Antibody-mediated therapy approaches in HIV-1 infection Florian - - PowerPoint PPT Presentation

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Antibody-mediated therapy approaches in HIV-1 infection Florian - - PowerPoint PPT Presentation

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Antibody-mediated therapy approaches in HIV-1 infection Florian Klein Arevir Meeting 4 th of May 2018 Institute of Virology University of Cologne Cologne Structure and antiviral activity of human antibodies Antigen (e.g. Virus) V H V H V L V L

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SLIDE 1

Antibody-mediated therapy approaches in HIV-1 infection

Florian Klein Institute of Virology University of Cologne Arevir Meeting 4th of May 2018 Cologne

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SLIDE 2

Structure and antiviral activity of human antibodies

VH CL CL CH CH CH CH CH CH COOH COOH

H

VH VL

Fab Fc

VL

Immune cells (effector functions) Antigen (e.g. Virus)

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SLIDE 3

Structure and antiviral activity of human antibodies

VH CL CL CH CH CH CH CH CH COOH COOH

H

VH VL

Fab Fc

VL

Immune cells (effector functions) Antigen (e.g. Virus)

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SLIDE 4

Structure and antiviral activity of human antibodies

V

H

CL CL CH CH CH CH CH CH COOH COOH

H

VH VL

Fab Fc

VL

Immune cells (effector functions) Antigen (e.g. Virus)

  • Target and neutralize broad

sprectrum of antigens

(Victora et al., Annu Rev Immunol. 2012)

  • Effector mechanisms to

clear infection (e.g. ADCC)

(Nimmerjahn et al., Nat Rev. Immunol 2007)

Control of infection

(Burton, Nat. Rev. Immunol., 2002)

Prevention of infection

(Plotkin, Clin. Vaccine Immunol. 2010)

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SLIDE 5

Elite Neutralizer (1%) HIV-1

Isolation of potent broadly HIV-1 neutralizing antibodies

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SLIDE 6

Scheid et al., Science 2011, Walker et al., Science 2009, Wu et al., Science 2010, Corti et al., Plos One 2010, Diskin et al., Science 2011, Walker et al., Nature 2011, Mouquet et al., PNAS 2012, Klein et al., J Exp Med 2012, Huang et al., Nature 2012, Bonsignori et al., J. Virol 2012

Elite Neutralizer (1%) HIV-1

Isolation of potent broadly HIV-1 neutralizing antibodies

bNAb

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SLIDE 7

Neutralization (breadth)

1994 - 2008 Elite Neutralizer (1%) bNAb HIV-1

Isolation of potent broadly HIV-1 neutralizing antibodies

Neutralization (potency) Neutralization (breadth)

2017

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SLIDE 8

Neutralization (breadth)

1994 - 2008

Neutralization (potency) Neutralization (breadth)

2017

Highly potent broadly HIV-1 neutralizing antibodies

V3 loop V1/V2 loop CD4bs MPER Interface

HIV-1 Envelope protein

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SLIDE 9

control

Days post SHIV challenge Days post SHIV challenge

bNAbs Moldt et al., PNAS 2012, Gautam et al., Nature 2016

Antibody-mediated preventtion

Viral load (copies/ml)

Highly potent broadly HIV-1 neutralizing antibodies

V3 loop V1/V2 loop CD4bs MPER Interface

HIV-1 Envelope protein Klein et al., Science, 2013

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SLIDE 10

control

Days post SHIV challenge Days post SHIV challenge

bNAbs

Antibody-mediated preventtion

Viral load (copies/ml)

Highly potent broadly HIV-1 neutralizing antibodies

V3 loop V1/V2 loop CD4bs MPER Interface

HIV-1 Envelope protein

Clinical Trials

(VRC01, phase 2b, ongoing)

  • HVTN 704/HPTN 85 (2700 subjects)
  • HVTN 703/HPTN 081 (1500 subjects)

Klein et al., Science, 2013

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SLIDE 11

HIV-1

Highly potent broadly HIV-1 neutralizing antibodies

V3 loop V1/V2 loop CD4bs MPER Interface

HIV-1 Envelope protein Klein et al., Science, 2013

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SLIDE 12

HIV-1+

Single Antibody

Evaluating bNAbs in HIV-1YU2-infected humanized mice

Single bNAbs

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SLIDE 13

HIV-1+

Single Antibody

Days post starting therapy Viral load (c/ml) gp120 envelope Sequencing at rebound

Evaluating bNAbs in HIV-1YU2-infected humanized mice

0 250 500

276-281 458, 459

45-46G54W HIV-1 escape

Single bNAbs

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SLIDE 14

HIV-1+

Single Antibody

Days post starting therapy Viral load (c/ml) gp120 envelope Sequencing at rebound 276-281 458, 459

45-46G54W HIV-1 escape

Evaluating bNAbs in HIV-1YU2-infected humanized mice

0 250 500

45-46G54W PG16 PGT128 10-1074

Single bNAbs

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SLIDE 15

HIV-1+

Single Antibody

Days post starting therapy Viral load (c/ml) gp120 envelope Sequencing at rebound 276-281 458, 459

45-46G54W HIV-1 escape

Evaluating bNAbs in HIV-1YU2-infected humanized mice

0 250 500

45-46G54W PG16 PGT128 10-1074

Single bNAbs

Monotherapy in hu-mice results in rapid HIV escape

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SLIDE 16

HIV-1+

Single Antibody

Viral load (c/ml) Sequencing at rebound 276-281 458, 459

45-46G54W HIV-1 escape

Evaluating bNAbs in HIV-1YU2-infected humanized mice

Single bNAbs

HIV-1+

3 - 5 Antibodies

Combination

Days post starting therapy gp120 envelope

0 250 500

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SLIDE 17

HIV-1+

Single Antibody

Viral load (c/ml) Sequencing at rebound 276-281 458, 459

45-46G54W HIV-1 escape

Evaluating bNAbs in HIV-1YU2-infected humanized mice

Single bNAbs

Klein et al., Nature 2012; Horwitz et al., PNAS 2013

HIV-1+

Days post starting therapy Viral load (c/ml) gp120 envelope Sequencing at rebound

0 250 500

3 - 5 Antibodies

Penta-Mix Tri-Mix

(45-46GW, PG16, 10-1074, PFT128, 3BNC176) (45-46GW, PG16, 10-1074)

Combination

Days post starting therapy gp120 envelope

0 250 500

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SLIDE 18

HIV-1+

Single Antibody

Viral load (c/ml) Sequencing at rebound 276-281 458, 459

45-46G54W HIV-1 escape

Evaluating bNAbs in HIV-1YU2-infected humanized mice

Single bNAbs

HIV-1+

Days post starting therapy Viral load (c/ml) gp120 envelope Sequencing at rebound

0 250 500

3 - 5 Antibodies

Penta-Mix Tri-Mix

(45-46GW, PG16, 10-1074, PFT128, 3BNC176) (45-46GW, PG16, 10-1074)

Combination

Days post starting therapy gp120 envelope

0 250 500

Antibody combination mediates sustained control

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SLIDE 19

3BNC117

(Scheid et al., Science 2011)

Clinical Investigation of bNAb 3BNC117

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Caskey* and Klein* et al., Nature 2015 HIV-1 uninfected T1/2 – 17,6 days HIV-1-infected T1/2 – 9,6 days

Days post single infusion mAb conc (µg/ml)

Safety, Tolerability, PK

  • 55 subjects enrolled, very well tolerated
  • No (related) SAE, AEs mostly mild (transient

fatigue, headache)

3BNC117

(Scheid et al., Science 2011)

Clinical Investigation of bNAb 3BNC117

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SLIDE 21

Caskey* and Klein* et al., Nature 2015

3BNC117 (CD4bs)

Days post infusion

Drop Viral load 1,48 log (0.8 – 2.5)

3BNC117

(Scheid et al., Science 2011)

Clinical Investigation of bNAb 3BNC117

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SLIDE 22

Caskey* and Klein* et al., Nature 2015; Caskey*, Schoofs*, Gruell*, et al., Nat Med 2017

3BNC117 (CD4bs)

Days post infusion

Drop Viral load 1,48 log (0.8 – 2.5)

10-1074 (V3stem)

Drop Viral load 1,52 log (1.0 – 2.1)

Days post infusion ∆log10 (copies/ml)

Clinical Investigation of bNAb 3BNC117 and 10-1074

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SLIDE 23

Caskey* and Klein* et al., Nature 2015; Caskey*, Schoofs*, Gruell*, et al., Nat Med 2017

10-1074 (V3stem)

Drop Viral load 1,52 log (1.0 – 2.1)

Days post infusion ∆log10 (copies/ml)

Clinical Investigation of bNAb 3BNC117 and 10-1074

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SLIDE 24

Clinical Investigation of bNAb 3BNC117 and 10-1074

Caskey*, Schoofs*, Gruell*, et al., Nat Med 2017

HIV-1 escape variants 10-1074 (V3stem)

Drop Viral load 1,52 log (1.0 – 2.1)

Days post infusion ∆log10 (copies/ml)

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SLIDE 25

Caskey*, Schoofs*, Gruell*, et al., Nat Med 2017

Clinical Investigation of bNAb 3BNC117 and 10-1074

10-1074 (V3stem)

Drop Viral load 1,52 log (1.0 – 2.1)

Days post infusion ∆log10 (copies/ml)

HIV-1 escape variants

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SLIDE 26

Caskey*, Schoofs*, Gruell*, et al., Nat Med 2017

Clinical Investigation of bNAb 3BNC117 and 10-1074

10-1074 (V3stem)

Drop Viral load 1,52 log (1.0 – 2.1)

Days post infusion ∆log10 (copies/ml)

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SLIDE 27

Immunological effects ?

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SLIDE 28

Viral and Immunologic effects after 3BNC117 infusion

3BNC117 Infusion

Sequence (Bulk/SGA) HIV Envelope Autologous Antibody response

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SLIDE 29

All viruses of all subjects

Schoofs*, Klein*, and Braunschweig* et al., Science 2016

Enhancing autologous neutralization by 3BNC117

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SLIDE 30

Vaccinal effect Emerging Antigens

Potential mechanism

Schoofs*, Klein*, and Braunschweig* et al., Science 2016

All viruses of all subjects

Enhancing autologous neutralization by 3BNC117

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SLIDE 31

Immune-mediated control of the HIV-1 viral reservoir

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SLIDE 32

Nishimura et al., Nature 2017, schematic illustration of results by Klein/Kreer

NHP control

Immune-mediated control of the HIV-1 viral reservoir

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SLIDE 33

NHP control ART

Nishimura et al., Nature 2017, schematic illustration of results by Klein/Kreer

Immune-mediated control of the HIV-1 viral reservoir

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SLIDE 34

NHP control ART bNAb

Nishimura et al., Nature 2017, schematic illustration of results by Klein/Kreer

Immune-mediated control of the HIV-1 viral reservoir

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SLIDE 35

NHP control ART bNAb

Nishimura et al., Nature 2017, schematic illustration of results by Klein/Kreer

Immune-mediated control of the HIV-1 viral reservoir

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SLIDE 36

Summary

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SLIDE 37

Summary

  • Discovery of a new generation of highly potent and broadly neutralizing

antibodies (bNAbs) targeting HIV-1.

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SLIDE 38

Summary

  • Discovery of a new generation of highly potent and broadly neutralizing

antibodies (bNAbs) targeting HIV-1.

  • Therapeutic potential of bNabs demonstrated in humanized mice and non-

human primates (combinations are necessary).

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SLIDE 39

Summary

  • Discovery of a new generation of highly potent and broadly neutralizing

antibodies (bNAbs) targeting HIV-1.

  • Therapeutic potential of bNabs demonstrated in humanized mice and non-

human primates (combinations are necessary).

  • CD4bs bNAbs (3BNC117, VRC01) and V3 bNAbs (10-1074) are well

tolerated and dropped viremia by 1.5 log (0.8 – 2.5)

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SLIDE 40

Summary

  • Discovery of a new generation of highly potent and broadly neutralizing

antibodies (bNAbs) targeting HIV-1.

  • Therapeutic potential of bNabs demonstrated in humanized mice and non-

human primates (combinations are necessary).

  • CD4bs bNAbs (3BNC117, VRC01) and V3 bNAbs (10-1074) are well

tolerated and dropped viremia by 1.5 log (0.8 – 2.5)

  • bNAbs differ from conventional ART by PK properties and effects on the

host immune response

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SLIDE 41

Summary

  • Discovery of a new generation of highly potent and broadly neutralizing

antibodies (bNAbs) targeting HIV-1.

  • Therapeutic potential of bNabs demonstrated in humanized mice and non-

human primates (combinations are necessary).

  • CD4bs bNAbs (3BNC117, VRC01) and V3 bNAbs (10-1074) are well

tolerated and dropped viremia by 1.5 log (0.8 – 2.5)

  • bNAbs differ from conventional ART by PK properties and effects on the

host immune response

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SLIDE 42

Combination of bNAb 3BNC117 and 10-1074

10-1074 V3 glycan 3BNC117 CD4bs gp120 gp41

Non-overlapping epitopes

Gristick et al., NSMB 2016

3BNC117/10-1074 combination Individuals (on ART) Individuals (viremic)

MCA906, NCT02825797 (Universität zu Köln, Rockefeller University)

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SLIDE 43

Combination of bNAb 3BNC117 and 10-1074 (ATI)

MCA906, NCT02825797 (Universität zu Köln, Rockefeller University)

ART ATI (Analytical Treatment interruption)

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SLIDE 44

Combination of bNAb 3BNC117 and 10-1074 (ATI)

MCA906, NCT02825797 (Universität zu Köln, Rockefeller University)

ART ATI (Analytical Treatment interruption)

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SLIDE 45

Combination of bNAb 3BNC117 and 10-1074 (ATI)

MCA906, NCT02825797 (Universität zu Köln, Rockefeller University)

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SLIDE 46

Combination of bNAb 3BNC117 and 10-1074 (ATI)

MCA906, NCT02825797 (Universität zu Köln, Rockefeller University)

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SLIDE 47

Combination of bNAb 3BNC117 and 10-1074 (ATI)

MCA906, NCT02825797 (Universität zu Köln, Rockefeller University)

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SLIDE 48

Outlook

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SLIDE 49

Outlook

Novel/modified bNAbs Novel approaches

iMab 10E8 Huang et al., Cell 2016 Sung et al., JCI 2015

Immune modulators Fc modification

Byrareddy et al., Science 2016

Anti-α4β7

Gautam et al., Nature 2016 Gaudinski et al., PLOS Med. 2018

VRC01 PGDM1400 10E8v4 Xu et al., Science 2017

T1/2

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SLIDE 50

Rockefeller University

Michel Nussenzweig Marina Caskey Till Schoofs Malte Braunschweig Sarah Schlesinger Julio Cesar Ari Halper-Stromberg Joshua Horwitz Lilian Noguira Johannes Scheid Hugo Mouquet

University of Cologne ID Soecialists Cologne

  • D. Gillor, S. Scholten, K. Römer

U Penn

Beatrice Hahn, Ted Kreidler

Harvard Med. School

Michael Seaman

Acknowledgement

Gerd Fätkenheuer Clara Lehmann Janne Vehreschild Tim Kümmerle Cristoph Weyn Isabel Suarez Martin Platten Gisela Kremer Ellen Thomas Stefanie Margane Oliver Cornely

Caltech

Pamela Bjorkman, A. West

Celldex Therapeutics

Audrey Louie, Tibor Keller

University Tübingen

  • N. Pfeifer, A. Feldmann, M. Döring

Patients and all study participants

Statistical Physics (UoC)

Michael Lässig

Ecole Normale Supérieure

Aleksandra Walczak

MPI Göttingen

Armita Nourmohammad

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SLIDE 51

Laboratory of Experimental Immunology (Institute of Virology, Cologne)

Henning Gruell, Daniela Weiland, Meryem Ercanoglu, Christoph Kreer, Carola Ruping, Kanika Jain, Silke Arzberger, Philipp Schommers, Stefanie Ehrhardt, Hanna Janicki, Leona Dold, Franziska Bach, Nathalie Lehnen, My-Kim Tran, Maike Schlotz, Matthias Zehner, Carlos Carvajal Fraile, Till Schoofs, Lutz Gieselmann, Kanika Vanshylla, Stefanie Böhm, Julian Potthoff

SFB1279

https://klein-lab.de

Acknowledgement

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SLIDE 52
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SLIDE 53

Sehr hohe HIV Neutralisation Mittlere HIV Neutralisation Niedrige HIV Neutralisation Keine HIV Neutralisation

HIV cohort (Germany, Tanzania, Cameroon)

Philipp Schommers, My-Kim Tran

Highly potent broadly HIV-1 neutralizing antibodies

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SLIDE 54

Highly potent broadly HIV-1 neutralizing antibodies

Sehr hohe HIV Neutralisation Mittlere HIV Neutralisation Niedrige HIV Neutralisation Keine HIV Neutralisation

HIV cohort (Germany, Tanzania, Cameroon)

Philipp Schommers, My-Kim Tran

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SLIDE 55

Highly potent broadly HIV-1 neutralizing antibodies

Sehr hohe HIV Neutralisation Mittlere HIV Neutralisation Niedrige HIV Neutralisation Keine HIV Neutralisation

single B cell cloning

HIV neutralizing antibody (1-18)

HIV cohort (Germany, Tanzania, Cameroon)

Novel primer design strategies

Philipp Schommers, My-Kim Tran

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SLIDE 56

Highly potent broadly HIV-1 neutralizing antibodies

Sehr hohe HIV Neutralisation Mittlere HIV Neutralisation Niedrige HIV Neutralisation Keine HIV Neutralisation

single B cell cloning

HIV neutralizing antibody (1-18)

3BNC117 VCR01 10-1074 PGT121 1-18

Global panel, IC50 in µg/ml HIV cohort (Germany, Tanzania, Cameroon)

Novel primer design strategies

Philipp Schommers, My-Kim Tran

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SLIDE 57

Highly potent broadly HIV-1 neutralizing antibodies

Sehr hohe HIV Neutralisation Mittlere HIV Neutralisation Niedrige HIV Neutralisation Keine HIV Neutralisation

single B cell cloning

HIV neutralizing antibody (1-18)

3BNC117 VCR01 10-1074 PGT121 1-18 Global panel, IC50 in µg/ml

HIV cohort (Germany, Tanzania, Cameroon)

Novel primer design strategies

Philipp Schommers, My-Kim Tran

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SLIDE 58

CAR-T cells carrying bNAbs

Henning Grüll, Franziska Bach

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SLIDE 59

CAR-T cells carrying bNAbs

Henning Grüll, Franziska Bach

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SLIDE 60

MPER CD4bs V1/V2 Interface V3 loop

CAR-T cells carrying bNAbs

Henning Grüll, Franziska Bach