Trastuzumab duocarmazine

Discontinued

SYD985; [vic-]trastuzumab duocarmazine

Target

HER2 · ERBB2

Sponsor

Byondis (ex-Synthon)

Indication

HER2+ breast cancer

Target family

Receptor tyrosine kinase

RP2D dose

1.2 mg/kg

Q3WRP2D

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

10 adverse-event terms

Ocular

Any-grade

78.1%

G3+

21.2%

RP2D

sagittal schematic · Mixed

↳

Tissues shaded by reported adverse-event rate.

Cornea

38.2%

Express.

46.2%

Limbus

Express.

61.99%

Conjunctiva

38.2%

Express.

61.13%

Lens

Express.

Retina / RPE

Express.

5.48%

7.5 nTPM

Dominant tissue

Mixed

Surface subtype

Mixed

Reversibility

Mixed

Reported ocular events

Ocular toxicity (grouped term)78.1%

G3+ 21.2%n=291

Keratitis38.2%

G3+ 12.2%n=291

Conjunctivitis38.2%

G3+ 5.6%n=291

Dry eye30.2%

G3+ 4.2%n=291

Lacrimation increased19.9%

G3+ 0%n=146

Blepharitis12.5%

Punctate keratitis11.1%

Vision blurred11%

G3+ 0.7%n=146

Periorbital oedema5.9%

Eyelid ptosis-

G3+ 0.3%

Construct

Molecular anatomy

Antibody

IgG1

Humanized

Linker

Cleavable

2.8

DAR

Payload

seco-DUBA

DNA alkylator

Linker structureC36H54N8O14

CC(C)C(NC(=O)OCCOCCN1C(=O)C=CC1=O)C(=O)NC(CCCNC(N)=N)C(=O)Nc1ccc(COC(=O)N(C)CCN(CCOCCO)C(=O)O)cc1

Payload structureC29H23ClN4O4

CC1=C2C(=CC=C1)C(=CC3=C2[C@@H](CN3C(=O)C4=CN5C=C(C=CC5=N4)NC(=O)C6=CC=C(C=C6)O)CCl)O

Antibody

Antibody & Fc engineering

Antibody

trastuzumab

Isotype

IgG1

Origin

Humanized

Fc modifications

None

Glycoengineering

Standard

Effector silencing

None

FcγR binding

Retained

C1q binding

Retained

Linker & conjugation

Linker chemistry

Linker profile

Linker

vc-seco-DUBA

Class

Cleavable

Cleavage

Cleavable

Attachment

Cysteine (interchain)

Conjugation

Conventional interchain Cys

Symmetry

Symmetric

DAR (mean)

2.8

DAR homogeneity

Heterogeneous

Plasma t½

4.0 d

Cleavage trigger

Cathepsin B (Val-Cit)

Release control

Conditional

Hydrophilicity mask

Discrete-PEG-spacer

Formula

C36H54N8O14

Linker MW

822.87 Da

Linker TPSA

297.8 Å²

Linker xLogP

-0.1919

ADCdb linker

LIN0HGTZQ

In-vitro stability

Stability note

acAb t½ ~4 d (cycle 1) inferred from Banerji Lancet Oncol 2019 Ph1 dose-escalation Q3W steady-state achieved by C2; vc-seco-DUBA self-inactivating payload — locked in inactive seco form, free DUBA self-destructs in plasma in minutes if prematurely released (Elgersma 2015)

Payload

Payload & physicochemistry

Payload profile

Payload

seco-DUBA

Class

DNA alkylator

Mechanism

DNA alkylator

Released catabolite

DUBA (activated duocarmycin)

Mechanistic subtype

DNA-alkylator

Stereochem / salt

Bystander

Yes

PAMPA rank

527 Da

XLogP3

5.3

logD₇.₄

3.7

TPSA

107 Å²

pKa

6.0 pKa

Charge pH 7.4

H-bond donors

H-bond acceptors

IC50 (HCEC)

2.2 nM

Formula

C29H23ClN4O4

PubChem CID

46240929

ADCdb payload

PAY0SOSMQ

Hydrophobicity · logD₇.₄

hydrophilic −2+3.7+4 lipophilic

Bioactivity note

seco-DUBA is a DNA-alkylating duocarmycin prodrug that spirocyclizes to the active DUBA cyclopropapyrroloindole, which binds the minor groove and alkylates adenine N3 of DNA. ADCdb reports preclinical PDX tumor growth inhibition of ~33% to 100% across HER2-expressing breast, gast

Dosing & regimen

Dosing

RP2D dose

1.2 mg/kg

Schedule

Q3W

Route

Fractionated

n at RP2D

291

Dose basis

TBW

Trial phase

Phase 3

Dose-OAE available

Yes

Tox summary basis

RP2D

Ocular & expression

Ocular profile & eye-tissue target expression

Target profile

OAE any-grade

78.1 %

OAE grade 3+

21.2 %

OAE data status

reported

Severity (weighted)

38.27

Keratopathy

38.2 %

Conjunctival

38.2 %

Dry eye

30.2 %

Blurred vision

Dominant tissue

Mixed

Surface subtype

Mixed

Grading scale

Unknown

Reversibility

Mixed

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

Cornea (central)

46.2 %

Cornea (limbal)

61.99 %

Conjunctiva

61.13 %

RPE

5.48 %

Retina (HPA)

7.5 nTPM

Cross-trial comparability

Ascertainment: Systematic eye examsScale: UnknownDenominator: RP2D⚠ OAE rate not directly comparable across trials

Identity & registry

Identifiers, registry & notes

ADC id

trastuzumab-duocarmazine

Approval status

Discontinued

Approval year

UniProt

P04626

ADCdb ADC

DRG0THGAW

ADCdb antibody

ANI0FIZAK

ADCdb target

TAR0THKZD

Primary source

Turner TULIP JCO 2025; PMID 39442070

Aliases & development codes

SYD985; [vic-]trastuzumab duocarmazine

Notes

Highest OAE in ERBB2 series; payload XLogP3 5.3 (highest); discontinuation 20.8%. V3.1: added dry eye 30.2% from Turner TULIP. Banerji Phase 1 PMID corrected 31257157→31257177.