Actemra
tocilizumab · IL-6RImmunogenic in monkeys with inverse dose relationship (ADA lower at high doses)
Sarclisa: which risks did reviewers probe?
isatuximab · CD38
Immune & cytokine safety
No significant cytokine release from human PBMCs or WBCs in vitro
“In contrast, no significant release of cytokines was observed after isatuximab incubation under any of the various assays and conditions used and for any of the donors tested.”
Biodistribution & persistence
Human TCR: lymphoid tissues and bone marrow, plus pituitary endothelium and prostate epithelium
“The TCR test indicated that isatuximab-specific binding was mainly in the lymphoid tissues (spleen, thymus, lymph node and tonsil) and in the bone marrow; binding was also detected in the pituitary gland (endothelial cells) and prostate gland (glandular epithelial cells).”
Modality-specific risk
No relevant tox species; safety assessment relies on mechanism of action and clinical findings
“The safety assessment of isatuximab for general toxicity is mainly based on the mechanism of action (MOA) and findings in patients.”
Anti-drug antibodies: animals
No ADA with the clinical batch; 4 of 6 monkeys given an expired batch ADA positive (titers 160-320)
“All samples collected from animals treated with batch C1053598 (20, 50 and 100 mg/kg/week) were found to be ADA negative, while the majority of the samples from animals (4 out of 6) that received the batch VAB-LCX1-000004, which was beyond its current shelf-life, were ADA positive, with titers ranging from 160 to 320.”
Anti-drug antibodies: patients
Treatment-emergent ADA 2.3% (N=564); persistent ADA 0.35%; neutralizing status not determined
“In antidrug-antibody (ADA) evaluable patients from all completed studies (N=564), the incidence of treatment emergent ADAs was low (2.3%), with 2 patients having a persistent treatment induced ADA (0.35%). However, since no confirmed positive ADA samples were detected in the pivotal Phase 3 study, the neutralizing ADA status was not determined.”
Same question, other monoclonal antibodies
Adakveo
crizanlizumab · P-selectinADA in 40% of treated monkeys in the 26-week study, with hypersensitivity reactions in some animals
Adbry
tralokinumab · IL-13No significant modulation of CD4/CD8 T cells, NK cells or mature B cells in 26-week monkey study
Aduhelm
aducanumab · Aggregated amyloid-βNo anti-drug antibodies in the 4-week monkey study
Aimovig
erenumab · CGRP receptorADA in 3 low-dose monkeys reduced drug exposure (Cmax and AUC)
Ajovy
fremanezumab · CGRPCiliary vessel inflammation with immune complex deposition in a monkey study (hypersensitivity-type); not reproduced in the 6-month study
Alhemo
concizumab · TFPIADA induced in all monkey repeat-dose studies, causing loss of exposure without affecting study interpretation
Andembry
garadacimab · Factor XIIaMouse deaths and premature euthanasia, mainly at low IV dose, attributed to immunogenicity to the human protein
Anthim
obiltoxaximab · B. anthracis PAAnti-drug antibodies in 8 of 12 monkeys (75%) after a single dose
Arzerra
ofatumumab · CD20Monkey complement activation and IL-6 rise suggesting mild cytokine release; ADA in all studies; reduced KLH antibody response
Avastin
bevacizumab · VEGF-ARabbits developed anti-drug antibodies 8-11 days after start of dosing, limiting rabbit study duration
Bavencio
avelumab · PD-L1Human PBMC cytokine release limited to a 5-7 fold TNFα increase at 24 hours
Benlysta
belimumab · BLyS (BAFF)ADA in 12 of 124 monkeys (6 with reduced exposure)
Beovu
brolucizumab · VEGF-AWeakly immunogenic; ADA in all groups (including pre-existing) without effect on exposure
Beyfortus
nirsevimab · RSV F proteinNo ADA during dosing; ADA in 4 (22.2%) recovery monkeys; no evidence of immunotoxicity
Bimzelx
bimekizumab · IL-17A/IL-17FIncreased infection risk from reduced muco-epidermal immunity in single and repeat-dose monkey studies
Briumvi
ublituximab · CD20No significant changes in serum IL-6, IL-8, IFN-γ or TNF-α in monkeys after repeated dosing
Cablivi
caplacizumab · von Willebrand factor (A1 domain)Anti-drug antibodies observed but did not affect exposure except in one 26-week monkey
Campath
alemtuzumab · CD52IL-6, IL-10, MCP-1 and TNF-α elevated 2-4 hours after dosing in huCD52 transgenic mice
Cimzia
certolizumab pegol · TNF-αAnti-drug antibody incidence 10-20% in main monkey toxicity studies
Cinqair
reslizumab · IL-5ADA in 3 monkeys in pivotal study; one at 25 mg/kg had repeated hypersensitivity-type infusion reactions
Cosentyx
secukinumab · IL-17AImmunotoxicity in one high-dose female: skin lesions, splenic lymphocytic atrophy, decreased NK cell activity and TDAR
Crysvita
burosumab · FGF23ADA in some monkeys reduced burosumab exposure and attenuated phosphate and vitamin D increases
Cyramza
ramucirumab · VEGFR2ADA in 5/7 monkeys at 5 mg/kg and 3/9 at 16 mg/kg; none at the high dose
Danyelza
naxitamab · GD2In vitro ADCC with nude rat effector cells ~22% vs 55% with human NK cells, underpredicting human activity
Darzalex
daratumumab · CD38Cytokine release (TNF-α, IL-6, IFN-γ) caused one chimpanzee death at 5 mg/kg shortly after dosing
Dupixent
dupilumab · IL-4RaNo effect of REGN646 on antibody response to KLH immunization
Ebanga
ansuvimab · Zaire ebolavirus glycoproteinNo exposure or activity changes suggesting meaningful anti-drug antibody formation in monkeys
Ebglyss
lebrikizumab · IL-13Low-level ADA in several monkeys without appreciable impact on exposure
Emgality
galcanezumab · CGRPDecreased plasma drug levels after repeat dosing attributed to ADA formation
Empliciti
elotuzumab · SLAMF7In vitro human whole-blood assay: elevated levels of 10 cytokines with elotuzumab
Enflonsia
clesrovimab · RSV F protein (site IV)In vitro interleukin release by human white blood cells prompted a clinical hold for potential cytokine release syndrome
Enjaymo
sutimlimab · Complement C1sMinimally immunogenic: ADA in 2/10 animals at 60 and 1/10 at 180 mg/kg/week, increased clearance, no immune complex disease
Enspryng
satralizumab · IL-6RLow cytokine release syndrome risk in human whole-blood cytokine assay
Entyvio
vedolizumab · α4β7-integrinNo T-lymphocyte activation or cytokine release in human whole blood in vitro
Erbitux
cetuximab · EGFRAnti-drug antibodies in 3/22 monkeys (13.6%), affecting serum concentration in one
Evenity
romosozumab · SclerostinNo adverse consequences of ADAs in rats and monkeys; immune complex disease in a few rabbits
Evkeeza
evinacumab · ANGPTL3Low ADA responses in rats and monkeys; highly immunogenic in rabbits
Exdensur
depemokimab · IL-5ADA in 6 monkeys, exposure reduced in one high-titer animal; immune-complex vasculitis in one monkey; no dedicated immunotoxicity studies
Fasenra
benralizumab · IL-5RαADA in 8.3%, 25% and 5.5% of monkeys in the 9-, 15- and 39-week studies
Gamifant
emapalumab · IFN-γTransient impairment of primary anti-KLH IgG response (TDAR) in monkeys; robust response after second challenge
Gazyva
obinutuzumab · CD20In vitro whole-blood assays: cytokine release (IL-6, IL-8, TNF) predicting first-infusion reactions; monkey ADA with hypersensitivity; opportunistic infections
Herceptin
trastuzumab · HER2Anti-drug antibodies rare: 1/84 animals in repeat-dose studies
Humira
adalimumab · TNF-αAnti-drug antibodies (MAHA, PAHA) after single doses in mice and monkeys; PAHA neutralising
Hympavzi
marstacimab · TFPINon-neutralizing ADA in ~28% of rats in 3-month study; no ADA in 3-month monkey or 6-month rat studies
Ilaris
canakinumab · IL-1βNo anti-drug antibodies detected in marmoset or mouse surrogate toxicity studies
Ilumya
tildrakizumab · IL-23 p19No tildrakizumab-related changes in infant lymphocyte counts or TDAR responses (PPND study)
Imaavy
nipocalimab · FcRnKLH TDAR suppressed as expected from mechanism; tetanus toxoid response preserved during recovery in monkeys
Imfinzi
durvalumab · PD-L1No cytokine release in a human whole blood assay
Imjudo
tremelimumab · CTLA-4No TNF-α, IL-6 or IL-1β release from unstimulated human PBMC or whole blood in vitro
Jemperli
dostarlimab · PD-1No in vitro cytokine release from human PBMCs at up to 400 µg/well
Kevzara
sarilumab · IL-6RSmall decreases in primary and secondary IgG TDAR responses to KLH at >=5 mg/kg/week, attributed to immunosuppression
Keytruda
pembrolizumab · PD-1No cytokine release (IL-2) from hPBMCs cultured on immobilized pembrolizumab
Kisunla
donanemab · Amyloid-β (N3pG)ADA in 1/6 low, 1/6 mid, 4/12 high-dose monkeys (1/12 controls); reduced exposure only in 2 high-titer recovery animals
Lartruvo
olaratumab · PDGFRαADA in at least 22% of monkeys causing variable exposure; peripheral blood immunophenotyping unremarkable
Leqembi
lecanemab · Amyloid-β protofibrilsNo ADAs detected in monkey IV repeat-dose and SC local irritation studies
Libtayo
cemiplimab · PD-1Anti-drug antibodies in 53% of monkeys in 26-week study (92%, 33%, 33% at 2, 10, 50 mg/kg)
Loqtorzi
toripalimab · PD-1In vitro cytokine release with immobilized or soluble antibody similar to negative control; cytokine release unlikely
Lucentis
ranibizumab · VEGF-AHighly immunogenic in rabbits; significant antigenicity in monkeys, even within the eye
Margenza
margetuximab · HER2No serum IFN-γ, IL-2, IL-5, IL-6, IL-10 or TNF-α increase in monkeys; partially reversible NK-cell decreases
Monjuvi
tafasitamab · CD19B-cell depletion with reduced serum IgG and reduced TDAR (KLH primary, tetanus toxoid secondary response)
Nemluvio
nemolizumab · IL-31RAIn vitro whole-blood cytokine release far below alemtuzumab/TGN1412 controls; no effects on monkey TDAR, lymphocyte subsets or serum cytokines; ADA in some monkeys
Niktimvo
axatilimab · CSF-1RADA inversely related to dose (6/12, 3/12, 1/12 animals in 13-week study), reducing exposure and PD effect
Nucala
mepolizumab · IL-5No effect on infant vaccine (Tripedia) titers in monkey PPND; ADA in one mother and its infant at 10 mg/kg
Ocrevus
ocrelizumab · CD20ADAs at all dose levels, most evident at 10 mg/kg or lower
Omvoh
mirikizumab · IL-23 p19No effect on immunophenotyping, T-dependent antibody response or NK-cell cytotoxicity in monkeys
Opdivo
nivolumab · PD-1No CDC, ADCC or direct cytokine release in the absence of TCR activation
Pasatru
garetosmab · Activin ASystemic hypersensitivity reactions and immunogenicity considered potential risks of treatment
Penpulimab
penpulimab · PD-1ADA incidence 63.33% (6-week study) and 93.33% (13-week study) in monkeys
Perjeta
pertuzumab · HER2No anti-pertuzumab antibodies detected in 7- and 26-week monkey studies; not immunogenic
Piasky
crovalimab · Complement C5ADA in 21/30 SC and 8/10 IV monkeys in the 26-week study
Portrazza
necitumumab · EGFRMonkey immunogenicity could not be assessed reliably (drug interference with ADA assay); exposure maintained on repeat dosing
Poteligeo
mogamulizumab · CCR4In vitro cytokine release (IL-6, TNF-α, IFN-γ) varied by assay format, greatest in solid-phase PBMC assays
Praluent
alirocumab · PCSK9Low anti-drug antibody incidence; neutralizing antibodies low in rats and negligible in monkeys
Praxbind
idarucizumab · DabigatranNo anti-dabigatran antibodies; circulating immune complexes normal; no renal immune complex deposition in monkeys
Prolia
denosumab · RANKLHighly immunogenic in monkeys (ADA in most studies); no major immunomodulatory changes; no dedicated immunotoxicity studies
Remicade
infliximab · TNF-αAnti-TNF-α antibodies reduce host defence in intracellular infection models, increasing infection-induced mortality
Repatha
evolocumab · PCSK9Apparent TDAR suppression in monkeys was no longer significant after restricting analysis to KLH-naive animals
Rituxan
rituximab · CD20B-cell depletion only; T-cells unaffected, no infections; monkey anti-chimeric antibodies formed
Rystiggo
rozanolixizumab · FcRnNo cytokine release in any of four in vitro assay formats
Saphnelo
anifrolumab · IFNAR1Arteritis in high-dose males attributed to ADA-mediated immune complex deposition (anifrolumab, IgM, C3b)
Siliq
brodalumab · IL-17RANo significant effects on standard immune endpoints, immunophenotyping or KLH TDAR in adult and juvenile monkeys
Simponi
golimumab · TNF-αMonkey anti-drug antibodies more frequent at lower doses (3-10 mg/kg) than at 25-50 mg/kg
Simulect
basiliximab · IL-2Rα (CD25)Anti-idiotype antibodies in 75% of low-dose monkeys after four weeks, increasing clearance; offspring immunotoxicity not studied
Skyrizi
risankizumab · IL-23 p19No immunosuppression (TDAR) or T-cell depletion in monkey toxicity studies
Soliris
eculizumab · Complement C5No lymph node findings with surrogate in 26-week mouse study; no dedicated immunotoxicity or cytokine studies
Spevigo
spesolimab · IL-36RHuman whole-blood cytokine release assay: no IL-2, IL-6, TNF-α or IFN-γ release; low cytokine release potential
Stelara
ustekinumab · IL-12/23 p40No adverse effects on functional immune responses, circulating lymphocyte subsets or lymphoid T- and B-cell distribution
Sylvant
siltuximab · IL-6Lower anti-KLH IgM/IgG (TDAR), reduced splenic germinal centers, lower globulin; first-dose infusion reaction (facial swelling) in 1/52 monkeys
Synagis
palivizumab · RSV F proteinImmunogenic in cynomolgus monkeys: anti-drug antibodies in low- and high-dose groups
Takhzyro
lanadelumab · Plasma kallikreinNeutralizing ADA in nearly all rats in the 4-week SC study
Taltz
ixekizumab · IL-17ANo effects on lymphocyte subsets or KLH TDAR; neutralizing ADA in one high-dose monkey after recovery
Tecentriq
atezolizumab · PD-L1No cytokine release from human PBMCs up to 250 µg/mL; minimal Fcγ receptor binding, no ADCC up to 10 µg/mL
Tepezza
teprotumumab · IGF-1RReversible thymic atrophy/lymphoid depletion without peripheral T-cell depletion or infections; juvenile TDAR (KLH) unimpaired; ADA accelerated clearance
Tevimbra
tislelizumab · PD-1In vitro immunotoxicity/cytokine release assays: only neutralising ADA and possible enhanced recall response
Tezspire
tezepelumab · TSLPMild to moderate decrease in anti-KLH IgG titers (TDAR) at 300 mg/kg
Tremfya
guselkumab · IL-23 p19No effect on hematology, immunophenotyping, TDAR, immune tissue histopathology or T/B-cell distribution in monkeys or offspring
Trogarzo
ibalizumab · CD4Anti-drug antibodies in 83% (25 mg/kg) and 58% (50 mg/kg) of cynomolgus monkeys
Tysabri
natalizumab · α4-integrinADA-driven shock-like reactions with complement activation and immune complexes in some monkeys
Tzield
teplizumab · CD3Transient cytokine increases (TNF, IL-6, IL-10, IFN-gamma) in chimpanzees; slight IL-6/IL-12 rise with surrogate in mice; anaphylaxis on intermittent surrogate dosing
Ultomiris
ravulizumab · Complement C5Repeat SC dosing in rabbits caused severe systemic immune-complex (type III) hypersensitivity; ADA in monkeys and rabbits
Unituxin
dinutuximab · GD2Rats: increased lymphocytes, neutrophils and NK cells; anti-drug antibodies affected exposure
Unloxcyt
cosibelimab · PD-L1ADA in 10-50% of monkeys during dosing or recovery, incidence decreasing with dose
Uplizna
inebilizumab · CD19Anti-drug antibodies mainly at lowest doses, correlated with B-cell depletion/recovery kinetics
Vectibix
panitumumab · EGFRAnti-panitumumab antibodies (MAHA) in 9/10 low-dose, 2/10 mid-dose and 1/10 high-dose monkeys
Veopoz
pozelimab · Complement C5ADA in 9 of 36 treated monkeys (26-week study); ADA did not notably affect exposure
Voyxact
sibeprenlimab · APRILADAs in 20% of monkeys at 25 and 50 mg/kg SC, none at high dose, no exposure effect
Vyepti
eptinezumab · CGRPAnaphylactoid reaction in a monkey associated with high ADA; animal immunogenicity not considered predictive of clinical risk
Vyloy
zolbetuximab · Claudin 18.2ADA in 13/18 monkeys after a single dose; none detected in the 4-week monkey toxicity study
Xolair
omalizumab · IgEOmalizumab:IgE complexes without immune complex disease; anti-drug antibodies in monkeys (all positive after inhalation), non-neutralizing
Yartemlea
narsoplimab · MASP-2ADA in 2 of 40 treated monkeys, with no effect on exposure
Yervoy
ipilimumab · CTLA-4Generally not immunogenic in monkeys; ADA in 12% including weak responders
Zinbryta
daclizumab · IL-2Rα (CD25)ADA detected in monkeys, reducing exposure in some animals without compromising study adequacy
Zinplava
bezlotoxumab · C. difficile toxin BNo anti-drug antibodies detected in treated mice
Zynyz
retifanlimab · PD-1No cytokine production by human PBMCs with soluble or immobilized antibody at 10-100 µg/mL
Raxibacumab
raxibacumab · B. anthracis protective antigenNot stated in public reviews