Enfortumab vedotin

FDA-approved

Padcev; ASG-22ME

Target

Nectin-4 · NECTIN4

Sponsor

Astellas/Seagen (Pfizer)

Indication

NECTIN4+ urothelial ca

Target family

Nectin / Ig-CAM

RP2D dose

1.25 mg/kg (max 125 mg)

D1+D8+D15 Q4WRP2D

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

3 adverse-event terms

Ocular

Any-grade

40%

G3+

0.7%

RP2D

sagittal schematic · Reversible

↳

Tissues shaded by reported adverse-event rate.

Cornea

Express.

71.38%

Limbus

Express.

82.84%

Conjunctiva

Express.

56.73%

Lens

Express.

Retina / RPE

Express.

0.33%

0 nTPM

Dominant tissue

Ocular surface

Surface subtype

Conjunctival (on-target)

Reversibility

Reversible

Reported ocular events

Ocular disorders (any)40%

n=384

Dry eye24%

G3+ 0%n=440

Vision blurred10%

n=384

Per-trial detail

Adverse events by trial

EV-302Phase 3EV 1.25 mg/kg; pembrolizumab 200 mg EV Days 1,8 q21dn=440CTCAE 4B

CT.gov NCT04223856 posted results: serious AEs (3/440; MedDRA v26.0) NCT04223856

205 adverse-event terms · 22 systems · expand a system below

GI28

Diarrhoea

36.6%G3+ 3.2%

161/440

Vomiting

10.9%G3+ 1.1%

48/440

Abdominal pain

10%G3+ 1.8%

44/440

Dry mouth

9.3%

41/440

Stomatitis

8.9%

39/440

Dyspepsia

5.7%G3+ 0.2%

25/440

Colitis

—G3+ 0.7%

Immune-mediated enterocolitis

—G3+ 0.7%

Enterovesical fistula

—G3+ 0.5%

Intestinal obstruction

—G3+ 0.5%

Pancreatitis

—G3+ 0.5%

Ascites

—G3+ 0.2%

Colitis ulcerative

—G3+ 0.2%

Colonic fistula

—G3+ 0.2%

Duodenal stenosis

—G3+ 0.2%

Duodenal ulcer

—G3+ 0.2%

Gastric ulcer

—G3+ 0.2%

Gastrointestinal haemorrhage

—G3+ 0.2%

Inguinal hernia

—G3+ 0.2%

Large intestinal ulcer haemorrhage

—G3+ 0.2%

Large intestine perforation

—G3+ 0.2%

Malignant gastrointestinal obstruction

—G3+ 0.2%

Mouth ulceration

—G3+ 0.2%

Oesophagitis

—G3+ 0.2%

Pancreatitis acute

—G3+ 0.2%

Rectal haemorrhage

—G3+ 0.2%

Rectal ulcer haemorrhage

—G3+ 0.2%

Small intestinal obstruction

—G3+ 0.2%

Infections27

Pulmonary19

Neurologic (other)17

Dermatologic14

Metabolic13

Investigations12

Cardiac11

Renal10

General8

Hematologic7

Hepatic6

Musculoskeletal6

Psychiatric5

Vascular5

Ocular4

Lacrimation increased

8.2%

36/440

Vision blurred

5.9%

26/440

Cataract

22/440

Keratitis

—G3+ 0.2%

Neoplasms4

Injury3

Ear2

Endocrine2

Immune1

Other1

Construct

Molecular anatomy

Antibody

IgG1

Human

Linker

Cleavable

3.8

DAR

Payload

MMAE

Tubulin inhibitor

Linker structureC28H40N6O7

[H]OC([H])([H])c1c([H])c([H])c(N([H])C(=O)[C@@]([H])(N([H])C(=O)[C@@]([H])(N([H])C(=O)C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])N2C(=O)C([H])=C([H])C2=O)C([H])(C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])C([H])([H])N([H])C(=O)N([H])[H])c([H])c1[H]

Payload structureC39H67N5O7

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

Antibody

Antibody & Fc engineering

Antibody

AGS-22C3 (enfortumab)

Isotype

IgG1

Origin

Human

Fc modifications

None

Glycoengineering

Standard

Effector silencing

None

FcγR binding

Retained

C1q binding

Retained

Target KD (nM)

0.01

Epitope / domain

Nectin-4 membrane-distal V

Linker & conjugation

Linker chemistry

Linker profile

Linker

MC-vc-PAB (vedotin)

Class

Cleavable

Cleavage

Cleavable

Attachment

Cysteine (interchain)

Conjugation

Conventional interchain Cys

Symmetry

Symmetric

DAR (mean)

3.8

DAR homogeneity

Heterogeneous

Plasma t½

3.6 d

Cleavage trigger

Cathepsin B (Val-Cit)

Release control

Conditional

Hydrophilicity mask

None

Platform

Vedotin

Cell line

CHO

Formula

C28H40N6O7

Linker MW

572.663 Da

Linker TPSA

200.03 Å²

Linker xLogP

0.6769

ADCdb linker

LIN0SQEDQ

In-vitro stability

Stability note

acAb t½ 3.6 d in pooled urothelial PK; shorter than brentuximab (5 d) and tisotumab (4 d) reflecting weight-based dosing in obese urothelial population and higher CL

Payload

Payload & physicochemistry

Payload profile

Payload

MMAE

Class

Auristatin

Mechanism

Tubulin inhibitor

Released catabolite

MMAE (free / unconjugated monomethyl auristatin E)

Mechanistic subtype

Tubulin-auristatin

Stereochem / salt

Bystander

Yes

PAMPA rank

718 Da

XLogP3

4.1

logD₇.₄

2.7

TPSA

150 Å²

pKa

9.1 pKa

Charge pH 7.4

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C39H67N5O7

PubChem CID

11542188

ADCdb payload

PAY0FSXOW

Hydrophobicity · logD₇.₄

hydrophilic −2+2.7+4 lipophilic

Bioactivity note

Payload MMAE is a microtubule (tubulin polymerization) inhibitor. ADCdb in-vitro: enfortumab vedotin IC50 ~1.2-4.7 ng/mL on PC-3 prostate carcinoma and 37.8 ng/mL on T-47D breast carcinoma cells. Clinically FDA-approved Dec 2019 for advanced urothelial cancer.

Dosing & regimen

Dosing

RP2D dose

1.25 mg/kg (max 125 mg)

Schedule

D1+D8+D15 Q4W

Route

Fractionated

Yes

n at RP2D

384

Dose basis

TBW

Trial phase

Approved

Dose-OAE available

Tox summary basis

RP2D

ADA rate (%)

5 %

Pharmacology

Clinical pharmacokinetics

By analyte · FDA label §12.3 + Drugs@FDA clinical-pharmacology reviews

	Intact ADC	Free payload
Cmax	28 (±6.1)µg/mL	5.5 (±3.0)ng/mL
AUC	110 (±26)µg·d/mL	85 (±50)ng·d/mL
Tmax	near end of infusion (~0.5)h	~2days
t½	3.6days+1	2.6days+1
CL	0.11L/h+1	2.11L/h+1
Vd	12.8L+1	218L

FDA label §12.3 Drugs@FDA reviewhover a value for dose / population / source · “+N” marks additional reported values

Ocular & expression

Ocular profile & eye-tissue target expression

Target profile

OAE any-grade

40 %

OAE grade 3+

0.7 %

OAE data status

reported

Severity (weighted)

12.49

Keratopathy

Conjunctival

Dry eye

30 %

Blurred vision

10 %

Dominant tissue

Ocular surface

Surface subtype

Conjunctival (on-target)

Grading scale

CTCAE v4.0

Reversibility

Reversible

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

Cornea (central)

71.38 %

Cornea (limbal)

82.84 %

Conjunctiva

56.73 %

RPE

0.33 %

Retina (HPA)

0 nTPM

Cross-trial comparability · source-verified

Ascertainment: Systematic eye examsScale: CTCAE v4Denominator: RP2D

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

EV 1.25 mg/kg

Days 1,8,15 q28d

40%

n=125 · EV-201 Cohort 1

1.25 mg/kg (max 125 mg)

Days 1, 8, 15 of 28-day cycle, IV

40%

n=384 · pooled single-agent (ophthalmologic-exam-scheduled subset)

EV 1.25 mg/kg

Days 1,8,15 q28d

30%

n=89 · EV-201 Cohort 2

EV 1.25 mg/kg; pembrolizumab 200 mg; sitravatinib (escalation)

EV Days 1,8 q21d

25%

n=4 · Sitravatinib+pembro+EV

EV 1.25 mg/kg; pembrolizumab 200 mg

EV Days 1,8 q21d

25%

n=121 · EV-103

EV 1.25 mg/kg

Days 1,8,15 q28d

24%

n=296 · EV-301

EV 1.25 mg/kg; pembrolizumab 200 mg

EV Days 1,8 q21d

24%

n=440 · EV-302

1.25 mg/kg

Days 1, 8 of 21-day cycle, IV (+ pembrolizumab)

24%

n=440 · EV-302

EV 1.25 mg/kg; pembrolizumab 200 mg

EV Days 1,8 q21d

21%

n=167 · EV-303

EV 1.25 mg/kg

Days 1,8,15 q28d

15.6%

n=45 · EV-202

EV 1.25 mg/kg; pembrolizumab 200 mg; sitravatinib 35 mg QD

EV Days 1,8 q21d

12.5%

n=8 · Sitravatinib+pembro+EV

EV 1.25 mg/kg

Days 1,8,15 q28d

12.5%

n=40 · EV China

EV 1.25 mg/kg

Days 1,8,15 q28d

10.1%

n=296 · EV-301

EV 1.25 mg/kg; pembrolizumab 200 mg

EV Days 1,8 q21d

9.8%

n=41 · EV-202

EV 1.25 mg/kg

Days 1,8,15 q28d

7.2%

n=125 · EV-201

EV 1.25 mg/kg

Days 1,8,15 q28d

2.4%

n=42 · EV-202

EV 1.25 mg/kg

Days 1,8,15 q28d

2.3%

n=43 · EV-202

EV 1.25 mg/kg

Days 1,8,15 q28d

1.1%

n=89 · EV-201

1.25 mg/kg (max 125 mg)

D1+D8+D15 Q4W (monotherapy)

0.7%

n=296 · EV-301

EV 1.25 mg/kg; pembrolizumab 200 mg

EV Days 1,8 q21d

0.2%

n=440 · EV-302

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

enfortumab-vedotin

Approval status

FDA-approved

Approval year

2019

UniProt

Q96NY8

ADCdb ADC

DRG0BBQSE

ADCdb antibody

ANI0LTVSQ

ADCdb target

TAR0MWTFE

Primary source

PADCEV HCP page; Dy 2024 Oncologist

Aliases & development codes

Padcev; ASG-22ME

Notes

Fractionated schedule reduces Cmax; surface-dominant mild OAE despite high NECTIN4 corneal expression. V3.1: oae_g3plus_pct=0.7 is DERIVED from Dy 2024 Oncologist; PADCEV label states 'No Grade 3-4 ocular toxicities reported' — value retained as C-tier derived estimate.