SEMA4D Blockade Safety and Brain Metabolic Activity in Alzheimer's Disease (AD)

Inclusion

1. Written informed consent from the participant and legally acceptable representative (trial partner).

2. Have a reliable and competent trial partner who must have a close relationship with the participant, who has face to face contact at least three days a week for a minimum of ten waking hours a week and is willing to accompany the participant to all trial visits. The trial partner should understand the nature of the trial and adhere to trial requirements (e.g., dose, visit schedules, receive phone calls, and evaluations).

3. Male and female participants between the ages of 55 to 85 (inclusive).

4. If female, not be of childbearing potential as indicated by one of the following:

a. Has reached natural menopause defined as either:

5. If male, must agree to use a reliable method of birth control (condoms with contraceptive forms or sexual abstinence) during the study and for 6 months after the last dose of study drug.

6. Must fulfill one of the following:

1. A documented amyloid PET scan (florbetaben F18, florbetapir F18, or flutametamol F18) determined as positive by the Investigator obtained at any time prior to the Screening visit; or

2. A documented positive amyloid CSF result obtained at any time prior to the Screening visit; or

3. Investigator has knowledge of positive amyloid PET scan or positive amyloid CSF result obtained previously; or

4. A positive amyloid CSF result at screening. The cut-off value for CSF Aβ1-42 or CSF Aβ1-42/Aβ1-40 ratio will be based on the value determined by Vaccinex

7. Evidence of cognitive impairment based on history and neuropsychological testing that meet the diagnostic criteria for probable Alzheimer's dementia.

8. Global Clinical Dementia Rating (CDR) of 0.5 or 1.0

9. MMSE score of 17-26, inclusive.

10. Adequate vision, hearing, and motor function to comply with testing.

11. If receiving medications for AD (including but not limited to donepezil, rivastigmine, galantamine, tacrine, and memantine), be on a stable dose for at least 8 weeks prior to Screening Visit.

12. If on stable doses of centrally-acting medications, be on a stable dose for 8 weeks prior to Screening Visit.

13. In the opinion of the Investigator, is in reasonably good health over the last 6 months and any chronic disease is stable based on medical history and screening assessments.

Exclusion

1. Inability to comply with visit schedule or other protocol requirements.

2. Have participated in an investigational drug or device study within 30 days of the Baseline Visit. If previous investigational drug was a monoclonal antibody, antibody-drug conjugate, or similar protein therapeutic, 180 days or 5 half-lives, whichever occurs first.

3. Have a known allergy to any ingredient in the study drug formulation.

4. Have a body weight greater than 125 kg.

5. Are a suicide risk, as determined by meeting any of the following criteria:

1. Suicide attempt within one year prior to the Baseline Visit.

2. Suicidal ideation as defined by a positive response to question 4 and 5 on the C-SSRS within 60 days of the Baseline Visit.

6. Have a history of substance abuse (based on DSMIV criteria) within the past 12 months prior to Screening.

7. Significant acute or chronic infection at Screening including, among others: Known history of human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as, HBV surface antigen positive or positive HCV antibody with reflex to positive HCV RNA) at Screening.

8. Have clinically significant laboratory or ECG abnormalities at Screening in the opinion of the Investigator.

9. Have clinically relevant hematologic, hepatic, cardiac, or renal disease.

10. Have a clinically significant medical, surgical, laboratory, or behavioral abnormality which in the judgment of the Investigator makes the participant unsuitable for the study, as well as anyone with a history of malignancy of any type within 2 years of Screening. Persons with a history of surgically excised non-melanoma skin cancers, superficial bladder or prostate cancer are permitted.

11. Participants who have a diagnosis of a neurological condition causing cognitive impairment other than sporadic mild dementia due to AD (e.g., Lewy body disease or frontotemporal dementia), a primary psychiatric diagnosis (e.g., Cognitive Impairment due to Schizophrenia, CIAS), history of frequent concussions or significant findings on brain MRI at screening inconsistent with AD (e.g., cerebrovascular disease or tumor).

12. Have any of the following conditions (which would exclude MRI or PET participation):

1. Participants deemed unable to cooperate due to claustrophobia, inability to lie on scanner bed for 45 minutes, or inability to achieve venous access sufficient for tracer or pepinemab administration.

2. An implant/device/condition that is contraindicated for MRI (e.g., pacemaker, severe claustrophobia, prosthetic heart valve, any metal fragments in the eyes or body--in some cases, an X-ray may be needed before an MRI scan, to ensure it is safe to enter the scanner).

3. Body habitus that would impede completion of imaging scans.

13. Has an MRI scan obtained at Screening that shows evidence of a neurological disorder other than early AD or > 4 cerebral microhemorrhages (regardless of their anatomical location or diagnostic characterization as "possible" or "definite"), a single area of superficial siderosis,

14. Any other clinically significant finding on MRI (e.g., any lesion that may account for their cognitive impairment, including but not limited to brain tumor, severe white matter disease arteriovenous malformation, cavernous hemangioma, or any infarct in a strategic cortical or subcortical location).

15. Are undergoing FDG-PET and have received research-related radiation exposure that exceeds institutional guidelines in the prior year if applicable.

16. Are undergoing a LP for CSF collection and have any of the following conditions: uncorrected bleeding or clotting disorders, skin infections near the site of the LP, suspicion of increased intracranial pressure, allergies to numbing medications (local anesthetics), acute spinal trauma.

17. Are undergoing a LP for CSF collection and taking any of the following types of anticoagulants: coumarins and indandiones, Factor Xa inhibitors, heparins, or thrombin inhibitors.

18. Has received treatment with any FDA accelerated approval therapy for treatment of Alzheimer's Disease

19. Has a Screening MRI that shows Amyloid-related imaging abnormalities edema (ARIA-E)