Bavencio: which risks did reviewers probe?

Immunogenic in monkeys with inverse dose relationship (ADA lower at high doses)

ADA in 40% of treated monkeys in the 26-week study, with hypersensitivity reactions in some animals

No significant modulation of CD4/CD8 T cells, NK cells or mature B cells in 26-week monkey study

No anti-drug antibodies in the 4-week monkey study

ADA in 3 low-dose monkeys reduced drug exposure (Cmax and AUC)

Ciliary vessel inflammation with immune complex deposition in a monkey study (hypersensitivity-type); not reproduced in the 6-month study

ADA induced in all monkey repeat-dose studies, causing loss of exposure without affecting study interpretation

Mouse deaths and premature euthanasia, mainly at low IV dose, attributed to immunogenicity to the human protein

Anti-drug antibodies in 8 of 12 monkeys (75%) after a single dose

Monkey complement activation and IL-6 rise suggesting mild cytokine release; ADA in all studies; reduced KLH antibody response

Rabbits developed anti-drug antibodies 8-11 days after start of dosing, limiting rabbit study duration

ADA in 12 of 124 monkeys (6 with reduced exposure)

Weakly immunogenic; ADA in all groups (including pre-existing) without effect on exposure

No ADA during dosing; ADA in 4 (22.2%) recovery monkeys; no evidence of immunotoxicity

Increased infection risk from reduced muco-epidermal immunity in single and repeat-dose monkey studies

No significant changes in serum IL-6, IL-8, IFN-γ or TNF-α in monkeys after repeated dosing

Anti-drug antibodies observed but did not affect exposure except in one 26-week monkey

IL-6, IL-10, MCP-1 and TNF-α elevated 2-4 hours after dosing in huCD52 transgenic mice

Anti-drug antibody incidence 10-20% in main monkey toxicity studies

ADA in 3 monkeys in pivotal study; one at 25 mg/kg had repeated hypersensitivity-type infusion reactions

Immunotoxicity in one high-dose female: skin lesions, splenic lymphocytic atrophy, decreased NK cell activity and TDAR

ADA in some monkeys reduced burosumab exposure and attenuated phosphate and vitamin D increases

ADA in 5/7 monkeys at 5 mg/kg and 3/9 at 16 mg/kg; none at the high dose

In vitro ADCC with nude rat effector cells ~22% vs 55% with human NK cells, underpredicting human activity

Cytokine release (TNF-α, IL-6, IFN-γ) caused one chimpanzee death at 5 mg/kg shortly after dosing

No effect of REGN646 on antibody response to KLH immunization

No exposure or activity changes suggesting meaningful anti-drug antibody formation in monkeys

Low-level ADA in several monkeys without appreciable impact on exposure

Decreased plasma drug levels after repeat dosing attributed to ADA formation

In vitro human whole-blood assay: elevated levels of 10 cytokines with elotuzumab

In vitro interleukin release by human white blood cells prompted a clinical hold for potential cytokine release syndrome

Minimally immunogenic: ADA in 2/10 animals at 60 and 1/10 at 180 mg/kg/week, increased clearance, no immune complex disease

Low cytokine release syndrome risk in human whole-blood cytokine assay

No T-lymphocyte activation or cytokine release in human whole blood in vitro

Anti-drug antibodies in 3/22 monkeys (13.6%), affecting serum concentration in one

No adverse consequences of ADAs in rats and monkeys; immune complex disease in a few rabbits

Low ADA responses in rats and monkeys; highly immunogenic in rabbits

ADA in 6 monkeys, exposure reduced in one high-titer animal; immune-complex vasculitis in one monkey; no dedicated immunotoxicity studies

ADA in 8.3%, 25% and 5.5% of monkeys in the 9-, 15- and 39-week studies

Transient impairment of primary anti-KLH IgG response (TDAR) in monkeys; robust response after second challenge

In vitro whole-blood assays: cytokine release (IL-6, IL-8, TNF) predicting first-infusion reactions; monkey ADA with hypersensitivity; opportunistic infections

Anti-drug antibodies rare: 1/84 animals in repeat-dose studies

Anti-drug antibodies (MAHA, PAHA) after single doses in mice and monkeys; PAHA neutralising

Non-neutralizing ADA in ~28% of rats in 3-month study; no ADA in 3-month monkey or 6-month rat studies

No anti-drug antibodies detected in marmoset or mouse surrogate toxicity studies

No tildrakizumab-related changes in infant lymphocyte counts or TDAR responses (PPND study)

KLH TDAR suppressed as expected from mechanism; tetanus toxoid response preserved during recovery in monkeys

No cytokine release in a human whole blood assay

No TNF-α, IL-6 or IL-1β release from unstimulated human PBMC or whole blood in vitro

No in vitro cytokine release from human PBMCs at up to 400 µg/well

Small decreases in primary and secondary IgG TDAR responses to KLH at >=5 mg/kg/week, attributed to immunosuppression

No cytokine release (IL-2) from hPBMCs cultured on immobilized pembrolizumab

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

ADA in at least 22% of monkeys causing variable exposure; peripheral blood immunophenotyping unremarkable

No ADAs detected in monkey IV repeat-dose and SC local irritation studies

Anti-drug antibodies in 53% of monkeys in 26-week study (92%, 33%, 33% at 2, 10, 50 mg/kg)

In vitro cytokine release with immobilized or soluble antibody similar to negative control; cytokine release unlikely

Highly immunogenic in rabbits; significant antigenicity in monkeys, even within the eye

No serum IFN-γ, IL-2, IL-5, IL-6, IL-10 or TNF-α increase in monkeys; partially reversible NK-cell decreases

B-cell depletion with reduced serum IgG and reduced TDAR (KLH primary, tetanus toxoid secondary response)

In vitro whole-blood cytokine release far below alemtuzumab/TGN1412 controls; no effects on monkey TDAR, lymphocyte subsets or serum cytokines; ADA in some monkeys

ADA inversely related to dose (6/12, 3/12, 1/12 animals in 13-week study), reducing exposure and PD effect

No effect on infant vaccine (Tripedia) titers in monkey PPND; ADA in one mother and its infant at 10 mg/kg

ADAs at all dose levels, most evident at 10 mg/kg or lower

No effect on immunophenotyping, T-dependent antibody response or NK-cell cytotoxicity in monkeys

No CDC, ADCC or direct cytokine release in the absence of TCR activation

Systemic hypersensitivity reactions and immunogenicity considered potential risks of treatment

ADA incidence 63.33% (6-week study) and 93.33% (13-week study) in monkeys

No anti-pertuzumab antibodies detected in 7- and 26-week monkey studies; not immunogenic

ADA in 21/30 SC and 8/10 IV monkeys in the 26-week study

Monkey immunogenicity could not be assessed reliably (drug interference with ADA assay); exposure maintained on repeat dosing

In vitro cytokine release (IL-6, TNF-α, IFN-γ) varied by assay format, greatest in solid-phase PBMC assays

Low anti-drug antibody incidence; neutralizing antibodies low in rats and negligible in monkeys

No anti-dabigatran antibodies; circulating immune complexes normal; no renal immune complex deposition in monkeys

Highly immunogenic in monkeys (ADA in most studies); no major immunomodulatory changes; no dedicated immunotoxicity studies

Anti-TNF-α antibodies reduce host defence in intracellular infection models, increasing infection-induced mortality

Apparent TDAR suppression in monkeys was no longer significant after restricting analysis to KLH-naive animals

B-cell depletion only; T-cells unaffected, no infections; monkey anti-chimeric antibodies formed

No cytokine release in any of four in vitro assay formats

Arteritis in high-dose males attributed to ADA-mediated immune complex deposition (anifrolumab, IgM, C3b)

No significant cytokine release from human PBMCs or WBCs in vitro

No significant effects on standard immune endpoints, immunophenotyping or KLH TDAR in adult and juvenile monkeys

Monkey anti-drug antibodies more frequent at lower doses (3-10 mg/kg) than at 25-50 mg/kg

Anti-idiotype antibodies in 75% of low-dose monkeys after four weeks, increasing clearance; offspring immunotoxicity not studied

No immunosuppression (TDAR) or T-cell depletion in monkey toxicity studies

No lymph node findings with surrogate in 26-week mouse study; no dedicated immunotoxicity or cytokine studies

Human whole-blood cytokine release assay: no IL-2, IL-6, TNF-α or IFN-γ release; low cytokine release potential

No adverse effects on functional immune responses, circulating lymphocyte subsets or lymphoid T- and B-cell distribution

Lower anti-KLH IgM/IgG (TDAR), reduced splenic germinal centers, lower globulin; first-dose infusion reaction (facial swelling) in 1/52 monkeys

Immunogenic in cynomolgus monkeys: anti-drug antibodies in low- and high-dose groups

Neutralizing ADA in nearly all rats in the 4-week SC study

No effects on lymphocyte subsets or KLH TDAR; neutralizing ADA in one high-dose monkey after recovery

No cytokine release from human PBMCs up to 250 µg/mL; minimal Fcγ receptor binding, no ADCC up to 10 µg/mL

Reversible thymic atrophy/lymphoid depletion without peripheral T-cell depletion or infections; juvenile TDAR (KLH) unimpaired; ADA accelerated clearance

In vitro immunotoxicity/cytokine release assays: only neutralising ADA and possible enhanced recall response

Mild to moderate decrease in anti-KLH IgG titers (TDAR) at 300 mg/kg

No effect on hematology, immunophenotyping, TDAR, immune tissue histopathology or T/B-cell distribution in monkeys or offspring

Anti-drug antibodies in 83% (25 mg/kg) and 58% (50 mg/kg) of cynomolgus monkeys

ADA-driven shock-like reactions with complement activation and immune complexes in some monkeys

Transient 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

Repeat SC dosing in rabbits caused severe systemic immune-complex (type III) hypersensitivity; ADA in monkeys and rabbits

Rats: increased lymphocytes, neutrophils and NK cells; anti-drug antibodies affected exposure

ADA in 10-50% of monkeys during dosing or recovery, incidence decreasing with dose

Anti-drug antibodies mainly at lowest doses, correlated with B-cell depletion/recovery kinetics

Anti-panitumumab antibodies (MAHA) in 9/10 low-dose, 2/10 mid-dose and 1/10 high-dose monkeys

ADA in 9 of 36 treated monkeys (26-week study); ADA did not notably affect exposure

ADAs in 20% of monkeys at 25 and 50 mg/kg SC, none at high dose, no exposure effect

Anaphylactoid reaction in a monkey associated with high ADA; animal immunogenicity not considered predictive of clinical risk

ADA in 13/18 monkeys after a single dose; none detected in the 4-week monkey toxicity study

Omalizumab:IgE complexes without immune complex disease; anti-drug antibodies in monkeys (all positive after inhalation), non-neutralizing

ADA in 2 of 40 treated monkeys, with no effect on exposure

Generally not immunogenic in monkeys; ADA in 12% including weak responders

ADA detected in monkeys, reducing exposure in some animals without compromising study adequacy

No anti-drug antibodies detected in treated mice

No cytokine production by human PBMCs with soluble or immobilized antibody at 10-100 µg/mL