ARX788

Investigational

anti-HER2-AS269 site-specific

Target

HER2 · ERBB2

Sponsor

Ambrx (NovaQuest/WuXi)

Indication

HER2+ breast/gastric

Target family

Receptor tyrosine kinase

RP2D dose

1.5 mg/kg

Q3WRP2D

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

13 adverse-event terms

Ocular

Any-grade

46.4%

G3+

4.3%

RP2D

sagittal schematic · Reversible

↳

Tissues shaded by reported adverse-event rate.

Cornea

46.4%

Express.

46.2%

Limbus

Express.

61.99%

Conjunctiva

Express.

61.13%

Lens

Express.

Retina / RPE

Express.

5.48%

7.5 nTPM

Off-target signature

46.4% 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

Blurred vision47%

G3+ 12.3%n=220

Dry eye43%

G3+ 9.1%n=220

Corneal epitheliopathy35%

G3+ 3%n=69

Keratopathy28.2%

G3+ 5.9%n=220

Dry eyes28.1%

Conjunctival congestion26%

Conjunctivitis25%

G3+ 2.3%n=220

Corneal epithelial injury (corneal epitheliopathy)23.3%

Dry eye (xerophthalmia)21.7%

G3+ 0%n=69

Vision blurred13.3%

Eye secretion increased12%

Ophthalmodynia (eye pain)12%

Visual impairment10%

Construct

Molecular anatomy

Antibody

IgG1

Humanized

Linker

Non-cleavable

DAR

Payload

pAF-AS269 catabolite

Tubulin inhibitor

Linker structureC8H19NO5

NOCCOCCOCCOCCO

Payload structureC47H82N6O12

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=CC=C2)C(=O)O)OC)OC)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N(C)CCOCCOCCOCCON

Antibody

Antibody & Fc engineering

Antibody

trastuzumab (engineered IgG1 with pAcF at HC-A114)

Isotype

IgG1

Origin

Humanized

Fc modifications

pAcF non-canonical AA at HC A114

Glycoengineering

Standard

Effector silencing

None

FcγR binding

Retained

C1q binding

Retained

Linker & conjugation

Linker chemistry

Linker profile

Linker

AS269 non-cleavable oxime (pAcF)

Class

Non-cleavable

Cleavage

Non-cleavable

Attachment

Site-specific (enzymatic/non-natural AA)

Conjugation

Other site-specific (oxime at pAcF)

Symmetry

Site-specific (unpaired)

DAR (mean)

DAR homogeneity

Homogeneous

Plasma t½

12.5 d

Cleavage trigger

Non-cleavable

Release control

Unconditional

Hydrophilicity mask

Discrete-PEG-spacer

Formula

C8H19NO5

Linker MW

209.242 Da

Linker TPSA

83.17 Å²

Linker xLogP

-1.0812

ADCdb linker

LIN0NUXKO

In-vitro stability

Stability note

ADC t½ ~12.5 d in mice (Skidmore 2020 MCT preclinical); clinical t½ ~100 h (≈4.2 d) at 1.5 mg/kg in Hurvitz 2021 ASCO Phase 1; oxime + non-cleavable amberstatin linker confers exceptional plasma stability — free pAF-AS269 Cmax ~0.1% and AUC ~0.18% of intact ADC on molar basis

Payload

Payload & physicochemistry

Payload profile

Payload

pAF-AS269 catabolite

Class

Auristatin

Mechanism

Tubulin inhibitor

Released catabolite

pAF-AS269

Mechanistic subtype

Tubulin-auristatin

Stereochem / salt

Bystander

PAMPA rank

1113 Da

XLogP3

1.2

logD₇.₄

TPSA

221 Å²

pKa

Charge pH 7.4

-1

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C47H82N6O12

PubChem CID

89283237

ADCdb payload

PAY0QLDVX

Bioactivity note

Released warhead is MMAF (microtubule inhibitor; inhibits tubulin polymerization). ADCdb payload page (PAY0QLDVX = MMAF) reports MMAF antiproliferative IC50: SK-BR-3 5.3 nM, HT-29 10 nM, Hep-G2 7 nM, HCT-116 2880 nM. ARX788 is potent in HER2-low and T-DM1-resistant breast/gastric

Dosing & regimen

Dosing

RP2D dose

1.5 mg/kg

Schedule

Q3W

Route

Fractionated

n at RP2D

Dose basis

TBW

Trial phase

Phase 2/3

Dose-OAE available

Yes

Tox summary basis

RP2D

Ocular & expression

Ocular profile & eye-tissue target expression

Target profile

OAE any-grade

46.4 %

OAE grade 3+

4.3 %

OAE data status

reported

Severity (weighted)

16.93

Keratopathy

46.4 %

Conjunctival

Dry eye

21.7 %

Blurred vision

21.7 %

Dominant tissue

Cornea

Surface subtype

Corneal (off-target)

Grading scale

CTCAE v5

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: Partial / unspecified monitoringScale: CTCAE v5Denominator: RP2D

Identity & registry

Identifiers, registry & notes

ADC id

arx788

Approval status

Investigational

Approval year

UniProt

P04626

ADCdb ADC

DRG0LNVKG

ADCdb antibody

ANI0LQVDF

ADCdb target

TAR0THKZD

Primary source

Shi CCR 2022 PMID 35766963

Aliases & development codes

anti-HER2-AS269 site-specific

Notes

Site-specific DAR 2 non-cleavable; charged catabolite; OAE intermediate between T-DM1 and belantamab. V3.1 RESOLUTION: antibody IS trastuzumab-based (per Skidmore MCT 2020 Ambrx authors, ADC Review, Zhang CCR 2022). Prior 'anbenitamab' hypothesis from Pasricha call notes not supported by primary literature — anbenitamab (KN026) is unrelated bispecific from Alphamab. Neoadjuvant MUKDEN 06 (Pan Nat Commun 2025 N=68): CE 32%, blurred 47%, dry eye 43% — not >95% as Pasricha mentioned.