Sirtratumab vedotin

Discontinued

AGS-15E; AGS15E; ASG-15ME; ASG-15E; ASG15ME; AGS15E/MMAE

Target

SLIT and NTRK-like protein 6 (SLITRK6) · SLITRK6

Sponsor

Agensys / Astellas (with Seagen vedotin/vc-MMAE technology)

Indication

Metastatic urothelial carcinoma

Target family

Other

RP2D dose

1.0 mg/kg

Days 1, 8, 15 of every 28-day cycle (weekly x3, 1 week off; QW 3/4)RP2D

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

7 adverse-event terms

Ocular

Any-grade

29%

G3+

2.2%

RP2D

sagittal schematic · Reversible

↳

Tissues shaded by reported adverse-event rate.

Cornea

Express.

Limbus

Express.

Conjunctiva

Express.

Lens

Express.

Retina / RPE

Express.

Dominant tissue

Cornea

Surface subtype

Corneal (off-target)

Reversibility

Reversible

Reported ocular events

Eye disorders (SOC, all-cause TEAE)32.3%

Eye disorders (any, drug-related)29%

Vision blurred (all-cause TEAE)17.2%

Blurred vision15.1%

G3+ 1.1%

Dry eye5.4%

Eye disorders (grade >=3)-

G3+ 2.2%

Diplopia-

G3+ 1.1%

Construct

Molecular anatomy

Antibody

IgG2

Human

Linker

Peptide

Cleavable

DAR

Payload

Monomethyl auristatin E (MMAE)

Microtubule-disrupting antimitotic (tubulin polymerization 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

Sirtratumab

Isotype

IgG2

Origin

Human

Fc modifications

Glycoengineering

Effector silencing

Native human IgG2 isotype (intrinsically low FcgammaR/effector engagement); no engineered Fc-silencing reported

FcγR binding

Retained

C1q binding

Unknown

Linker & conjugation

Linker chemistry

Linker profile

Linker

Mc-Val-Cit-PABC (maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl; vedotin/vc linker)

Class

Peptide

Cleavage

Cleavable

Attachment

Cysteine (interchain)

Conjugation

Cysteine conjugation via partial interchain disulfide reduction (random cysteines)

Symmetry

Symmetric

DAR (mean)

DAR homogeneity

Heterogeneous

Plasma t½

Cleavage trigger

Cathepsin B (lysosomal cysteine protease; Val-Cit dipeptide cleavage)

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

Monomethyl auristatin E (MMAE)

Class

Auristatin

Mechanism

Microtubule-disrupting antimitotic (tubulin polymerization inhibitor)

Released catabolite

Free MMAE (monomethyl auristatin E), released after cathepsin B cleavage of the Val-Cit linker; cys-mcMMAE intermediate

Mechanistic subtype

Tubulin-auristatin

Stereochem / salt

N/A (biologic ADC; no defined small-molecule salt form)

Bystander

Yes

PAMPA rank

717.97 Da

XLogP3

4.1

logD₇.₄

TPSA

150 Å²

pKa

9 pKa

Charge pH 7.4

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C39H67N5O7

PubChem CID

11542188

ADCdb payload

PAY0FSXOW

Bioactivity note

Payload (MMAE) free-drug potency: sub-nanomolar (e.g. 0.13 nM MDA-MB-231; 0.25 nM Granta-519/SU-DHL-4) per ADCdb payload PAY0FSXOW. ADC (AGS-15E): in vitro IC50 0.99 nM on SLITRK6-positive CHP-212 cells vs >10 µM on SLITRK6-negative IGROV-1 (target-selective killing); in vivo PDX

Dosing & regimen

Dosing

RP2D dose

1.0 mg/kg

Schedule

Days 1, 8, 15 of every 28-day cycle (weekly x3, 1 week off; QW 3/4)

Route

Fractionated

n at RP2D

Dose basis

TBW

Trial phase

Phase 1

Dose-OAE available

Yes

Tox summary basis

RP2D

Ocular & expression

Ocular profile & eye-tissue target expression

Target profile

OAE any-grade

29 %

OAE grade 3+

2.2 %

OAE data status

reported

Severity (weighted)

10.24

Keratopathy

Conjunctival

Dry eye

5.4 %

Blurred vision

15.1 %

Dominant tissue

Cornea

Surface subtype

Corneal (off-target)

Grading scale

CTCAE v4

Reversibility

Reversible

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

sirtratumab-vedotin

Approval status

Discontinued

Approval year

UniProt

Q9H5Y7

ADCdb ADC

DRG0QZHYU

ADCdb antibody

ANI0FQFZL

ADCdb target

TAR0CREXX

Primary source

Petrylak Clin Cancer Res 2024;30(1):63 (PMID 37861407)

Aliases & development codes

AGS-15E; AGS15E; ASG-15ME; ASG-15E; ASG15ME; AGS15E/MMAE

Notes

Anti-SLITRK6 fully human IgG2 MMAE ADC (AGS-15E / ASG-15ME), random-cysteine vc-MMAE, DAR 4. Phase 1 (n=93 metastatic urothelial carcinoma) shows a clear MMAE-type ocular signal: drug-related eye disorders 29% (27/93), blurred vision 15.1% (1 G3), dry eye 5.4%, diplopia (1 G3). Ocular G3+ = 2/93 (2.2%); mostly G1-2, reversible, no discontinuations for ocular toxicity. Ocular AEs (and peripheral neuropathy) onset at doses >=0.75 mg/kg; vision disorders higher with prior checkpoint-inhibitor exposure (33.3% vs 17.2%). Notably NO corneal/keratopathy/conjunctivitis terms reported (consistent with MMAE causing visual/blurred-vision rather than the corneal-microcyst keratopathy of MMAF/DM4 payloads); ocular_surface_subtype coded Visual (blurred vision dominant) with secondary dry-eye surface component. oae_any_pct=29 is the documented SOC 'eye disorders (drug-related)' rate in the pooled total population (n=93; 60/93 at RP2D 1.0 mg/kg); single highest ocular PT = blurred vision 15.1%. Hepatic, pulmonary/ILD and infusion-reaction AEs were not broken out as distinct preferred terms in the published safety tables (left blank, not 0). Most common G3+ TEAEs were anaemia and fatigue (each 5.4%). Program terminated. PAYLOAD PHYSCHEM CAVEAT: PubChem PUG-REST (CID 11542188, retrieved 2026-06-08) returned XLogP3=4.1, TPSA=150, MW 717.97 (C39H67N5O7), formal charge 0; some older ADC review tables cite MMAE XLogP3 ~3.1, so curator may wish to reconcile. payload_charge_pH7_4=+1 reflects the protonated secondary amine at physiological pH (PubChem formal charge is 0); pKa and logD7.4 are standard/inferred (tier C/D). Linker physchem (formula/MW/TPSA/xLogP/SMILES) from ADCdb linker LIN0SQEDQ.