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

Per-trial detail

Adverse events by trial

TAK-264 (MLN0264) Phase 1 dose-escalation/expansion, advanced GI malignancies (NCT01577758)Phase 11.8 mg/kg IV 30-min infusion on Day 1 of every 21-day cycle (Q3W)n=28B

ClinicalTrials.gov posted results — NCT01577758 (MLN0264 1.8 mg/kg) [4/28] NCT01577758

53 adverse-event terms · 14 systems · expand a system below

GI9

Nausea

53.6%

15/28

Diarrhoea

35.7%

10/28

Abdominal pain

25%

7/28

Vomiting

25%

7/28

Abdominal discomfort

3.6%

1/28

Abdominal pain lower

3.6%

1/28

Dry mouth

3.6%

1/28

Gastrooesophageal reflux disease

3.6%

1/28

Stomatitis

3.6%

1/28

Investigations9

Musculoskeletal5

Dermatologic5

Metabolic4

Neurologic (other)4

Hematologic3

General3

Psychiatric3

Infections2

Renal2

Pulmonary2

Cardiac1

Injury1

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

Dev code

5F9

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

5.5 d

Cleavage trigger

Cathepsin B (Val-Cit)

Release control

Conditional

Hydrophilicity mask

None

Platform

Seagen vedotin

Cell line

CHO DG44

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

Fractionated

n at RP2D

Dose basis

TBW

Trial phase

Phase 1/2

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 v4.03

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

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

dose-escalation 1.2-1.8 mg/kg, all participants

IV 30-min infusion on Day 1 of every 21-day cycle (Q3W)

8.3%

n=12 · TAK-264 (MLN0264) Phase 1 dose-escalation, Asian advanced GI carcinoma

1.2-1.8 mg/kg

Q3W

8.3%

n=12 · NCT02391038

1.8 mg/kg

Q3W

n=109 · NCT01577758 (1.8mg/kg arm) + NCT02202759 + NCT02202785

2.4 mg/kg

IV 30-min infusion on Day 1 of every 21-day cycle (Q3W)

100%

n=1 · TAK-264 (MLN0264) Phase 1 dose-escalation/expansion, advanced GI malignancies

2.4 mg/kg

Q3W

2.4%

n=41 · NCT01577758

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

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).