Pharmacy and Poisons Board
Protocol No: ECCT/20/11/02 Date of Protocol: 26-11-2019
Study Title:
Safety and Pharmacokinetics of the Combination Broadly Neutralizing  Antibodies, 3BNC117-LS-J and 10-1074-LS-J, in Healthy American and
African Adults (IAVI C100)

N/A

Safety and Pharmacokinetics of the Combination Broadly Neutralizing  Antibodies, 3BNC117-LS-J and 10-1074-LS-J, in Healthy American and
African Adults (IAVI C100)
Study Objectives:
Primary:
1. To evaluate the safety and tolerability of two broadly neutralizing monoclonal human antibodies, 3BNC117-LS-J and 10-1074-LS-J, when given alone and in combination, intravenously (IV) or subcutaneously (SC) to healthy American and African adults.
2. To evaluate the pharmacokinetic profile of two broadly neutralizing monoclonal human antibodies, 3BNC117-LS-J and 10-1074-LS-J, when given alone or in combination, IV or SC to healthy American and African adults.
3. To identify a regimen of the two antibodies that, when given SC every 3 months, will maintain a serum trough level of >10 μg/mL for each antibody in >80% of the study population.
 
Secondary:
1. To evaluate the effect of participant characteristics, e.g., sex, body weight or body mass index (BMI), on pharmacokinetic parameters.
2. To conduct pharmacokinetic modelling to assess the effect of dose, dose ratio, dosing frequency and loading dose on serum trough levels of each antibody.
3. To assess the incidence and titers of anti-drug antibodies (ADA) against each antibody.
 
Exploratory:
1. To evaluate the effect of geographic region, immunoglobulin levels, and the subcutaneous site on injection (abdomen vs. arm) on pharmacokinetic parameters.
2. To characterize the bNAb neutralization potency in serum or plasma.
3. To investigate the effect of ADA on antibody concentration and neutralizing potency and the potential occurrence of ADA-related adverse events.
4. To characterize mucosal distribution of the bNAbs in a subset of participants enrolled in African sites.

 
1 Primary: 1. To evaluate the safety and tolerability of two broadly neutralizing monoclonal human antibodies, 3BNC117-LS-J and 10-1074-LSJ, when given alone and in combination, intravenously (IV) or subcutaneously (SC) to healthy American and African adults. 2. To evaluate the pharmacokinetic profile of two broadly neutralizing monoclonal human antibodies, 3BNC117-LS-J and 10-1074-LS-J, when given alone or in combination, IV or SC to healthy American and African adults. 3. To identify a regimen of the two antibodies that, when given SC every 3 months, will maintain a serum trough level of >10 μg/mL for each antibody in >80% of the study population. Secondary: 1. To evaluate the effect of participant characteristics, e.g., sex, body weight or body mass index (BMI), on pharmacokinetic parameters. 2. To conduct pharmacokinetic modelling to assess the effect of dose, dose ratio, dosing frequency and loading dose on serum trough levels of each antibody. 3. To assess the incidence and titers of anti-drug antibodies (ADA) against each antibody. Exploratory: 1. To evaluate the effect of geographic region, immunoglobulin levels, and the site of subcutaneous injection (abdomen vs. arm) on pharmacokinetic parameters. 2. To characterize the bNAb neutralization potency in serum. 3. To investigate the effect of ADA on serum antibody concentration and neutralizing potency and the potential occurrence of ADArelated adverse events. 4. To characterize mucosal distribution of the bNAbs (optional substudy carried out at selected clinical centers). 5. To evaluate pharmacokinetic interaction between two bNAbs. 6. To assess the tolerability and acceptability of SC volumes and preferences for anatomic site of injection. 7. To assess willingness to receive antibody injections every 3 months for HIV prevention.
2 N/A
Laymans Summary:

Anti-HIV neutralizing antibodies were first cloned from B cells of HIV-infected individuals. The antibodies selected for clinical testing showed the ability to neutralize (block infection of new cells) HIV strains of multiple clades at very low concentrations. These two antibodies are specific for two different regions of the HIV envelope protein, the outer layer of the virus. 3BNC117 binds to the CD4 binding site and 10-1074 to the V3 loop of HIV. The combination of both antibodies covers a larger number of viral strains than either antibody alone. When the antibodies were given to mice and non-human primates, the antibodies protected the animals from infection or lowered viral loads in infected animals.

The antibodies that were originally found in two HIV-infected individuals were cloned and manufactured in the laboratory for clinical testing. In early clinical trials the antibodies have showed good safety profiles and half-lives of about 2 weeks. Both antibodies were able to lower viral loads in HIV-infected persons not taking antiretrovirals. The combination of antibodies was able to maintain undetectable viral loads during a period of ART interruption.

3BNC117 and 10-1074 were subsequently modified to improve their half-lives and also their stability as future drug products. The two changes made to improve half-life prolonged half-life of 3BNC117 from about 2 weeks to about 10 weeks, and of 10-1074 from about 3 weeks to about 13 weeks. These long-acting antibodies (3BNC117-LS and 10-1074-LS) are being testing in two clinical trials in the US. So far, the antibodies have shown very good safety profiles, similar to the original unmodified antibodies. The antibodies that will be used in this proposed study have additional modifications to improve the antibody chemical characteristics, but these modifications do interfere with the antibody activities.

 
1 N/A
2 Anti-HIV neutralizing antibodies were first cloned from B cells of HIV-infected individuals. The antibodies selected for clinical testing showed the ability to neutralize (block infection of new cells) HIV strains of multiple clades at very low concentrations. These two antibodies are specific for two different regions of the HIV envelope protein, the outer layer of the virus. 3BNC117 binds to the CD4 binding site and 10-1074 to the V3 loop of HIV. The combination of both antibodies covers a larger number of viral strains than either antibody alone. When the antibodies were given to mice and non-human primates, the antibodies protected the animals from infection or lowered viral loads in infected animals. The antibodies that were originally found in two HIV-infected individuals were cloned and manufactured in the laboratory for clinical testing. In early clinical trials the antibodies have showed good safety profiles and half-lives of about 2 weeks. Both antibodies were able to lower viral loads in HIV-infected persons not taking antiretrovirals. The combination of antibodies was able to maintain undetectable viral loads during a period of ART interruption. 3BNC117 and 10-1074 were subsequently modified to improve their half-lives and also their stability as future drug products. The two changes made to improve half-life prolonged half-life of 3BNC117 from about 2 weeks to about 10 weeks, and of 10-1074 from about 3 weeks to about 13 weeks. These long-acting antibodies (3BNC117-LS and 10-1074-LS) are being testing in two clinical trials in the US. So far, the antibodies have shown very good safety profiles, similar to the original unmodified antibodies. The antibodies that will be used in this proposed study have additional modifications to improve the antibody chemical characteristics, but these modifications do interfere with the antibody activities.
Abstract of Study:
According to the Joint United Nations Programme on HIV/AIDS and the World Health Organization, as of the end of 2018, over 37.9 million people [32.7 – 44 million], were estimated to be living with HIV/AIDS. It is estimated that in 2018 alone, 1.7 million [1.6 – 2.3 million] were newly infected with HIV and 770,000 [570,000-1.1 million] people died of AIDS-related illnesses.The use of antiretroviral agents by HIV-uninfected individuals before potential sexual exposure to HIV-infected partners, known as pre-exposure prophylaxis (PrEP), is a new effective preventive approach against HIV-1. However, an important challenge to the success of such strategy is that its efficacy is highly dependent on adherence to a daily oral drug regimen.Therefore, the search for novel preventive and therapeutic interventions with a longer duration of action is of high priority. A new generation of highly potent broadly neutralizing antibodies (bNAbs) may represent a novel
strategy to combat HIV-1 infection. Monoclonal antibodies, which are made in the laboratory but based upon natural human antibodies with high potency, are considered to be promising candidates for safe, long-acting preventive agents. In the past decade, a number of antibodies have been developed that have broad neutralizing ability, that is to say they neutralize a large number of HIV-1 isolates from different clades and geographic regions. Combinations of these antibodies have even broader activity. It will be important to have broad coverage, to protect against the wide variety of HIV-1 variants that are found in Africa and globally. In this study, we propose to study two such broadly neutralizing antibodies (bNAbs), in combination. Novel, Potent bNAbs: Selection and Preclinical characterization.The advent of single-cell cloning techniques allowed the identification of potent bNAbs that target multiple epitopes on the HIV-1 envelope. Some of the new bNAbs demonstrate in vitro neutralizing activity against over 90% of HIV-1 pseudoviruses derived from diverse clades, even at low concentrations. Broadly neutralizing antibodies are potential alternatives to standard antiretroviral drugs as they are likely to be safe and well tolerated, and to persist at neutralizing levels for longer periods of time. Below the characteristics of two novel bNAbs are described. Both antibodies have been evaluated in clinical studies, either alone or in combination. 3BNC117 and 10-1074 have shown favorable safety profiles in both HIV-infected and HIV-uninfected participants. Single infusions of 3BNC117
or 10-1074 led to decline in plasma viremia of approximately 1.5 log10 copies/mL in viremic individuals, Experience with 3BNC117.
 
Neutralizing Activity
3BNC117 and 10-1074 are two of the most potent broadly neutralizing antibodies available. 3BNC117 targets the CD4 binding site, while 10-1074 targets the V3 loop of HIV-1 gp 120. They were chosen for clinical development for their neutralizing breadth and potency, and their antiretroviral activity when tested in humanized mice (hu-mice) and non-human primate (NHP) models. The neutralizing activities of 3BNC117 and 10-1074 were evaluated in vitro against large pseudovirus panels including diverse clades. 3BNC117 showed neutralizing activity against 82.5% of 399 pseudoviruses tested, while 10-1074 neutralized 61.7% of 295 pseudoviruses tested. The combination of these two antibodies, which target two nonoverlapping epitopes on HIV-1 gp 120 provides higher breadth and potency than either antibody alone. In vitro, the combination showed neutralizing activity against 96% of 125 viruses from multiple clades, with average IC80 0.15 μg/mL [15]. The 3BNC117 and 10-1074 combination neutralizing titers against a panel of 200 clade C viruses were predicted using the Bliss-Hill model. Against this panel, the 3BNC117 plus 10-1074 combination covered 87% of viral strains with IC80 of 0.16 μg/mL.
1

N/A

2
According to the Joint United Nations Programme on HIV/AIDS and the World Health Organization, as of the end of 2018, over 37.9 million people [32.7 – 44 million], were estimated to be living with HIV/AIDS. It is estimated that in 2018 alone, 1.7 million [1.6 – 2.3 million] were newly infected with HIV and 770,000 [570,000-1.1 million] people died of AIDS-related illnesses.The use of antiretroviral agents by HIV-uninfected individuals before potential sexual exposure to HIV-infected partners, known as pre-exposure prophylaxis (PrEP), is a new effective preventive approach against HIV-1. However, an important challenge to the success of such strategy is that its efficacy is highly dependent on adherence to a daily oral drug regimen.Therefore, the search for novel preventive and therapeutic interventions with a longer duration of action is of high priority. A new generation of highly potent broadly neutralizing antibodies (bNAbs) may represent a novel
strategy to combat HIV-1 infection. Monoclonal antibodies, which are made in the laboratory but based upon natural human antibodies with high potency, are considered to be promising candidates for safe, long-acting preventive agents. In the past decade, a number of antibodies have been developed that have broad neutralizing ability, that is to say they neutralize a large number of HIV-1 isolates from different clades and geographic regions. Combinations of these antibodies have even broader activity. It will be important to have broad coverage, to protect against the wide variety of HIV-1 variants that are found in Africa and globally. In this study, we propose to study two such broadly neutralizing antibodies (bNAbs), in combination. Novel, Potent bNAbs: Selection and Preclinical characterization.The advent of single-cell cloning techniques allowed the identification of potent bNAbs that target multiple epitopes on the HIV-1 envelope. Some of the new bNAbs demonstrate in vitro neutralizing activity against over 90% of HIV-1 pseudoviruses derived from diverse clades, even at low concentrations. Broadly neutralizing antibodies are potential alternatives to standard antiretroviral drugs as they are likely to be safe and well tolerated, and to persist at neutralizing levels for longer periods of time. Below the characteristics of two novel bNAbs are described. Both antibodies have been evaluated in clinical studies, either alone or in combination. 3BNC117 and 10-1074 have shown favorable safety profiles in both HIV-infected and HIV-uninfected participants. Single infusions of 3BNC117
or 10-1074 led to decline in plasma viremia of approximately 1.5 log10 copies/mL in viremic individuals, Experience with 3BNC117.
 
Neutralizing Activity
3BNC117 and 10-1074 are two of the most potent broadly neutralizing antibodies available. 3BNC117 targets the CD4 binding site, while 10-1074 targets the V3 loop of HIV-1 gp 120. They were chosen for clinical development for their neutralizing breadth and potency, and their antiretroviral activity when tested in humanized mice (hu-mice) and non-human primate (NHP) models. The neutralizing activities of 3BNC117 and 10-1074 were evaluated in vitro against large pseudovirus panels including diverse clades. 3BNC117 showed neutralizing activity against 82.5% of 399 pseudoviruses tested, while 10-1074 neutralized 61.7% of 295 pseudoviruses tested. The combination of these two antibodies, which target two nonoverlapping epitopes on HIV-1 gp 120 provides higher breadth and potency than either antibody alone. In vitro, the combination showed neutralizing activity against 96% of 125 viruses from multiple clades, with average IC80 0.15 μg/mL [15]. The 3BNC117 and 10-1074 combination neutralizing titers against a panel of 200 clade C viruses were predicted using the Bliss-Hill model. Against this panel, the 3BNC117 plus 10-1074 combination covered 87% of viral strains with IC80 of 0.16 μg/mL.
1