A Study of the Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRCHIVMAB0115-00-AB (VRC01.23LS), Administered Intravenously or Subcutaneously to Healthy Adults

Study Design:

This first-in-human, open-label study evaluated VRC01.23LS (VRCHIVMAB0115- 00-AB) in a dose-escalation design to examine safety, tolerability, dose, and pharmacokinetics (PK) in healthy adults. The primary hypothesis was that subcutaneous (SC) and intravenous (IV) administrations of VRC01.23LS will be safe and well-tolerated in healthy adults. A secondary hypothesis was that VRC01.23LS will be detectable in human sera with a definable half-life.

Study Products:

The VRC01.23LS broadly neutralizing monoclonal antibody (bnAb) targets the CD4 binding site in the HIV-1 envelope, is human in origin, and contains two amino acid modifications within the C-terminus of the heavy chain constant region designed to improve the antibody half-life in vivo. VRC01.23LS was developed by the VRC/NIAID/NIH and manufactured under cGMP regulations at the VRC Pilot Plant operated under contract by the Vaccine Clinical Materials Program (VCMP), Leidos Biomedical Research, Inc., Frederick. MD.

Subjects:

Healthy adults, 18-60 years of age

Study Plan:

This open-label study included 6 groups to evaluate VRC01.23LS administered as a single dose or as repeated doses, given 12 weeks apart as shown in the table below. Enrollment began with the 5 mg/kg dose groups, and enrollment in subsequent dose groups proceeded after dose-escalation safety reviews. Assessment of safety included solicited reactogenicity, clinical observation, and monitoring of hematological and metabolic parameters at clinical visits throughout the study.

• INCLUSION CRITERIA:

A subject must meet all of the following criteria:

• Willing and able to complete the informed consent process.
• Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
• Available for clinical follow-up through the last study visit.
• 18 to 60 years of age.
• In good general health without clinically significant medical history.
• Physical examination without clinically significant findings within the 56 days prior to enrollment.
• Adequate venous access if assigned to an IV group or adequate abdominal subcutaneous tissue if assigned to SC group.
• Willing to have blood samples collected, stored indefinitely, and used for research purposes.

Laboratory Criteria within 56 days prior to enrollment:

• White blood cell count (WBC): 2,500-12,000/mm3.
• WBC differential either within institutional normal range or accompanied by the Principal Investigator (PI) or designee approval.
• Platelets: 125,000 - 500,000/mm3.
• Hemoglobin within institutional normal range or accompanied by PI or designee approval.
• Creatinine: <= 1.1 x Upper Limit of Normal (ULN).
• ALT: <= 1.25 x ULN.
• AST: <= 1.25 x ULN.
• Negative for HIV infection by an FDA approved method of detection.

Female-Specific Criteria:

• Agrees to use an effective means of birth control from 21 days prior to enrollment through the duration of study participation.
• Negative Beta-HCG (human chorionic gonadotropin) pregnancy test (urine or serum) on day of enrollment for women presumed to be of reproductive potential.

Exclusion criteria

A subject will be excluded if one or more of the following conditions apply:

• Woman who is breast-feeding or planning to become pregnant during study participation.
• Weight > 115 kg.
• Any history of a severe allergic reaction with generalized urticaria, angioedema or anaphylaxis prior to enrollment that has a reasonable risk of recurrence during the study.
• Hypertension that is not well controlled.
• Receipt of any investigational study product within 28 days prior to enrollment (Note: Emergency Use Authorization of a COVID-19 vaccine is not exclusionary).
• Receipt of an investigational HIV vaccine or anti-HIV monoclonal antibody.
• Receipt of any live attenuated vaccine within 28 days prior to enrollment.
• Receipt of any vaccine within 2 weeks prior to enrollment.
• Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties with IM injections or blood draws.
• Any other chronic or clinically significant medical condition that in the opinion of the investigator would jeopardize the safety or rights of the volunteer, including but not limited to: diabetes mellitus type I, chronic hepatitis; OR clinically significant forms of: drug or alcohol abuse, asthma, infectious disease, autoimmune disease, psychiatric disorder, heart disease, or cancer.