title: Nonclinical Safety Evaluation of VX15/2503, a Humanized IgG4 Anti-SEMA4D Antibody.
abstract: The humanized IgG4 monoclonal antibody VX15/2503 bound with 1 to 5 nmol/L affinity to purified recombinant semaphorin 4D (SEMA4D; CD100) produced using murine, rat, cynomolgus macaque, and human sequences. The affinity for native SEMA4D expressed on macaque T lymphocytes was approximately 0.6 nmol/L. Tissues from rats and cynomolgus macaques demonstrated specific staining only with resident lymphocytes. Single-dose and one-month toxicology/PK studies used VX15/2503 dose levels of 0 to 100 mg/kg. No toxicity was observed with either species in these studies, thus the no observed adverse effect level (NOAEL) was 100 mg/kg. Cmax, exposure, and half-life values were similar for both rats and macaques. The NOAEL in a primate maximum feasible dose study was 200 mg/kg. Saturation of T-cell-associated SEMA4D occurred following administration of single doses of 0.1 mg/kg and above; five weekly injections of VX15/2503 at a dose level of 100 mg/kg produced saturation lasting for more than 120 and 130 days, respectively, for rats and primates. Macaques administered five weekly doses of VX15/2503 showed dose-dependent reductions of 2- to 3-fold in T-cell SEMA4D (cSEMA4D) expression levels compared with controls. Reduced cSEMA4D expression levels continued until serum antibody concentrations were 2 to 5 μg/mL, and thereafter normal cSEMA4D levels were restored. On the basis of these data, a phase I clinical study of the safety and tolerability of VX15/2503 was conducted, enrolling adult patients with advanced solid tumor diseases; a single-dose, dose escalation, phase I safety study was also initiated with subjects with multiple sclerosis.
authors: Vaccinex, Inc., Rochester, New York. jleonard@vaccinex.com.
authors: John E
authors: JE
authors: Leonard
authors: Vaccinex, Inc., Rochester, New York.
authors: Terrence L
authors: TL
authors: Fisher
authors: Vaccinex, Inc., Rochester, New York.
authors: Laurie A
authors: LA
authors: Winter
authors: Vaccinex, Inc., Rochester, New York.
authors: Chad A
authors: CA
authors: Cornelius
authors: Vaccinex, Inc., Rochester, New York.
authors: Christine
authors: C
authors: Reilly
authors: Vaccinex, Inc., Rochester, New York.
authors: Ernest S
authors: ES
authors: Smith
authors: Vaccinex, Inc., Rochester, New York.
authors: Maurice
authors: M
authors: Zauderer
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism; D018655:Lymphocyte Count; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D039961:Semaphorins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000970:Antineoplastic Agents; C093224:CD100 antigen; D039961:Semaphorins; C000604277:VX15-2503 monoclonal antibody