What is the place of the monoclonal antibodies in the clinic?

What is the place of the monoclonal antibodies in the clinic? Dr Julià Blanco 2018/04/26

DISCLOSURE AlbaJuna Therapeutics, S.L.

ANTIBODIES IN HIV INFECTION. ANTIVIRAL (NEUTRALIZING) ACTIVITY env

THE BROADLY NEUTRALIZING ACTIVITY

Breadth POTENCY vs BREADTH 100 80 60 40 4E10 2F5 10E8 IgGb12 PG145 N6 VRC07 VRC01 3BNC117 PG9 PGDM1400 10-1074 PGT128 PGT121 PGT151 CAP256 PGDM1400 VRC34.01 Old Mabs CD4bs V2 V3 INTERFACE MPER 20 2G12 35022 0 10 1 0.1 Potency (µg/ml) 0.01 100 10 1 Potency (nm) 0.1

CELLULAR TARGETS

ANTIBODIES IN HIV INFECTION. EFFECTOR FUNCTIONS Modulates effector functions Different strategies for viral and cellular targets

ANTIBODIES IN HIV INFECTION. EFFECTOR FUNCTIONS Modulates plasma half-life Immunoglobulin Fc-Fusion Proteins Linderholm and Chamow Bioprocess Intl 16, 2014 Mutations in the Fc region expand antibody

Natural History of Infection Vaccine development Prevention Therapy Cure?

PREVENTION. ANIMAL MODELS

Breadth PREVENTION. HUMAN TRIALS A Phase 1, Randomized, Blinded, Dose-escalation Study of raav1-pg9dp Recombinant AAV Vector Coding for PG9 Antibody in Healthy Male Adults. 100 80 60 4E10 10E8 N6 VRC07 VRC01 3BNC117 PG9 PG145 PGDM1400 Old Mabs CD4bs V2 V3 INTERFACE MPER 40 2F5 IgGb12 10-1074 PGT121 PGT151 VRC34.01 PGDM1400 20 2G12 35022 0 10 1 0.1 Potency (µg/ml) 0.01 https://clinicaltrials.gov/ct2/show/nct01937455

PREVENTION. HUMAN TRIALS Evaluating the Safety and Efficacy of the VRC01 Antibody in Reducing Acquisition of HIV-1 Infection Among Men and Transgender Persons Who Have Sex With Men (2700 participants) Evaluating the Safety and Efficacy of the VRC01 Antibody in Reducing Acquisition of HIV-1 Infection in Women (1900 participants) PreP counseling IV administration Every 8 weeks https://ampstudy.org/ 3 groups: 10 mg/kg 30mg/Kg Placebo

TARGET PRODUCT PROFILE. mab for HIV PREVENTION Indication Prevention of HIV infection Product Efficacy Target Population Dose/route Tolerability Cost Two mabs, combine different specificities Coverage > 98% of HIV strains Adolescent/adults at high risk Infants of HIV+ mothers (birth, breastfeeding) Adolescent/adults 5 mg/kg q3-6 months Infants single dose 20 mg/kg Rare adverse events < $50 per person/year Adapted from D Kuritzkes. CROI 2018. Boston Further development will depend on data arising from human trials.

Natural History of Infection Vaccine development Prevention Therapy Cure?

Breadth TREATMENT. THE PIONEERS 2G12, 4E10 and 2F5 100 80 60 4E10 10E8 N6 VRC07 VRC01 3BNC117 PG9 PG145 PGDM1400 Old Mabs CD4bs V2 V3 INTERFACE MPER 40 20 2F5 IgGb12 2G12 10-1074 PGT121 PGT151 VRC34.01 PGDM1400 35022 2005!!!! 0 10 1 0.1 Potency (µg/ml) 0.01 SAFE BUT INACTIVE

TREATMENT. THE NEW ANTIBODIES 2G12 + 4E10 + 2F5 30 mg/kg IV Nat Med, 2005, 11:615 VRC01 3BNC117 10-1074 VRC07-523LS 10-1074 + 3BNC117 Up to 40 mg/kg (IV // SC) Up to 30 mg/kg IV Up to 30 mg/kg IV Up to 40 mg/kg (IV // SC) Up to 30 mg/kg IV Sci Transl Med. 2015, 23 Nature. 2015, 522:487 Nat Med. 2017, 23:185 CROI 2018, p 1061 (UNINF) Ongoing SAFE in HIV infected and uninfected individuals ACTIVE, CONCERN on PREEXISTING AND DEVELOPED RESISTANCE

Breadth TREATMENT. THE NEW ANTIBODIES VRC01 100 80 60 4E10 10E8 N6 VRC07 VRC01 3BNC117 PG9 PG145 PGDM1400 Old Mabs CD4bs V2 V3 INTERFACE MPER 40 2F5 IgGb12 10-1074 PGT121 PGT151 VRC34.01 PGDM1400 20 2G12 35022 0 10 1 0.1 Potency (µg/ml) 0.01 SAFE, ACTIVE, CONCERN on RESISTANCE

LIMITATIONS Availability. There is still a limited number of broad and potent antibodies. Resistance. Naturally resistant viruses. Rapid development of resistances (Env as the paradigm of plastic proteins) Manufacture. GMP production is still expensive.

OVERCOMING LIMITATIONS: DESIGNING MULTIFUNCTIONAL ANTIBODIES

OVERCOMING NATURAL RESISTANCE. DESIGNING MULTIFUNCTIONAL ANTIBODIES

CROI 2018

TARGET PRODUCT PROFILE. mab for HIV TREATMENT Indication Treatment of HIV infection Product Efficacy Follow up Dose/route Tolerability Cost >2 mabs, combining different specificities Coverage > 98% of circulating HIV strains (at least two active specificities) No need for susceptibility testing. >48 weeks viral suppression. Infrequent emergence of resistances <30 mg/kg, ideally 1 mg/kg Home (SC) or infusion center (IV) Rare adverse events. No increases in inflammation. Low ADA levels. Price similar to first line therapy Adapted from D Kuritzkes. CROI 2018. Boston

ANTIBODIES IN HIV INFECTION. EFFECTOR FUNCTIONS Antibodies show a range of immune functions beyond antiviral activity

Natural History of Infection Vaccine development Prevention Therapy Cure?

EXPLOITING THE FULL RANGE OF ANTIBODY FUNCTIONS Antibody-dependent cell-mediated virus inhibition (ADCVI). Antibody-dependent cellular phagocytosis (ADCP): cells of the immune system (i.e., macrophages, granulocytes, and dendritic cells) phagocytose target cells that have been bound by specific antibodies. Antibody-dependent cell-mediated cytotoxicity (ADCC): cells of the immune system (mainly NK) lyse a target cell that has been bound by specific antibodies. Antibody-boosted antigen presentation: immunocomplexes modulate antigen presentation. Complement-dependent cytotoxicity (CDC): antibody binding to the complement activates the classical complement cascade, leading to the lysis of cells targeted by the antibody. Stegall et al, 2012 Nat R Nephrol 8, 670; Pincetic et al, 2014 Nat Immunol 15, 707 716; Pellegrin et al, 2015 Trends in Microbiol, 2015, 23, 10

TREATING HIV infection with ANTIBODIES? Data suggest that in vivo activity of antibodies goes beyond the antiviral activity

Exploring immunomodulatory action of antibodies Early antibody therapy (3x 10 mg/kg dose) incudes long term control of SHIV replication Associated with CD8-dependent long-lasting immunity to SHIV (in rhesus macaques) Not observed in ART treated animals Long term follow-up and CD8 T cell depletion Nishimura et al. Nature 2017

Exploring immunomodulatory action of antibodies Antibody therapy (3x 10 mg/kg dose) in early ART treated animals incudes long term control of SHIV replication Synergistic with TLR7 agonists ART (TDF/FTC/DTG) 0 1 96 114 130 150 SHAM 10x TLR7 5x PGT121 COMBO D Barouch. CROI 2018, Boston

CONCLUSIONS Anti-HIV Antibody therapy is safe in humans (at least for human mabs) Antibody-based prevention and treatment strategies are feasible, and could be relevant in some target populations (Fragile populations) Anti-Env antibodies are much more than antiviral compounds, they emerge as powerful immunomodulatory agents and are new players in HIV cure (NK cells). Engineered antibody-derivatives emerge as new tools in this field Proof of concept trials in humans are required to evaluate the potential contribution of antibodies to HIV eradication

THANKS!