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ARX788 Investigational anti-HER2-AS269 site-specific
Sponsor
Ambrx (NovaQuest/WuXi)
Indication
HER2+ breast/gastric
Target family
Receptor tyrosine kinase
RP2D dose
1.5 mg/kg Q3W RP2D
01 Multi-organ toxicity
Fingerprint & organ drill-down Any-grade Grade 3+
Ocular
46.4%
Hepatic
70.9%
Neutrop.
23.3%
Thrombo.
36.7%
Anemia
25%
GI
20%
ILD
34.8%
Neuro.
-
Also reported Other · 15 · 4 systems
13 adverse-event terms
Ocular Toxicity Target expression Compare
sagittal schematic · Reversible
↳ Tissues shaded by reported adverse-event rate.
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.
Surface subtype
Corneal (off-target)
Reported ocular events
Corneal epitheliopathy 35%
Conjunctival congestion 26%
Corneal epithelial injury (corneal epitheliopathy) 23.3%
Dry eye (xerophthalmia) 21.7%
Eye secretion increased 12%
Ophthalmodynia (eye pain) 12%
Per-trial detail
Adverse events by trial MUKDEN 06 (NCT05426486) · Phase 2b — 26 events, n=68 ACE-Breast-06 · Phase 2 — 21 events, n=32 ARX788 Phase 1 gastric/GEJ · Phase 1 — 20 events, n=30 ACE-Breast-02 · Phase 3 — 19 events, n=220 ACE-Breast-06 · Phase 2 — 18 events, n=32 ACE-Gastric-01 · Phase 1 — 15 events, n=30 MUKDEN 06 (NCT05426486) · Phase 2b — 7 events ACE-Breast-02 · Phase 3 — 6 events, n=220 ACE-Breast-01 · Phase 1 — 4 events, n=69 Unattributed cohort — 3 events Unattributed cohort — 3 events ARX788 Phase 1 breast (Zhang/Shi 2022) · Phase 1 — 2 events, n=69 Unattributed cohort — 2 events MUKDEN 06 (NCT05426486) Phase 2b ARX788 1.5 mg/kg + pyrotinib 320 mg QD ARX788 IV day1 Q3W n=68 CTCAE 5.0 C to verify
Xiao/Cheng Nat Commun 2025 (PMC12214574) [derived: G1-2+G3+G4 sum, Table 3] PMID 40593759
26 adverse-event terms · 10 systems · expand a system below
Vision blurred
47.1% G3+ 0%
Dry eye syndrome
42.6% G3+ 0%
Corneal epitheliopathy
35.3% G3+ 3%
Conjunctival congestion
26.5% G3+ 0%
Eye secretion increased
11.8% G3+ 0%
Ophthalmodynia (eye pain)
11.8% G3+ 0%
02 Construct
Molecular anatomy Linker structure C8H19NO5
NOCCOCCOCCOCCO copy
Payload structure C47H82N6O12
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 copy
03 Antibody
Antibody & Fc engineering Antibody
trastuzumab (engineered IgG1 with pAcF at HC-A114)
Linker
AS269 non-cleavable oxime (pAcF)
Attachment
Site-specific (enzymatic/non-natural AA)
Conjugation
Other site-specific (oxime at pAcF)
Symmetry
Site-specific (unpaired)
DAR homogeneity
Homogeneous
Cleavage trigger
Non-cleavable
Release control
Unconditional
Hydrophilicity mask
Discrete-PEG-spacer
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
pAF-AS269 catabolite
Mechanism
Tubulin inhibitor
Released catabolite
pAF-AS269
Mechanistic subtype
Tubulin-auristatin
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
08 Ocular & expression
Ocular profile & eye-tissue target expression Target profile → Surface subtype
Corneal (off-target)
Target expression in eye tissues (HCA detection · HPA bulk)
Cross-trial comparability · source-verified
Ascertainment: Partial / unspecified monitoring Scale: CTCAE v5 Denominator: RP2D
Dose & schedule → ocular toxicity · keratopathy (any-grade) by cohort
ARX788 1.5 mg/kg + pyrotinib 320 mg QD
ARX788 IV day1 Q3W
n=68 · MUKDEN 06
1.5 mg/kg + pyrotinib 400 mg/d
Q3W x6 (neoadjuvant)
· MUKDEN 06
1.3-1.7 mg/kg (pooled)
IV Q3W
n=30 · ARX788 Phase 1 gastric/GEJ
Per-cohort rates from the per-trial extraction, sorted by dose. Cross-trial comparison is subject to ascertainment / scale differences (see comparability above) — e.g. an early symptom-driven trial can read lower than a later systematic-exam trial at a higher dose.
Ocular AE grading reference — interspecialty consensus · 6 scales + dose modification 09 Identity & registry
Identifiers, registry & notes Approval status
Investigational
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.