PF-06804103

Discontinued

trastuzumab-pelidotin; T-vc0101; trastuzumab-vc0101; HER2-vc0101; NG-HER2 ADC; Anti-NG-HER2 ADC; PF 06804103

Target

HER2 (receptor tyrosine-protein kinase erbB-2) · ERBB2

Sponsor

Pfizer

Indication

HER2-expressing breast cancer (HER2+ and HR+/HER2-low); gastric cancer

Target family

Receptor tyrosine kinase

RP2D dose

4.0 mg/kg (3.0 mg/kg permitted as reduced dose; no formal RP2D declared before discontinuation)

Q3WPooled

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

26 adverse-event terms

Ocular

Any-grade

9.5%

G3+

Pooled

sagittal schematic · -

↳

Tissues shaded by reported adverse-event rate.

Cornea

9.7%

Express.

46.2%

Limbus

Express.

61.99%

Conjunctiva

Express.

61.13%

Lens

Express.

Retina / RPE

Express.

5.48%

7.5 nTPM

Off-target signature

9.7% corneal toxicity, yet the HER2 (receptor tyrosine-protein kinase erbB-2) 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

Reported ocular events

Keratitis (incl. keratopathy + keratitis preferred terms)9.7%

n=93

Dry eye9.5%

n=95

Vision blurred9.5%

n=95

Keratitis (PT-level)5.3%

n=95

Keratopathy (PT-level)4.2%

n=95

Blepharitis3.2%

n=95

Periorbital oedema3.2%

n=95

Visual acuity reduced3.2%

n=95

Eye swelling2.1%

Eye disorder (unspecified PT)2.1%

Ulcerative keratitis1.1%

n=95

Blindness unilateral1.1%

n=95

Conjunctivitis1.1%

n=95

Corneal disorder1.1%

Eye pain1.1%

Photophobia1.1%

Foreign body sensation in eyes1.1%

Xerophthalmia1.1%

Lacrimation increased1.1%

Eye discharge1.1%

Eyelid ptosis1.1%

Eyelid rash1.1%

Visual impairment1.1%

Visual brightness1.1%

Hordeolum (stye; coded Infections SOC)1.1%

Keratitis/keratopathy (any eye event)-

G3+ 0%n=93

Construct

Molecular anatomy

Antibody

IgG1

Humanized

Linker

Cleavable

DAR

Payload

Aur0101 (PF-06380101 / Aur-06380101; payload moiety 'pelidotin')

Tubulin inhibitor (microtubule disruption; G2-M arrest)

Linker structureC28H40N6O7

CC(C)C(C(=O)NC(CCCNC(=O)N)C(=O)NC1=CC=C(C=C1)CO)NC(=O)CCCCCN2C(=O)C=CC2=O

Payload structureC39H62N6O6S

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)C3=NC=CS3)OC)OC)N(C)C(=O)[C@H](C(C)C)NC(=O)C(C)(C)N

Antibody

Antibody & Fc engineering

Antibody

Trastuzumab variant T-(kK183C+K290C) (engineered double-cysteine trastuzumab)

Isotype

IgG1

Origin

Humanized

Fc modifications

None

Glycoengineering

Standard

Effector silencing

None reported — wild-type human IgG1 Fc retained (no LALA/effector-silencing mutations); engineered cysteines kappa LC-K183C + HC-Fc-K290C (EU numbering) introduced solely as site-specific conjugation handles

FcγR binding

Abolished

C1q binding

Reduced

Linker & conjugation

Linker chemistry

Linker profile

Linker

mc-Val-Cit-PABC (vc0101)

Class

Cleavable

Cleavage

Cleavable

Attachment

Site-specific (engineered Cys)

Conjugation

Site-specific engineered cysteine (THIOMAB-like double-Cys mutant kK183C/K290C) via maleimidocaproyl maleimide

Symmetry

Site-specific (paired)

DAR (mean)

DAR homogeneity

Homogeneous

Plasma t½

Cleavage trigger

Cathepsin B (lysosomal cysteine cathepsins); Val-Cit dipeptide with p-aminobenzylcarbamate (PABC) self-immolative spacer

Release control

Conditional

Hydrophilicity mask

None

Formula

C28H40N6O7

Linker MW

572.66 Da

Linker TPSA

200.03 Å²

Linker xLogP

0.6769

ADCdb linker

LIN0SQEDQ

In-vitro stability

Payload

Payload & physicochemistry

Payload profile

Payload

Aur0101 (PF-06380101 / Aur-06380101; payload moiety 'pelidotin')

Class

Auristatin

Mechanism

Tubulin inhibitor (microtubule disruption; G2-M arrest)

Released catabolite

Aur0101 (free auristatin; PF-06380101 / Aur-06380101) — membrane-permeable cytotoxic catabolite released after cathepsin B cleavage and PABC self-immolation; supports bystander killing (more permeable than Lys-mcc-DM1)

Mechanistic subtype

Tubulin-auristatin

Stereochem / salt

Bystander

Yes

PAMPA rank

743 Da

XLogP3

4.1

logD₇.₄

TPSA

184 Å²

pKa

Charge pH 7.4

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C39H62N6O6S

PubChem CID

71569947

ADCdb payload

PAY0WDZAK

Bioactivity note

ADCdb reports 100% Tumor Growth Inhibition (TGI) in two cell-line-derived xenograft models: gastric NCI-N87 (HER2 3+) and breast BT474-M1 (HER2 2+). No IC50 values reported. Payload Aur0101 is a potent dolastatin-10-analogue auristatin microtubule inhibitor.

Dosing & regimen

Dosing

RP2D dose

4.0 mg/kg (3.0 mg/kg permitted as reduced dose; no formal RP2D declared before discontinuation)

Schedule

Q3W

Route

Fractionated

n at RP2D

Dose basis

TBW

Trial phase

Phase 1

Dose-OAE available

Yes

Tox summary basis

dose-escalation

Ocular & expression

Ocular profile & eye-tissue target expression

Target profile

OAE any-grade

9.5 %

OAE grade 3+

0 %

OAE data status

reported

Severity (weighted)

2.85

Keratopathy

9.7 %

Conjunctival

0 %

Dry eye

9.5 %

Blurred vision

9.5 %

Dominant tissue

Cornea

Surface subtype

Corneal (off-target)

Grading scale

CTCAE v4

Reversibility

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: CTCAE v4Denominator: RP2D

Identity & registry

Identifiers, registry & notes

ADC id

pf-06804103

Approval status

Discontinued

Approval year

UniProt

P04626

ADCdb ADC

DRG0AWQJG

ADCdb antibody

ANI0MFYJE

ADCdb target

TAR0THKZD

Primary source

Meric-Bernstam et al., Mol Cancer Ther 2023;22(10):1191 (PMC10543980); ClinicalTrials.gov NCT03284723 posted results

Aliases & development codes

trastuzumab-pelidotin; T-vc0101; trastuzumab-vc0101; HER2-vc0101; NG-HER2 ADC; Anti-NG-HER2 ADC; PF 06804103

Notes

PF-06804103 = trastuzumab-pelidotin (T-vc0101), a site-specific anti-HER2 ADC: trastuzumab engineered with double cysteine mutations (kappa LC-K183C + HC-Fc-K290C, EU numbering) conjugated via cleavable mc-Val-Cit-PABC (vc0101) to the membrane-permeable auristatin Aur0101 (PF-06380101) at DAR 4; bystander-active. First-in-human Phase 1 NCT03284723 (Meric-Bernstam et al., Mol Cancer Ther 2023;22(10):1191); program discontinued. OCULAR (qualifying signal): Clear on-target/payload corneal auristatin toxicity. Treatment-related keratitis (incl. keratopathy+keratitis PTs) 9 (9.7%) of N=93, with 3 (3.2%) leading to drug withdrawal; maximum ocular grade was Grade 2 (NO Grade >=3 ocular events documented). CT.gov posted all-cause eye-disorder PTs over N=95 (pooled across 0.15-5.0 mg/kg dose-escalation): dry eye 9.5% (9/95), vision blurred 9.5% (9/95), keratitis 5.3% (5/95), keratopathy 4.2% (4/95), blepharitis / periorbital oedema / visual acuity reduced 3.2% (3/95) each, plus single (1/95) cases of ulcerative keratitis, blindness unilateral, corneal disorder, eye pain, photophobia, xerophthalmia, lacrimation increased, macular degeneration, cataract, and infective conjunctivitis. No eye disorders appeared in the serious-events table. Dominant tissue = corneal; subtype = Corneal (off-target). DENOMINATOR NOTE: Paper safety population = 93 (monotherapy Parts 1A+2A); CT.gov AE tables = 95 (adds 2 Part 1B combination patients). Pooled all-cause PT rates computed over N=95 by summing per-cohort affected counts (CT.gov posts per dose group at a 5% threshold), and reproduce the screen's oae_hint exactly. RP2D not formally declared before discontinuation; 4.0 mg/kg was the selected Part 2 dose (3.0 mg/kg permitted as reduced dose). REVERSIBILITY CAVEAT / SOURCE CORRECTION: ae_reversibility left blank because the primary trial publication (MCT 2023) does not state reversibility, and verification indicates the Can J Ophthalmol 2021 paper 'Reversible HER2 antibody-drug conjugate-induced ocular toxicity' (cited in the screen's best_source) actually describes A166 (a different HER2 ADC, RP2D 4.8 mg/kg, corneal epitheliopathy ~30.9%), NOT PF-06804103 — so its 'reversible microcystic keratopathy' finding was excluded to avoid mis-attribution. CHEMISTRY: payload_charge_pH7_4 (+1) is structure-derived (free primary amine at the Aib N-terminus of Aur0101; no carboxylate), tier C; payload MW/XLogP3/TPSA are PubChem-computed for the free payload (CID 71569947, C39H62N6O6S). No clean in-vitro %-intact stability figure available; Graziani 2020 reports high in vivo conjugate stability (cyno ADC/antibody ratio >=0.87; lower free-payload serum exposure than the conventional conjugate). PubChem 'pelidotin' (CID 89582456, C68H100N12O14S, MW 1341.7) is the full mc-vc-PABC-Aur0101 linker-payload, distinct from the free payload used in payload_physchem.