10E8.4/iMab Bispecific Antibody in HIV-uninfected and HIV-infected Adults

Inclusion Criteria for HIV uninfected volunteers: Arms 1, 2 and 4:

• Healthy volunteers born male and female as assessed by medical history and physical examination
• Aged >18 and <60 years at the time of screening
• Ability and willingness to provide written informed consent
• Willingness to comply with protocol schedule
• Willingness to undergo HIV-1 testing
• Non-reactive 4th generation point of care HIV-1 test at screening
• Hepatitis B Surface antigen negative
• Hepatitis C antibody negative, or if reactive, Hepatitis C RNA undetectable in plasma
• Volunteers born female of reproductive potential, sexually active with a male sex partner must agree to use one effective method of contraception from the time of signing the consent to completion of the study and agree to pregnancy testing as per the schedule of events.
• Study participants born female with reproductive potential are defined as pre-menopausal volunteers born female who have not had a sterilization procedure (e.g. hysterectomy, bilateral oophorectomy, tubal ligation or salpingectomy). Volunteers born female are considered menopausal if they have not had a menses for at least 12 months and have an follicle stimulating hormone (FSH) of greater than 40 IU/L or if FSH testing is not available, they have had amenorrhea for 24 consecutive months.

Inclusion Criteria for HIV-1-Infected Viremic Subjects: Arm 3

• Aged >18 and <60 years at the time of screening
• Ability and willingness to provide written informed consent
• Willingness to comply with protocol schedule
• Willingness to undergo HIV-1 testing
• Reactive 4th generation point of care HIV-1 test at screening
• Plasma HIV-1 RNA levels > 2,000 copies/mL and < 100,000 copies/mL in subjects who are either:
• ART-naïve
• ART-experienced and in consultation with their primary provider have discontinued therapy for at least 8 weeks
• ART-experienced, clinically stable and without changes to their ART regimen for at least 8 weeks
• Current CD4+ T cell count > 350 cells/mm3 and a nadir CD4+ T cell count > 250 cells/mm3
• Agrees not to begin or change antiretroviral therapy for 6 weeks after 10E8.4/iMab infusion despite a clear explanation of current Department of Health and Human Services (DHHS) guidelines
• Hepatitis B Surface antigen negative
• Hepatitis C antibody negative or if reactive Hepatitis C RNA undetectable in plasma
• Volunteers born female of reproductive potential, sexually active with a male sex partner agree to use one effective method of contraception from the time of signing the consent to completion of the study and agree to pregnancy testing as per the schedule of events.
• Study participants born female with reproductive potential are defined as pre-menopausal volunteers born female who have not had a sterilization procedure (e.g. hysterectomy, bilateral oophorectomy, tubal ligation or salpingectomy). Volunteers born female are considered menopausal if they have not had a menses for at least 12 months and have an FSH of greater than 40 IU/L or if FSH testing is not available, they have had amenorrhea for 24 consecutive months.

Exclusion Criteria for HIV uninfected volunteers: Arms 1, 2 and 4:

• Confirmed HIV-1 infection
• At high risk of HIV-1 infection as defined by:
• Unprotected intercourse with a casual or HIV-infected partner over the past 12 months
• In a serodisconcordant relationship with an HIV-1 infected partner
• A diagnosed new sexually transmitted infection within the past 12 months
• Exchange of money or drugs for sex in the last 12 months
• More than 2 sexual partners, defined as insertive or receptive vaginal or anal intercourse, within the past 6 months
• Weight above 100 kg at screening. Note that subjects above 80 kg may not be randomized into the SC dosing group in Arm 4.
• Any acute or chronic medical condition that in the opinion of the investigator would preclude participation
• Immunodeficiency or chronic autoimmune disease
• Intravenous drug use
• Excessive use of alcohol or recreational drugs that in the opinion of the investigator would preclude participation.
• Decompensated psychiatric illness
• Need for chronic immunotherapy including systemic corticosteroids, other monoclonal antibody therapy, or immunosuppressive drugs
• If born female, pregnant, lactating or planning on becoming pregnant over the study period
• Any of the following laboratory parameters:
• Hemoglobin <10.0 g/dL
• Absolute neutrophil count <1,000/mm3
• Absolute lymphocyte count <500/mm3
• Platelet count <100,000/mm3
• Prothrombin time (PT) >1.25xULN
• Partial thromboplastin time (PTT) >1.66xULN
• Creatinine >1.25x Upper limit of normal (ULN)
• Aminotransferase (AST) >1.5X ULN
• Alanine Aminotransferase (ALT) >1.5X ULN
• Glucose (non-fasting) >160mg/dL
• Proteinuria: 2+ or greater
• Hematuria: >10 RBC per high power field
• Serum calcium < 8.5 mg/dL or >10.2 mg/dL
• Serum parathyroid hormone (PTH) levels <10 pg/mL or >65 pg/mL
• Any vaccine administration within 14 days of study entry
• Experimental HIV-1 vaccine in past (active arm of an HIV-1 vaccine trial if applicable)
• Previous receipt of an experimental mAb to HIV-1 in a research study
• History of severe allergic reactions to drugs, vaccines, or drug infusion
• Participation in another investigational clinical trial within the past 12 weeks or anticipated during the course of the current study

Exclusion Criteria for HIV-1-Infected Viremic Subjects: Arm 3

• Any acute or chronic medical condition that in the opinion of the investigator would preclude participation
• A history of virologic failure of two or more combination antiretroviral treatment regimens. A regimen switch due solely to intolerance and not virologic failure does not qualify as a failed regimen.
• Weight above 100 kg at the time of screening.
• Intravenous drug use
• Excessive use of alcohol or recreational drugs that in the opinion of the investigator would preclude participation
• Decompensated psychiatric illness
• Need for chronic immunotherapy including systemic corticosteroids, other monoclonal antibody therapy, or immunosuppressive drugs
• If born female, pregnant, lactating or planning on becoming pregnant over the study period
• Any of the following laboratory parameters
• Hemoglobin <10.0 g/dL
• Absolute neutrophil count <1,000/mm3
• Absolute lymphocyte count <500/mm3
• Platelet count <100,000/mm3
• PT >1.25xULN
• PTT >1.66xULN
• Creatinine >1.25x Upper limit of normal (ULN)
• AST >1.5X ULN
• ALT >1.5X ULN
• Glucose (non-fasting) >160mg/dL
• Proteinuria: 2+ or greater
• Hematuria: >10 RBC per high power field
• Serum calcium < 8.5 mg/dL and >10.2 mg/dL
• Serum PTH level <10 pg/mL or >65 pg/mL
• Any vaccine administration within 14 days of study entry
• Experimental HIV-1 vaccine in past (active arm of an HIV-1 vaccine trial if applicable)
• Participation in a research study of a neutralizing monoclonal antibody (mAb) to HIV-1
• History of severe allergic reactions to drugs, vaccines, or drug infusion
• Participation in another investigational clinical trial within the past 12 weeks or anticipated during the course of the current study