A166

Investigational

anti-HER2-vc-Duostatin-5 site-specific

Target

HER2 · ERBB2

Sponsor

Sichuan Kelun-Biotech/Klus Pharma

Indication

HER2+ breast

Target family

Receptor tyrosine kinase

RP2D dose

4.8 mg/kg

Q3WRP2D

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

100%

G3+

40.7%

RP2D

sagittal schematic · Reversible

↳

Tissues shaded by reported adverse-event rate.

Cornea

84%

Express.

46.2%

Limbus

Express.

61.99%

Conjunctiva

Express.

61.13%

Lens

Express.

Retina / RPE

Express.

5.48%

7.5 nTPM

Off-target signature

84% corneal toxicity, yet the HER2 target is detected in only 46.2% of central cornea - toxicity is not explained by target expression.

Dominant tissue

Cornea

Surface subtype

Corneal (off-target)

Reversibility

Reversible

Reported ocular events

Corneal epitheliopathy100%

G3+ 40.7%n=81

Vision blurred85.2%

G3+ 25.9%n=81

Dry eye33.3%

G3+ 11.1%n=81

Construct

Molecular anatomy

Antibody

IgG1

Humanized

Linker

Cleavable

DAR

Payload

Duostatin-5

Tubulin inhibitor

Linker structureC28H42N6O8

CC(C)C(NC(=O)CCC(=O)N1CCC(C(=O)O)CC1)C(=O)NC(CCCNC(N)=N)C(=O)Nc1ccc(CO)cc1

Payload structureC40H69N9O6

CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@@H]([C@@H](C)C(=O)N[C@@H](CC2=CC=C(C=C2)N)CN=[N+]=[N-])OC)OC)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N(C)C

Antibody

Antibody & Fc engineering

Antibody

trastuzumab (INN: trastuzumab botidotin)

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

MC-vc-PAB + K-Lock (site-specific)

Class

Cleavable

Cleavage

Cleavable

Attachment

Site-specific (engineered Cys)

Conjugation

Other site-specific (K-Lock)

Symmetry

Site-specific (paired)

DAR (mean)

DAR homogeneity

Homogeneous

Plasma t½

8.3 d

Cleavage trigger

Cathepsin B (Val-Cit)

Release control

Conditional

Hydrophilicity mask

None

Formula

C28H42N6O8

Linker MW

590.678 Da

Linker TPSA

220.26 Å²

Linker xLogP

0.2949

ADCdb linker

LIN0EBCCY

In-vitro stability

Stability note

Mean t½ 1.17–11.04 d across dose range 0.3–6.0 mg/kg per Hu npj Breast Cancer 2023 / Liu 2024 Ph1 N=58; t½ 8.29 d at the RP2D 4.8 mg/kg cohort. Free Duo-5 Cmax ~0.1% and AUC ~0.2% of total ADC (Hu 2023) — exceptional stability

Payload

Payload & physicochemistry

Payload profile

Payload

Duostatin-5

Class

Auristatin

Mechanism

Tubulin inhibitor

Released catabolite

Duostatin-5 (Duo-5)

Mechanistic subtype

Tubulin-auristatin

Stereochem / salt

Bystander

PAMPA rank

772 Da

XLogP3

5.5

logD₇.₄

TPSA

161 Å²

pKa

9 pKa

Charge pH 7.4

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C40H69N9O6

PubChem CID

138320017

ADCdb payload

PAY0EQOWS

Hydrophobicity · logD₇.₄

hydrophilic −2+3+4 lipophilic

Bioactivity note

No payload-level IC50 reported by PubChem or ADCdb. Duostatin-5 is a microtubule-disrupting MMAF-derived auristatin. ADC clinical efficacy (A166/trastuzumab botidotin): ORR 73.90% at 4.8 mg/kg and partial-response rate ~25.92% in Phase 1 (per ADCdb DRG0TIZXC).

Dosing & regimen

Dosing

RP2D dose

4.8 mg/kg

Schedule

Q3W

Route

Fractionated

n at RP2D

Dose basis

TBW

Trial phase

Phase 1/2

Dose-OAE available

Yes

Tox summary basis

RP2D

Ocular & expression

Ocular profile & eye-tissue target expression

Target profile

OAE any-grade

100 %

OAE grade 3+

40.7 %

OAE data status

reported

Severity (weighted)

42.63

Keratopathy

84 %

Conjunctival

Dry eye

32.1 %

Blurred vision

74.1 %

Dominant tissue

Cornea

Surface subtype

Corneal (off-target)

Grading scale

Unknown

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 · source-verified

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

Identity & registry

Identifiers, registry & notes

ADC id

a166

Approval status

Investigational

Approval year

UniProt

P04626

ADCdb ADC

DRG0TIZXC

ADCdb antibody

ANI0FIZAK

ADCdb target

TAR0THKZD

Primary source

Li/Hu npj Breast Cancer 2023

Aliases & development codes

anti-HER2-vc-Duostatin-5 site-specific

Notes

High OAE (~70%) and severe G3+ (31%); Duostatin-5 most lipophilic payload (XLogP3 5.5). V3.1: n_rp2d 81→27 (RP2D cohort at 4.8 mg/kg; prev 81 was total enrollment). Antibody confirmed as trastuzumab-based per Hu 2023 ('same amino acid sequence as trastuzumab'; INN trastuzumab botidotin). 'K-Lock' conjugation naming flagged — not explicitly named in primary publication.