Indusatumab vedotin

Discontinued

TAK-264; TAK264; MLN0264; MLN-0264; 5F9vcMMAE; GCC antibody-drug conjugate

Target

Guanylyl cyclase C (GCC) · GUCY2C

Sponsor

Takeda / Millennium Pharmaceuticals (vedotin linker-payload licensed from Seagen)

Indication

GUCY2C+ gastrointestinal adenocarcinoma (gastric/GEJ, pancreatic, colorectal)

Target family

Other

RP2D dose

1.8 mg/kg

Q3W (day 1 of 21-day cycle)RP2D

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

G3+

RP2D

sagittal schematic · Unknown

↳

Tissues shaded by reported adverse-event rate.

Cornea

Express.

Limbus

Express.

Conjunctiva

Express.

Lens

Express.

Retina / RPE

Express.

Dominant tissue

Periorbital/adnexa

Surface subtype

None

Reversibility

Unknown

Reported ocular events

Eye discharge8.3%

n=12

Periorbital oedema2.4%

n=41

Any ocular AE (Eye disorders SOC) at RP2D0%

n=109

Construct

Molecular anatomy

Antibody

IgG1

Human

Linker

Cleavable

4.2

DAR

Payload

MMAE

Tubulin inhibitor (microtubule)

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

Indusatumab (5F9)

Isotype

IgG1

Origin

Human

Fc modifications

None

Glycoengineering

Standard

Effector silencing

None (wild-type IgG1)

FcγR binding

Retained

C1q binding

Retained

Linker & conjugation

Linker chemistry

Linker profile

Linker

Mc-Val-Cit-PABC (vedotin; mc-vc-PAB)

Class

Cleavable

Cleavage

Cleavable

Attachment

Cysteine (interchain)

Conjugation

Conventional interchain Cys (maleimide); ADCdb: random cysteines

Symmetry

Symmetric

DAR (mean)

4.2

DAR homogeneity

Heterogeneous

Plasma t½

Cleavage trigger

Cathepsin B (Val-Cit)

Release control

Conditional

Hydrophilicity mask

None

Formula

C28H40N6O7

Linker MW

572.663 Da

Linker TPSA

200.03 Å²

Linker xLogP

0.6769

ADCdb linker

LIN0SQEDQ

In-vitro stability

Payload

Payload & physicochemistry

Payload profile

Payload

MMAE

Class

Auristatin

Mechanism

Tubulin inhibitor (microtubule)

Released catabolite

MMAE (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

ADCdb reports in-vitro cytotoxicity IC50 <25 ug/mL across pancreatic cancer cell lines, PDX tumor growth inhibition 34-70.1% across pancreatic models, and clinical ORR 0-5.56% across Phase 1/2 trials. Payload MMAE is a potent anti-tubulin auristatin (sub-nanomolar free-drug cytot

Dosing & regimen

Dosing

RP2D dose

1.8 mg/kg

Schedule

Q3W (day 1 of 21-day cycle)

Route

Other

Fractionated

n at RP2D

Dose basis

TBW

Trial phase

Phase 2

Dose-OAE available

Tox summary basis

RP2D

Ocular & expression

Ocular profile & eye-tissue target expression

Target profile

OAE any-grade

0 %

OAE grade 3+

0 %

OAE data status

documented-absent

Severity (weighted)

Keratopathy

0 %

Conjunctival

Dry eye

0 %

Blurred vision

0 %

Dominant tissue

Periorbital/adnexa

Surface subtype

None

Grading scale

CTCAE v4

Reversibility

Unknown

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

Cornea (central)

Cornea (limbal)

Conjunctiva

RPE

Retina (HPA)

Cross-trial comparability · source-verified

Ascertainment: Systematic eye examsScale: CTCAE v4Denominator: RP2D

Identity & registry

Identifiers, registry & notes

ADC id

indusatumab-vedotin

Approval status

Discontinued

Approval year

UniProt

P25092

ADCdb ADC

DRG0FSHWJ

ADCdb antibody

ANI0WDEHD

ADCdb target

TAR0ZYWVJ

Primary source

Almhanna FIH Ph1 TAK-264/MLN0264, Clin Cancer Res 2016;22(20):5049 (NCT01577758) + Ph2 gastric (NCT02202759) & pancreatic (NCT02202785, Invest New Drugs 2017) + Asian Ph1 (NCT02391038, Cancer Res Treat 2018); ClinicalTrials.gov results; ADCdb DRG0FSHWJ/LIN0SQEDQ

Aliases & development codes

TAK-264; TAK264; MLN0264; MLN-0264; 5F9vcMMAE; GCC antibody-drug conjugate

Notes

TAK-264 / MLN0264 (5F9vcMMAE): fully human anti-GUCY2C (GCC) IgG1-kappa antibody (indusatumab / clone 5F9) conjugated to MMAE via the cleavable Mc-Val-Cit-PABC (mc-vc-PAB) vedotin linker - the SAME linker (ADCdb LIN0SQEDQ) as brentuximab vedotin; conventional interchain-Cys conjugation, DAR ~4.2. RP2D 1.8 mg/kg IV Q3W. Sponsor Takeda/Millennium (vedotin tech from Seagen). Program terminated at Phase 2: both the gastric/GEJ (NCT02202759, N=38) and pancreatic (NCT02202785, N=43) Ph2 studies failed stage-1 interim for INSUFFICIENT EFFICACY (not toxicity). OCULAR (reason for inclusion; signal is soft/atypical): Across 4 trials (~134 pts - FIH NCT01577758 N=41; Asian Ph1 NCT02391038 N=12; gastric Ph2 N=38; pancreatic Ph2 N=43) the ONLY Eye-disorders-SOC terms were periorbital oedema (1 pt at 2.4 mg/kg, FIH) and eye discharge (1/12, Asian Ph1) - both single-patient, non-serious, and NON-ocular-surface. There were NO corneal/keratopathy, dry-eye, blurred-vision, or visual-acuity events at any dose, including 109 patients at the 1.8 mg/kg RP2D (FIH 1.8mg/kg N=28 + gastric N=38 + pancreatic N=43). This MMAE ADC therefore lacks the classic auristatin ocular-surface toxicity. ocular oae_any/g3plus and the corneal/dry-eye/blurred-vision subtype fields are set to 0 to reflect documented absence at the CT.gov reporting thresholds: serious AEs are listed without a frequency threshold (none ocular) -> G3+ ocular truly 0 (tier C); any-grade ocular <=~4% (below the 5% otherEvents threshold) -> 0 imputed (tier D). ocular_surface_subtype=None (no ocular-surface pattern); dominant ocular tissue = periorbital/adnexal. SOURCING NOTE: the wave1 screen attributed periorbital oedema to the Asian Ph1 (NCT02391038); ClinicalTrials.gov results actually place periorbital oedema in the FIH study (NCT01577758, 2.4 mg/kg arm), while the Asian Ph1's lone eye term is eye discharge (1/12). Conclusion (low/soft ocular case) is unchanged. NON-OCULAR toxicity is dominated by GI (nausea ~53%, decreased appetite ~29%, vomiting, constipation, diarrhoea), hematologic (anaemia 18-39% depending on cohort, neutropenia ~13-25%, febrile neutropenia 3/28 at RP2D, thrombocytopenia ~18% in FIH), and hepatic transaminase elevations (FIH 1.8mg/kg AST 28.6%/ALT 21.4%; <5% in the Ph2 cohorts). PN is modest MMAE-type (~7-11%, low grade). No ILD/pneumonitis and no infusion-related reactions reported across the program. Aggregate grade >=3 drug-related AEs: gastric Ph2 37% (14/38), pancreatic Ph2 35% (15/43). CTCAE v4.03 throughout. Composition + linker physchem from ADCdb DRG0FSHWJ/LIN0SQEDQ; MMAE payload physchem are standard DB values (PubChem CID 11542188).