Depatuxizumab mafodotin

Discontinued

ABT-414; depatux-m

Target

EGFR · EGFR

Sponsor

AbbVie

Indication

EGFR-amplified GBM

Target family

Receptor tyrosine kinase

RP2D dose

1.25 mg/kg

Q2WRP2D

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

38 adverse-event terms

Ocular

Any-grade

94%

G3+

60%

RP2D

sagittal schematic · Mixed

↳

Tissues shaded by reported adverse-event rate.

Cornea

94%

Express.

89.35%

Limbus

Express.

97.58%

Conjunctiva

Express.

93.02%

Lens

Express.

Retina / RPE

Express.

83.36%

9.4 nTPM

Off-target signature

94% corneal toxicity, yet the EGFR target is detected in only 89.35% of central cornea - toxicity is not explained by target expression.

Dominant tissue

Cornea

Surface subtype

Corneal (off-target)

Reversibility

Mixed

Reported ocular events

Corneal epitheliopathy (composite)94%

G3+ 60.4%n=323

Corneal epitheliopathy (eye disorders, composite)71.4%

G3+ 23.8%n=84

Vision blurred65%

G3+ 5%n=66

Keratopathy62%

n=1904

KERATOPATHY32.36%

poolednon-seriousn=958

Dry eye29%

G3+ 3%n=66

Keratitis27%

G3+ 17%n=66

Photophobia27%

n=66

Eye pain26%

n=66

VISION BLURRED12.84%

poolednon-seriousn=958

PHOTOPHOBIA10.86%

poolednon-seriousn=958

Punctate keratitis7.9%

n=1904

CONJUNCTIVITIS7.87%

non-seriousn=178

EYE PAIN7.41%

poolednon-seriousn=958

KERATITIS7.41%

poolednon-seriousn=958

DRY EYE7.2%

poolednon-seriousn=958

Corneal epithelial microcysts6.4%

n=1904

Lacrimation increased5.8%

n=1904

VISUAL IMPAIRMENT5.06%

non-seriousn=178

Cataract4.8%

n=1904

PUNCTATE KERATITIS4.7%

poolednon-seriousn=958

EYE IRRITATION4.49%

non-seriousn=178

CORNEAL EPITHELIAL MICROCYSTS3.44%

poolednon-seriousn=958

ACQUIRED EPIBLEPHARON2.63%

non-seriousn=38

CONJUNCTIVITIS ALLERGIC2.63%

non-seriousn=38

CORNEAL ABRASION2.63%

non-seriousn=38

DIPLOPIA2.63%

non-seriousn=38

FOREIGN BODY SENSATION IN EYES2.63%

non-seriousn=38

INTRAOCULAR PRESSURE INCREASED2.63%

non-seriousn=38

LACRIMATION INCREASED2.4%

poolednon-seriousn=958

OCULAR HYPERAEMIA1.88%

poolednon-seriousn=958

CATARACT1.77%

poolednon-seriousn=958

CORNEAL OPACITY1.69%

non-seriousn=178

PUPILLARY REFLEX IMPAIRED1.69%

non-seriousn=178

EYE INFECTION0.56%

non-seriousn=178

OCULAR DISCOMFORT0.56%

non-seriousn=178

EYELID PTOSIS0.56%

non-seriousn=178

VISUAL FIELD DEFECT0.31%

poolednon-seriousn=958

Per-trial detail

Adverse events by trial

INTELLANCE-1 (NCT02573324)Phase 3Depatux-M 2.0 mg/kg IV Q2W + adjuvant TMZ Adjuvant TMZ; depatux-M Q2Wn=273CTCAE MedDRA 24.1 (CT.gov seBrate reproduced

CT.gov posted results NCT02573324 (non-serious AE (>=5% threshold); 14/273) NCT02573324

167 adverse-event terms · 20 systems · expand a system below

Neurologic (other)34

Seizure

9.16%serious

25/273

Dizziness

8.06%

22/273

Somnolence

5.13%

14/273

Memory impairment

3.3%

9/273

Paraesthesia

2.56%

7/273

Brain oedema

2.56%serious

7/273

Dysgeusia

1.83%

5/273

Peripheral sensory neuropathy

1.83%

5/273

Hydrocephalus

1.47%serious

4/273

Epilepsy

1.1%serious

3/273

Haemorrhage intracranial

1.1%serious

3/273

Hemiparesis

1.1%serious

3/273

Status epilepticus

0.73%serious

2/273

Aphasia

0.73%serious

2/273

Cerebral haemorrhage

0.73%serious

2/273

Cognitive disorder

0.73%serious

2/273

Encephalopathy

0.73%serious

2/273

Parosmia

0.37%

1/273

Syncope

0.37%serious

1/273

Transient ischaemic attack

0.37%serious

1/273

Vasogenic cerebral oedema

0.37%serious

1/273

Ataxia

0.37%serious

1/273

Central nervous system necrosis

0.37%serious

1/273

Cerebral cyst

0.37%serious

1/273

Cerebrovascular accident

0.37%serious

1/273

Depressed level of consciousness

0.37%serious

1/273

Focal dyscognitive seizures

0.37%serious

1/273

Generalised tonic-clonic seizure

0.37%serious

1/273

Headache

0.37%serious

1/273

Intracranial pressure increased

0.37%serious

1/273

Nervous system disorder

0.37%serious

1/273

Neurological decompensation

0.37%serious

1/273

Partial seizures

0.37%serious

1/273

Peripheral motor neuropathy

0.37%serious

1/273

Ocular17

Keratopathy

32.6%

89/273

Photophobia

12.09%

33/273

Keratitis

10.99%

30/273

Eye pain

7.33%

20/273

Punctate keratitis

6.59%

18/273

Dry eye

5.49%

15/273

Corneal epithelial microcysts

4.03%

11/273

Ocular hyperaemia

2.93%

8/273

Lacrimation increased

1.1%

3/273

Cataract

0.73%serious

2/273

Ulcerative keratitis

0.73%serious

2/273

Visual field defect

0.37%

1/273

Cataract nuclear

0.37%serious

1/273

Corneal lesion

0.37%serious

1/273

Eyelid function disorder

0.37%serious

1/273

Optic ischaemic neuropathy

0.37%serious

1/273

Vision blurred

0.37%serious

1/273

Infections17

GI12

General10

Investigations10

Injury9

Musculoskeletal9

Neoplasms8

Hematologic6

Metabolic6

Dermatologic6

Psychiatric4

Pulmonary4

Vascular4

Hepatic3

Overall/Summary3

Renal3

Immune1

Other1

Construct

Molecular anatomy

Antibody

IgG1

Humanized

Linker

Non-cleavable

DAR

Payload

Cys-mcMMAF

Tubulin inhibitor

Linker structureC10H13NO4

O=C(O)CCCCCN1C(=O)C=CC1=O

Payload structureC52H83N7O13S

drag · scroll to zoom

CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@@H]([C@@H](C)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)O)OC)OC)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N(C)C(=O)CCCCCN3C(=O)CC(C3=O)SC[C@@H](C(=O)O)N

Antibody

Antibody & Fc engineering

Antibody

ABT-806 (depatuxizumab)

Isotype

IgG1

Origin

Humanized

Fc modifications

None^inferred

Glycoengineering

Standard^inferred

Effector silencing

None^inferred

FcγR binding

Retained

C1q binding

Retained

Target KD (nM)

Epitope / domain

Conformational disulfide-bonded loop EGFR aa 287-302

Linker & conjugation

Linker chemistry

Linker profile

Linker

mc (non-cleavable)

Class

Non-cleavable

Cleavage

Non-cleavable

Attachment

Cysteine (interchain)

Conjugation

Conventional interchain Cys

Symmetry

Symmetric

DAR (mean)

DAR homogeneity

Heterogeneous

Plasma t½

10.0 d

Cleavage trigger

Non-cleavable

Release control

Unconditional

Hydrophilicity mask

None^inferred

Formula

C10H13NO4

Linker MW

211.217 Da

Linker TPSA

74.68 Å²

Linker xLogP

0.5564

ADCdb linker

LIN0TAFAV

In-vitro stability

Stability note

Harmonic mean terminal t½: depatux-m (intact ADC) ~10 d; total depatux ~12 d; cys-mafodotin (released payload) ~4 d (Goss Cancer 2018 advanced solid tumor Ph1). Linear PK; no target-mediated disposition

Payload

Payload & physicochemistry

Payload profile

Payload

Cys-mcMMAF

Class

Auristatin

Mechanism

Tubulin inhibitor

Released catabolite

Cys-mcMMAF (Cys-mafodotin)

Mechanistic subtype

Tubulin-auristatin

Stereochem / salt

Bystander

PAMPA rank

1046.3 Da

XLogP3

1.4

logD₇.₄

-1

TPSA

301 Å²

pKa

3.5 pKa

Charge pH 7.4

-1

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C52H83N7O13S

PubChem CID

86278355

ADCdb payload

PAY0QLDVX

Hydrophobicity · logD₇.₄

hydrophilic −2-1+4 lipophilic

Bioactivity note

ADCdb (DRG0PXQWR) reports IC50 range 10.00-35.00 ug/mL across mesothelioma cell lines and tumor growth inhibition of approximately 87.5% in the MSTO-211H xenograft model. The free payload MMAF/Cys-mcMMAF is a potent tubulin polymerization inhibitor (anti-microtubule auristatin).

Dosing & regimen

Dosing

RP2D dose

1.25 mg/kg

Schedule

Q2W

Route

Fractionated

n at RP2D

323

Dose basis

TBW

Trial phase

Phase 3

Dose-OAE available

Yes

Tox summary basis

RP2D

ADA rate (%)

0 %

Ocular & expression

Ocular profile & eye-tissue target expression

Target profile

OAE any-grade

94 %

OAE grade 3+

60 %

OAE data status

reported

Severity (weighted)

70.2

Keratopathy

94 %

Conjunctival

Dry eye

29 %

Blurred vision

65 %

Dominant tissue

Cornea

Surface subtype

Corneal (off-target)

Grading scale

CTCAE v4.0

Reversibility

Mixed

Target expression in eye tissues (HCA detection · HPA bulk)

Cornea (central)

89.35 %

Cornea (limbal)

97.58 %

Conjunctiva

93.02 %

RPE

83.36 %

Retina (HPA)

9.4 nTPM

Cross-trial comparability · source-verified

Ascertainment: Systematic eye examsScale: CTCAE v4Denominator: RP2D

Dose & schedule → ocular toxicity · keratopathy (any-grade) by cohort

Depatux-M 1.0 mg/kg IV (RPTD)

Depatux-M Q2W + TMZ

72.4%

n=29 · INTELLANCE-J

Depatux-M (ABT-414); dose reduced to 1 mg/kg for grade 3 OSE

Depatux-M Q2W (28-day cycles)

20%

n=10 · Parrozzani confocal-microscopy ocular study (Padova, no NCT)

1.25 mg/kg (reduced to 1.0 mg/kg)

Q2W

71.4%

n=84 · INTELLANCE-2 / EORTC 1410

Depatux-M 0.5/1.0/1.25 mg/kg IV (dose-escalation)

Depatux-M Q2W monotherapy

33.3%

n=9 · INTELLANCE-J

Depatux-M 1.25 mg/kg IV (RP2D)

Depatux-M Q2W monotherapy

27.3%

n=66 · M12-356 / INTELLANCE-3 Arm B

1.25 mg/kg

Q2W (D1, D15 of 28-day cycle)

27%

n=66 · ABT-414 Ph1 monotherapy (recurrent GBM)

Depatux-M 1.25 mg/kg IV (RP2D)

Depatux-M Q2W + temozolomide

20%

n=60 · M12-356 / INTELLANCE-3 Arm C

Depatux-M 1.25 mg/kg IV Q2W

Depatux-M Q2W monotherapy

1.19%

n=84 · INTELLANCE-2 / EORTC 1410

Depatux-M 1.25 mg/kg IV Q2W + TMZ

Depatux-M Q2W + TMZ

1.14%

n=88 · INTELLANCE-2 / EORTC 1410

Depatux-M (ABT-414) 1.5 mg/kg IV

Depatux-M Q2W (28-day cycles) +/- TMZ

26.7%

n=15 · Parrozzani long-term ocular safety (Padova, no NCT)

2.0 mg/kg during RT, then 1.25 mg/kg

Q2W (D1, D15 of 28-day cycle)

94%

n=323 · INTELLANCE-1

Depatux-M 2.0 mg/kg IV Q2W + RT + TMZ

Standard steroids

64.3%

n=14 · UNITE

2.0 mg/kg

62%

n=1904

Depatux-M 2.0 mg/kg IV Q2W + RT + TMZ

RT+TMZ then adjuvant TMZ; depatux-M/placebo Q2W

60.4%

n=323 · INTELLANCE-1

Depatux-M (ABT-414) up to RP2D 2.0 mg/kg IV

Depatux-M Q2W + RT + TMZ, then adjuvant TMZ

33.3%

n=45 · M12-356 / INTELLANCE-3 Arm A

Depatux-M 2.0 mg/kg IV Q2W + RT + TMZ

Q2W; ocular prophylaxis per arm

24%

n=38 · UNITE

Open-label Depatux-M 2.0 mg/kg IV Q2W + adjuvant TMZ

Adjuvant TMZ; depatux-M Q2W

16.67%

n=6 · INTELLANCE-1

Open-label Depatux-M 2.0 mg/kg IV Q2W + RT + TMZ

RT + concurrent TMZ; depatux-M Q2W

16.67%

n=6 · INTELLANCE-1

Depatux-M 2.0 mg/kg IV Q2W + RT + TMZ

RT + concurrent TMZ; depatux-M Q2W

11.4%

n=342 · INTELLANCE-1

Depatux-M 2.0 mg/kg IV Q2W + adjuvant TMZ

Adjuvant TMZ; depatux-M Q2W

10.99%

n=273 · INTELLANCE-1

Depatux-M 2.0 mg/kg IV Q2W + RT + TMZ

Enhanced steroids + vasoconstrictor + cold compress

8.33%

n=12 · UNITE

Depatux-M 0.5-4.0 mg/kg IV; MTD 3.0 mg/kg Q3W (process A) / RP2D varied

Q3W (and prolonged-infusion / alternate-schedule cohorts)

7.1%

n=56 · M13-379 first-in-human

Depatux-M (per INTELLANCE-2 schedule)

Depatux-M Q2W + TMZ

67%

n=36 · Real-world monocentric cohort (Italy, no NCT)

—

21.35%

n=178 · INTELLANCE-2

Depatux-M (pediatric)

Depatux-M Q2W

16.67%

n=6 · INTELLANCE-2 / EORTC 1410

—

7.9%

n=3808

—

3.44%

n=958 · Intellance1

—

2.63%

n=38 · UNITE Study: Understanding New Interventions With GBM ThErapy

Lomustine (CCNU)

Per investigator

1.79%

n=56 · INTELLANCE-2 / EORTC 1410

Placebo + adjuvant TMZ

Adjuvant TMZ; placebo Q2W

1.05%

n=285 · INTELLANCE-1

Placebo + RT + TMZ

RT + concurrent TMZ; placebo Q2W

0.6%

n=335 · INTELLANCE-1

Placebo + RT + TMZ

RT+TMZ then adjuvant TMZ; depatux-M/placebo Q2W

0.6%

n=313 · INTELLANCE-1

Per-cohort rates from the per-trial extraction, sorted by dose. Cross-trial comparison is subject to ascertainment / scale differences (see comparability above) — e.g. an early symptom-driven trial can read lower than a later systematic-exam trial at a higher dose.

Ocular AE grading reference — interspecialty consensus · 6 scales + dose modification

Identity & registry

Identifiers, registry & notes

ADC id

depatuxizumab-mafodotin

Approval status

Discontinued

Approval year

2019

UniProt

P00533

ADCdb ADC

DRG0PXQWR

ADCdb antibody

ANI0TJUOM

ADCdb target

TAR0UYFIF

Primary source

Lassman INTELLANCE-1 Neuro-Oncol 2023; PMC9925712^{no such source}

Aliases & development codes

ABT-414; depatux-m

Notes

V3.1 MAJOR CORRECTION: G3+ OAE 27→60% per Lassman Neuro-Oncol 2023 INTELLANCE-1 direct quote ('Grade 3 CE 55%, grade 4 perforation/blindness 5%'). Prior 27% misattributed. Severity ratio now 0.638 (was 0.287).^{no such source}