting eod-gt8 60-mer Courtesy of Bill Schief

17 Germline-targeting immunogens: eod-gt8 60-mer Clinical trial Germline-targeting prime eod-gt8 60-mer 0 2 Vaccinations (months) Lead scientist Funder Manufacturer Schief GMP finished Q Clinical trial start Clinical site BMGF (IAVI NAC & VxPDC) Paragon Bioservices Q12018 G.W. Univ. & FHCRC Goals: Evaluate the safety and immunogenicity of two doses of eod-gt8 60-mer / AS01b in healthy adults Evaluate whether eod-gt8 60-mer vaccine can activate VRC01-class precursor B cells in humans Evaluate whether eod-gt8 60-mer can select early somatic mutations on the path towards broadly neutralizing antibodies Evaluate whether eod-gt8 60-mer can generate VRC01-class memory B cells that bind to candidate boost immunogens Courtesy of Bill Schief

18 Germline-targeting immunogens: BG505 SOSIP.v4.1-GT1.1 Preclinical observations in vitro BG505 SOSIP.v4.1-GT1.1 (GT1.1) engages multiple broadly neutralizing antibody germline precursors GT1.1 activates B cells expressing germline VRC01 as their BCR Medina-Ramirez et al J.Exp.Med, in press and unpublished results Preclinical observations in vivo GT1.1 induces BG505 neutralizing antibodies in rabbits GT1.1 activates multiple broadly neutralizing antibody germline precursors (prerearranged and unrearranged) in multiple knock-in mouse models Medina-Ramirez et al J.Exp.Med, in press and unpublished results germline VRC01 expressing B cells (stable) BG505 SOSIP.664 BG505 SOSIP.v4.1-GT nm trimer BG505 SOSIP.v4.1-GT1 BG505 SOSIP.664

19 Germline-targeting immunogens: BG505 SOSIP.v4.1-GT1.1 Progress on cgmp manufacturing Stable CHO-cell line development at Weill Medical College of Cornell University Stable CHO-cell pools COMPLETED Serum free adaptation and cell cloning at KBI Biopharma Stable CHO-cell clones Research Cell Bank (RCB) Master Cell Bank (MCB) ONGOING Process & Product Development at KBI Biopharma Upstream & downstream processes similar to ones used for BG505 SOSIP.664 (Purification based on 2G12 bnab + SEC) Antu Dey, Al Cupo

20 Germline-targeting immunogens: BG505 SOSIP.v4.1-GT1.1 Possible clinical trial outline Goals: Evaluate the safety and Germline-targeting prime immunogenicity of GT1.1 / AS01b in BG505 SOSIP.v4.1-GT1.1 healthy adults vs. BG505 SOSIP.664 control?? Evaluate whether the GT1.1 trimer can 0 2 activate VRC01-class and V2-apex 12 class precursor B cells in humans Evaluate whether such B cells can be further matured by boosting with Vaccinations (months) heterologous trimers Lead scientists Sanders/Moore Funders NIH (HIVRAD) & BMGF (IAVI VxPDC) Manufacturer KBI Biopharma GMP finished Q3 2018? Clinical trial start Q4 2018? Clinical sites TBD

21 Germline-targeting immunogens: BG505 SOSIP.v4.1-GT1.1 Possible clinical trial outline Germline-targeting prime BG505 SOSIP.v4.1-GT1.1 vs. BG505 SOSIP.664 control?? Mature trimer boost BG505 SOSIP.664 and/or ConM SOSIP.v Vaccinations (months) Lead scientists Sanders/Moore Funders NIH (HIVRAD) & BMGF (IAVI VxPDC) Manufacturer KBI Biopharma GMP finished Q3 2018? Clinical trial start Q4 2018? Clinical sites TBD

22 Summary/Conclusions 1. Native-like trimers are a promising platform for the induction of HIV-1 neutralizing antibodies 2. Lineage immunogens derived from patients that developed broadly neutralizing antibodies might guide the antibody response towards neutralization breadth 3. Germline-targeting might prime those naive B cells that have the capacity to generate broadly neutralizing antibodies None of these strategies are mutually exclusive. In fact, in the coming years these strategies are likely to converge Germline priming followed by native-like trimer boosting Lineage immunogens based on trimers Germline priming followed by lineage immunogens Etc. There is hope for an HIV-1 vaccine that induces broadly neutralizing antibodies