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

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 Fab C H C H C L C L H C H C H Fc C H C H COOH COOH Immune cells (effector functions)

Structure and antiviral activity of human antibodies Antigen (e.g. Virus) V H V H V L V L Fab C H C H C L C L H C H C H Fc C H C H COOH COOH Immune cells (effector functions)

Structure and antiviral activity of human antibodies Antigen (e.g. Virus) • Target and neutralize broad sprectrum of antigens (Victora et al ., Annu Rev Immunol. 2012) V H V V L H V L Fab C H C H • Effector mechanisms to C L C L clear infection (e.g. ADCC) H (Nimmerjahn et al. , Nat Rev. Immunol 2007) C H C H Fc Control of infection C H C H (Burton, Nat. Rev. Immunol., 2002) COOH COOH Prevention of infection (Plotkin, Clin. Vaccine Immunol. 2010) Immune cells (effector functions)

Isolation of potent broadly HIV-1 neutralizing antibodies Elite Neutralizer (1%) HIV-1

Isolation of potent broadly HIV-1 neutralizing antibodies Elite Neutralizer (1%) bNAb HIV-1 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

Isolation of potent broadly HIV-1 neutralizing antibodies 1994 - 2008 Neutralization ( breadth ) Elite Neutralizer (1%) 2017 Neutralization ( breadth ) bNAb HIV-1 Neutralization ( potency )

Highly potent broadly HIV-1 neutralizing antibodies 1994 - 2008 Neutralization ( breadth ) V1/V2 loop V3 loop CD4bs 2017 MPER Neutralization ( breadth ) Interface HIV-1 Envelope protein Neutralization ( potency )

Highly potent broadly HIV-1 neutralizing antibodies Antibody-mediated preventtion V1/V2 loop V3 loop bNAbs control CD4bs Viral load (copies/ml) MPER Interface Days post SHIV challenge Days post SHIV challenge HIV-1 Envelope protein Moldt et al. , PNAS 2012, Gautam et al. , Nature 2016 Klein et al. , Science, 2013

Highly potent broadly HIV-1 neutralizing antibodies Antibody-mediated preventtion V1/V2 loop V3 loop bNAbs control CD4bs Viral load (copies/ml) MPER Interface Days post SHIV challenge Days post SHIV challenge 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

Highly potent broadly HIV-1 neutralizing antibodies V1/V2 loop V3 loop CD4bs MPER Interface HIV-1 HIV-1 Envelope protein Klein et al. , Science, 2013

Evaluating bNAbs in HIV-1 YU2 -infected humanized mice Single bNAbs Single Antibody HIV-1 +

Evaluating bNAbs in HIV-1 YU2 -infected humanized mice Single bNAbs 276-281 458, 459 45-46 G54W HIV-1 escape Sequencing at rebound Viral load (c/ml) Single Antibody HIV-1 + 0 250 500 Days post starting therapy gp120 envelope

Evaluating bNAbs in HIV-1 YU2 -infected humanized mice Single bNAbs 276-281 458, 459 45-46 G54W HIV-1 escape Sequencing at rebound Viral load (c/ml) Single Antibody HIV-1 + 0 250 500 Days post starting therapy gp120 envelope 45-46 G54W PG16 PGT128 10-1074

Evaluating bNAbs in HIV-1 YU2 -infected humanized mice Single bNAbs 276-281 458, 459 45-46 G54W HIV-1 escape Sequencing at rebound Viral load (c/ml) Single Antibody HIV-1 + 0 250 500 Days post starting therapy gp120 envelope 45-46 G54W PG16 PGT128 10-1074 Monotherapy in hu-mice results in rapid HIV escape

Evaluating bNAbs in HIV-1 YU2 -infected humanized mice Single bNAbs 276-281 458, 459 45-46 G54W HIV-1 escape Sequencing at rebound Viral load (c/ml) Single Antibody HIV-1 + 0 250 500 Days post starting therapy gp120 envelope Combination 3 - 5 Antibodies HIV-1 +

Evaluating bNAbs in HIV-1 YU2 -infected humanized mice Single bNAbs 276-281 458, 459 45-46 G54W HIV-1 escape Sequencing at rebound Viral load (c/ml) Single Antibody HIV-1 + 0 250 500 Days post starting therapy gp120 envelope Combination Penta-Mix Tri-Mix Sequencing at rebound (45-46GW, PG16, (45-46GW, PG16, Viral load (c/ml) 3 - 5 Antibodies 10-1074, PFT128, 10-1074) 3BNC176) HIV-1 + 0 250 500 Days post starting therapy gp120 envelope Klein et al. , Nature 2012; Horwitz et al. , PNAS 2013

Evaluating bNAbs in HIV-1 YU2 -infected humanized mice Single bNAbs 276-281 458, 459 45-46 G54W HIV-1 escape Sequencing at rebound Viral load (c/ml) Single Antibody HIV-1 + 0 250 500 Days post starting therapy gp120 envelope Combination Penta-Mix Tri-Mix Sequencing at rebound (45-46GW, PG16, (45-46GW, PG16, Viral load (c/ml) 3 - 5 Antibodies 10-1074, PFT128, 10-1074) 3BNC176) HIV-1 + 0 250 500 Days post starting therapy gp120 envelope Antibody combination mediates sustained control

Clinical Investigation of bNAb 3BNC117 3BNC117 (Scheid et al ., Science 2011)

Clinical Investigation of bNAb 3BNC117 Safety, Tolerability, PK • 55 subjects enrolled, very well tolerated • No (related) SAE, AEs mostly mild (transient fatigue, headache) 3BNC117 (Scheid et al ., Science 2011) HIV-1 uninfected mAb conc (µg/ml) T 1/2 – 17,6 days HIV-1-infected T 1/2 – 9,6 days Days post single infusion Caskey* and Klein* et al. , Nature 2015

Clinical Investigation of bNAb 3BNC117 3BNC117 ( CD4bs ) 3BNC117 (Scheid et al ., Science 2011) Days post infusion Drop Viral load 1,48 log (0.8 – 2.5) Caskey* and Klein* et al. , Nature 2015

Clinical Investigation of bNAb 3BNC117 and 10-1074 10-1074 ( V3stem ) 3BNC117 ( CD4bs ) ∆ log 10 (copies/ml) Days post infusion Days post infusion Drop Viral load Drop Viral load 1,52 log (1.0 – 2.1) 1,48 log (0.8 – 2.5) Caskey* and Klein* et al. , Nature 2015; Caskey*, Schoofs*, Gruell*, et al. , Nat Med 2017

Clinical Investigation of bNAb 3BNC117 and 10-1074 10-1074 ( V3stem ) ∆ log 10 (copies/ml) Days post infusion Drop Viral load 1,52 log (1.0 – 2.1) Caskey* and Klein* et al. , Nature 2015; Caskey*, Schoofs*, Gruell*, et al. , Nat Med 2017

Clinical Investigation of bNAb 3BNC117 and 10-1074 10-1074 ( V3stem ) HIV-1 escape variants ∆ log 10 (copies/ml) Days post infusion Drop Viral load 1,52 log (1.0 – 2.1) Caskey*, Schoofs*, Gruell*, et al. , Nat Med 2017

Clinical Investigation of bNAb 3BNC117 and 10-1074 10-1074 ( V3stem ) HIV-1 escape variants ∆ log 10 (copies/ml) Days post infusion Drop Viral load 1,52 log (1.0 – 2.1) Caskey*, Schoofs*, Gruell*, et al. , Nat Med 2017

Clinical Investigation of bNAb 3BNC117 and 10-1074 10-1074 ( V3stem ) ∆ log 10 (copies/ml) Days post infusion Drop Viral load 1,52 log (1.0 – 2.1) Caskey*, Schoofs*, Gruell*, et al. , Nat Med 2017

Immunological effects ?

Viral and Immunologic effects after 3BNC117 infusion 3BNC117 Infusion Sequence (Bulk/SGA) HIV Envelope Autologous Antibody response

Enhancing autologous neutralization by 3BNC117 All viruses of all subjects Schoofs*, Klein*, and Braunschweig* et al ., Science 2016

Enhancing autologous neutralization by 3BNC117 All viruses of all subjects Potential mechanism Vaccinal effect Emerging Antigens Schoofs*, Klein*, and Braunschweig* et al ., Science 2016

Immune-mediated control of the HIV-1 viral reservoir

Immune-mediated control of the HIV-1 viral reservoir NHP control Nishimura et al ., Nature 2017, schematic illustration of results by Klein/Kreer

Immune-mediated control of the HIV-1 viral reservoir NHP control ART Nishimura et al ., Nature 2017, schematic illustration of results by Klein/Kreer

Immune-mediated control of the HIV-1 viral reservoir 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 NHP control ART bNAb Nishimura et al ., Nature 2017, schematic illustration of results by Klein/Kreer

Summary

Summary • Discovery of a new generation of highly potent and broadly neutralizing antibodies (bNAbs) targeting HIV-1.

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).

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)