Lynozyfic
linvoseltamab
Species
Monkey
Longest study
14 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“Overall, data indicate that linvoseltamab bound human and Cynomolgus monkey BCMA, but not rat or mouse BCMA.”
Why that species
Binds human and monkey BCMA (monkey lower affinity, KD 24.6 nM vs 437 pM human) and CD3 on both; no rat/mouse BCMA binding
“Overall, data indicate that linvoseltamab bound human and Cynomolgus monkey BCMA, but not rat or mouse BCMA.”
Surrogate molecule
No surrogate; clinical molecule (REGN5458) tested in cynomolgus monkey
“Two repeat dose toxicology studies were performed by the applicant, (Study R5458-TX-17179 and Study r5458-tx-20118).”
Study lengthopen answer page →
Longest pivotal study
14 weeks
“The subsequent toxicology study was initially programmed for 26 weeks of treatment but due to declining clinical condition that necessitated early sacrifice of a number of animals for welfare reasons, the study was stopped after 9 (total of 9 doses; 20 mg/kg group) or 14 weeks”
Pivotal GLP studies
GLP cynomolgus 5-week IV (0.1/1/10 mg/kg, 12-wk recovery) and 9- or 14-week IV (1/5/20 mg/kg, 13-wk recovery) studies
“Study R5458-TX-17179: A 5-Week Intravenous Infusion Toxicity and Toxicokinetic Study in Cynomolgus Monkeys With a 12-Week Dose-Free Recovery Phase”
Route in tox
IV (infusion/bolus)
“Male and female Cynomolgus monkeys, assigned to 4 groups, were administered once weekly for 5 weeks via intravenous infusion”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (antibody not expected to interact with DNA)
“No genotoxicity studies were conducted with linvoseltamab as antibodies are not expected to interact directly with DNA or other chromosomal material.”
Carcinogenicity
Not conducted (ICH S9, advanced malignancy)
“As linvoseltamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with linvoseltamab, consistent with ICH S9 guideline Nonclinical Evaluation of Anticancer Pharmaceuticals.”
Reproductive & developmental
Not conducted; weight-of-evidence (T-cell activation, cytokine release, B-cell depletion, placental IgG transfer)
“The Applicant provided a weight of evidence (WOE)-based risk assessment to assess the potential for reproductive and developmental toxicities.”
Safety pharmacology
Incorporated into 5-week GLP monkey study (telemetry ECG, BP, respiration, CNS); no effects to 10 mg/kg/week
“Safety pharmacology evaluations were integrated into a GLP-compliant repeat-dose toxicology study conducted in Cynomolgus monkeys using linvoseltamab (R5458-TX-17179, also see Repeat dose toxicity).”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
5-week: HNSTD 10 mg/kg/wk; 9/14-week: NOAEL not determined (early sacrifice at all doses; multi-organ inflammation, peritonitis/pleuritis, body weight loss)
“In the 9- or 14-week study, a NOAEL could not be determined.”
Risksopen answer page →
Immune & cytokine safety
Transient emesis with CRP/cytokine increase; sustained CRP, IL-2, IL-6, MCP-1 inflammation; ADA in 36-47% of monkeys reduced exposure
“the most severely impacted animals showed a dose-dependent induction of CRP that correlated with increased IL-2, IL-6, and MCP-1.”
Biodistribution & persistence
No distribution studies; GLP tissue cross-reactivity (human and monkey, incl. fetal) limited to mononuclear leukocytes, no unanticipated binding
“No unanticipated cross-reactivity of linvoseltamab was observed in either study.”
Modality-specific risk
Cytokine release/T-cell activation with multi-organ inflammation and infection risk from B-cell/plasma cell depletion
“Decreased B-cells and plasma cells likely contributed to decreased immunoglobulins causing secondary infections.”