Evaluating the Safety, Tolerability, and Pharmacokinetics of Monoclonal Antibodies in Healthy Participants

A Phase 1 Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Monoclonal Antibodies VRC01.23LS, PGT121.414.LS and PGDM1400LS Administered Via Intravenous Infusion in Adults Without HIV

Part A:

The purpose of this part is to study how the body's immune system reacts to a lab-made HIV-1 monoclonal antibody against HIV antigen when given in different doses. The study will also evaluate if the antibody is safe to give to people and does not make them too uncomfortable.

Part B:

The purpose of this part is to study how the body's immune system reacts to a combination of lab-made HIV-1 monoclonal antibodies against HIV antigens when given in different doses. The study also wants to see if the way the antibodies are given affects the immune response.

This study aims to evaluate the safety, tolerability, dose, and PK of VRC01.23LS administered IV and in combination with PGDM1400LS, a V2-apex-targeting mAb, and PGT121.414.LS, a V3-glycan-targeting mAb.

There are 2 parts to this study: Part A and Part B.

In Part A, 15 participants will be randomly assigned to test one study antibody at different doses.

After we see the results from Part A, we will decide whether or not to do Part B of the study.

In Part B, 62 participants will be randomly assigned to test a combination of 3 study antibodies, including the one tested in Part A.

Inclusion Criteria:

1. Age of 18 through 50 years

2. Access to a participating CRS and willingness to be followed for the planned duration of the study

3. Ability and willingness to provide informed consent

4. Assessment of understanding (AoU): volunteer demonstrates understanding of this study and completes a questionnaire prior to first study-product administration with verbal demonstration of understanding of all questionnaire items answered incorrectly

5. Agrees not to enroll in another study of an investigational research agent until completion of the last required protocol clinic visit.

6. Good general health as shown by medical history, physical exam, and screening laboratory tests

7. Willingness to receive HIV test results

8. Willingness to discuss HIV acquisition and amenable to HIV risk-reduction counseling.

9. Assessed by the clinic staff as having a low likelihood of HIV acquisition and is committed to avoid behaviors associated with a higher likelihood of acquiring HIV through the last required protocol clinic visit.

10. Hemoglobin

    • ≥ 11.0 g/dL for AFAB volunteers
    • ≥ 13.0 g/dL for AMAB volunteers and transgender men who have been on hormone therapy for more than 6 consecutive months
    • ≥ 12.0 g/dL for transgender women who have been on hormone therapy for more than 6 consecutive months
    • For transgender volunteers who have been on hormone therapy for less than 6 consecutive months, determine hemoglobin eligibility based on their sex assigned at birth

11. White blood cell (WBC) count = 2,500 to 12,000 cells/mm3

12. WBC differential either within institutional normal range or with site clinician approval

13. Platelets = 125,000 to 550,000 cells/mm3

14. Chemistry panel: alanine aminotransferase (ALT) < 1.25 times the institutional upper limit of normal (ULN) (ie, < 1.25 times the reference range upper limit) and creatinine < 1.1 times the institutional ULN (ie, < 1.1 times the reference range upper limit)

15. Negative HIV-1 and -2 blood test: Sites may use locally available assays that have been approved by HVTN and HPTN Laboratory Operations

16. Negative Hepatitis B surface antigen (HBsAg)

17. Negative anti-Hepatitis C virus Abs (anti-HCV) or negative HCV PCR if the anti-HCV is positive

18. Negative or trace urine protein

19. AFAB volunteers or volunteers who were intersex at birth and are capable of becoming pregnant (hereafter referred to as "persons of pregnancy potential"): negative serum or urine beta human chorionic gonadotropin (β-HCG) pregnancy test(s) performed within 48 hours prior to initial study-product administration. Persons who are NOT of pregnancy potential due to having undergone total hysterectomy or bilateral oophorectomy (verified by medical records) are not required to undergo pregnancy testing.

20. Persons of pregnancy potential must:

    • Agree to use effective contraception for sexual activity that could lead to pregnancy from at least 21 days prior to enrollment through the last required protocol visit. Effective contraception is defined as using one of the following methods:

      • Condoms (internal and external) with or without a spermicide,
      • Diaphragm or cervical cap with spermicide,
      • Intrauterine device (IUD),
      • Hormonal contraception,
      • Tubal ligation, or
      • Any other contraceptive method approved by the HVTN 143/HPTN 109 PSRT
      • Successful vasectomy in any AMAB partner (considered successful if a volunteer reports that an AMAB partner has [1] documentation of azoospermia by microscopy or [2] a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity postvasectomy); or,

    • Not be of pregnancy potential, such as having reached menopause (no menses for 1 year) or having undergone hysterectomy or bilateral oophorectomy; or,

    • Be sexually abstinent.

21. AFAB volunteers or who were intersex at birth must also agree not to seek pregnancy through alternative methods, such as oocyte retrieval, artificial insemination, or in vitro fertilization from at least 21 days prior to enrollment through 8 weeks until after the last required protocol clinic visit

Exclusion Criteria:

1. Weight < 35 kg or > 115 kg

2. Blood products received within 120 days before first study-product administration, unless eligibility for earlier enrollment is determined by the HVTN 143/HPTN 109 PSRT

3. Investigational research agents received within 30 days before first study-product administration

4. Intent to participate in another study of an investigational research agent or any other study that requires non-Network HIV Ab testing during the planned duration of the HVTN 143/HPTN 109 study

5. Pregnant or breastfeeding

6. HIV vaccine(s) received in a prior HIV vaccine trial. Volunteers who have received control/placebo in an HIV vaccine trial are not excluded from HVTN 143/HPTN 109.

7. SARS-CoV-2 vaccine(s) received within 7 days prior to HVTN 143/HPTN 109 enrollment or planned within 7 days after enrollment.

8. Jynneos vaccine for MPOX received within 14 days prior to enrollment or planned within 14 days after enrollment.

9. ACAM2000 vaccine for MPOX received within 28 days prior to enrollment or, if ACAM2000 was received more than 28 days prior to enrollment, vaccination scab still present; or planned within 14 days after enrollment

10. Receipt of humanized or human mAbs, whether licensed or investigational.

11. Previous receipt of mAbs targeting HIV (eg, cap256, VRC01, VRC01LS, VRC07-523LS, PGDM1400, PGDM1400LS, PGT121, PGT121.414.LS)

12. Immunosuppressive medications received within 30 days before first study-product administration (not exclusionary: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3] topical corticosteroids for mild, uncomplicated dermatological condition; or [4] a single course of oral/parenteral prednisone or equivalent at doses < 20 mg/day and length of therapy < 14 days, but completed at least 7 days prior to first infusion)

13. Serious adverse reactions to VRC01.23LS, PGDM1400LS, or PGT121.414.LS formulation components, including history of anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain.

14. Immunoglobulin received within 60 days before first study-product administration (for mAb, see criterion 10 above)

15. Autoimmune disease (not exclusionary: volunteer with mild, stable, and uncomplicated autoimmune disease that does not require immunosuppressive medication and that, in the judgment of the CRS investigator, is likely not subject to exacerbation and likely not to complicate solicited and unsolicited AE assessments)

16. Immunodeficiency

17. Clinically significant medical condition, physical examination findings, clinically significant abnormal laboratory results, or past medical history with clinically significant implications for current health. A clinically significant condition or process includes but is not limited to:

    • Symptoms consistent with COVID-19 or known SARS-CoV-2 acquisition,
    • A process that would affect the immune response,
    • A process that would require medication that affects the immune response,
    • Any contraindication to repeated infusions or blood draws, including inability to establish venous access,
    • A condition that requires active medical intervention or monitoring to avert grave danger to the volunteer's health or well-being during the study period,
    • A condition or process (eg, chronic urticaria or recent injection or infusion with evidence of residual inflammation) for which signs or symptoms could be confused with reactions to the study product, or
    • Any condition specifically listed among the exclusion criteria.

18. Any medical, psychiatric, or skin condition (eg, tattoos) or occupational responsibility that, in the judgment of the investigator, would interfere with or serve as a contraindication to protocol adherence, assessment of safety or solicited AEs, or a participant's ability to give informed consent.

19. Psychiatric condition that precludes compliance with the protocol. Specifically excluded are persons with psychoses, ongoing risk for suicide, or history of suicide attempt within the past 3 years.

20. Current anti-tuberculosis (TB) therapy

21. Asthma other than mild, well-controlled asthma (symptoms of asthma severity as defined in the most recent National Asthma Education and Prevention Program [NAEPP] Expert Panel report).

    Exclude a volunteer who:

    • Uses a short-acting rescue inhaler (typically a beta 2 agonist) daily; or

    • Uses moderate/high-dose, inhaled corticosteroids; or

    • In the past year, has had either of the following:

      • Greater than 1 exacerbation of symptoms treated with oral/parenteral corticosteroids;
      • Emergency care, urgent care, hospitalization, or intubation for asthma.

22. Diabetes mellitus type 1 or type 2 (not exclusionary: type-2 cases controlled with diet alone or a history of isolated gestational diabetes)

23. Hypertension

    • If a person has been found to have elevated blood pressure or hypertension during screening or previously, exclude for blood pressure that is not well controlled. Well-controlled blood pressure is defined in this protocol as consistently ≤ 140 mm Hg systolic and ≤ 90 mm Hg diastolic, with or without medication, with only isolated, brief instances of higher readings, which must be ≤ 150 mm Hg systolic and ≤ 100 mm Hg diastolic. For these volunteers, blood pressure must be ≤ 140 mm Hg systolic and ≤ 90 mm Hg diastolic at enrollment.
    • If a person has NOT been found to have elevated blood pressure or hypertension during screening or previously, exclude for systolic blood pressure ≥ 150 mm Hg at enrollment or diastolic blood pressure ≥ 100 mm Hg at enrollment.

24. Bleeding disorder diagnosed by a clinician (eg, factor deficiency, coagulopathy, or platelet disorder requiring special precautions)

25. Malignancy (not exclusoinary: volunteer who has had malignancy excised surgically and who, in the investigator's estimation, has a reasonable assurance of sustained cure, or who is unlikely to experience recurrence of malignancy during the period of the study)

26. Seizure disorder: History of seizure(s) within past 3 years. Also exclude if volunteer has used medications in order to prevent or treat seizure(s) at any time within the past 3 years.

27. Asplenia: any condition resulting in the absence of a functional spleen

28. History of generalized urticaria, angioedema, or anaphylaxis (not exclusionary: angioedema or anaphylaxis to a known trigger with at least 5 years since last reaction to demonstrate satisfactory avoidance of trigger)