Trastuzumab deruxtecan

FDA-approved

T-DXd; Enhertu; DS-8201a

Target

HER2 · ERBB2

Sponsor

Daiichi Sankyo/AstraZeneca

Indication

HER2+ breast/gastric/NSCLC

Target family

Receptor tyrosine kinase

RP2D dose

5.4 mg/kg (breast/NSCLC); 6.4 mg/kg (gastric)

Q3WRP2D

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

2 adverse-event terms

Ocular

Any-grade

11%

G3+

0.4%

RP2D

sagittal schematic · Reversible

↳

Tissues shaded by reported adverse-event rate.

Cornea

Express.

46.2%

Limbus

Express.

61.99%

Conjunctiva

Express.

61.13%

Lens

Express.

Retina / RPE

Express.

5.48%

7.5 nTPM

Dominant tissue

Ocular surface

Surface subtype

Conjunctival (on-target)

Reversibility

Reversible

Reported ocular events

Dry eye11%

G3+ 0.4%n=234

Vision blurred3.5%

n=257

Construct

Molecular anatomy

Antibody

IgG1

Humanized

Linker

Cleavable

DAR

Payload

DXd

TopoI inhibitor

Linker structureC25H31N5O8

[H]OC(=O)C([H])([H])N([H])C(=O)[C@@]([H])(N([H])C(=O)C([H])([H])N([H])C(=O)C([H])([H])N([H])C(=O)C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])N1C(=O)C([H])=C([H])C1=O)C([H])([H])c1c([H])c([H])c([H])c([H])c1[H]

Payload structureC26H24FN3O6

CC[C@@]1(C2=C(COC1=O)C(=O)N3CC4=C5[C@H](CCC6=C5C(=CC(=C6C)F)N=C4C3=C2)NC(=O)CO)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

GGFG tetrapeptide

Class

Cleavable

Cleavage

Cleavable

Attachment

Cysteine (interchain)

Conjugation

Conventional interchain Cys

Symmetry

Symmetric

DAR (mean)

DAR homogeneity

Heterogeneous

Plasma t½

7.5 d

Cleavage trigger

Cathepsin B/L (GGFG tetrapeptide)

Release control

Conditional

Hydrophilicity mask

Hydrophilic-linker

Formula

C25H31N5O8

Linker MW

529.55 Da

Linker TPSA

191.08 Å²

Linker xLogP

-1.3675

ADCdb linker

LIN0ECMCR

In-vitro stability

>97%@21d/human-plasma

Stability note

acAb t½ 7–8 d in clinical (Yin Clin Pharmacokinet 2021); GGFG is exceptionally plasma-stable cleavable linker (1–2% DXd released at 21 d in rat/mouse/human plasma per Nakada 2019); profiles of T-DXd and total antibody nearly superimposable, indicating linker stability in circulation

Payload

Payload & physicochemistry

Payload profile

Payload

DXd

Class

Topoisomerase I inhibitor

Mechanism

TopoI inhibitor

Released catabolite

DXd

Mechanistic subtype

TopoI

Stereochem / salt

Free base (conjugate formulated with no payload salt counterion); DXd payload is a single (1S,9S) stereoisomer (exatecan derivative)

Bystander

Yes

PAMPA rank

493.5 Da

XLogP3

logD₇.₄

1.4

TPSA

129 Å²

pKa

9.2 pKa

Charge pH 7.4

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C26H24FN3O6

PubChem CID

117888634

ADCdb payload

PAY0UXDSB

Hydrophobicity · logD₇.₄

hydrophilic −2+1.4+4 lipophilic

Bioactivity note

Free DXd payload: TOP1 (DNA topoisomerase I) inhibitor; in vitro IC50 ~0.5 nM (MDA-MB-468) and ~4 nM (KPL-4) per ADCdb. T-DXd ADC IC50 0.7 ng/mL (SK-BR-3), 8.1 ng/mL (NCI-N87); cell-kill ranges ~0.7 to >3000 ng/mL by HER2 expression. Source: ADCdb PAY0UXDSB / DRG0ERKBH.

Dosing & regimen

Dosing

RP2D dose

5.4 mg/kg (breast/NSCLC); 6.4 mg/kg (gastric)

Schedule

Q3W

Route

Fractionated

n at RP2D

234

Dose basis

TBW

Trial phase

Approved

Dose-OAE available

Tox summary basis

RP2D

Ocular & expression

Ocular profile & eye-tissue target expression

Target profile

OAE any-grade

11 %

OAE grade 3+

0.4 %

OAE data status

reported

Severity (weighted)

3.58

Keratopathy

Conjunctival

Dry eye

11 %

Blurred vision

Dominant tissue

Ocular surface

Surface subtype

Conjunctival (on-target)

Grading scale

Mixed

Reversibility

Reversible

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: Monitoring unknownScale: MixedDenominator: RP2D⚠ OAE rate not directly comparable across trials

Identity & registry

Identifiers, registry & notes

ADC id

trastuzumab-deruxtecan

Approval status

FDA-approved

Approval year

2019

UniProt

P04626

ADCdb ADC

DRG0ERKBH

ADCdb antibody

ANI0FIZAK

ADCdb target

TAR0THKZD

Primary source

ENHERTU PI (pooled DB01+J101, N=234)

Aliases & development codes

T-DXd; Enhertu; DS-8201a

Notes

V3.1: Dry eye 11 / G3 0.4 in pooled DB01+J101 (ENHERTU PI). G3+ corrected 0.5→0.4.