PF-06647263

Investigational

PF-6647263; anti-EFNA4 calicheamicin ADC; huE22-AcButDMH-N-Ac-calicheamicin conjugate; Anti-EFNA4-ADC

Target

Ephrin-A4 · EFNA4

Sponsor

Pfizer

Indication

Advanced solid tumors (dose-expansion in metastatic triple-negative breast cancer)

Target family

Ephrin ligand

RP2D dose

0.015 mg/kg

QW (weekly)RP2D

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

17 adverse-event terms

Ocular

Any-grade

G3+

RP2D

sagittal schematic · Unknown

↳

Tissues shaded by reported adverse-event rate.

Cornea

Express.

Limbus

Express.

Conjunctiva

Express.

Lens

Express.

Retina / RPE

Express.

Dominant tissue

Mixed

Surface subtype

Unknown

Reversibility

Unknown

Reported ocular events

Dry eye10%

n=60

Lacrimation increased10%

n=60

Vision blurred6.7%

n=60

Conjunctivitis5%

non-seriousn=60

Eye irritation3.3%

n=60

Ocular hyperaemia3.3%

n=60

Mydriasis1.7%

n=60

Eye symptom (NOS)1.7%

n=60

Vitreous floaters1.7%

n=60

Eye haemorrhage1.7%

n=60

Eye discharge1.7%

n=60

Eye pruritus1.7%

n=60

Cataract1.7%

n=60

Diplopia1.7%

n=60

Conjunctival haemorrhage1.7%

n=60

Iritis1.7%

n=60

Eye symptom1.67%

non-seriousn=60

Per-trial detail

Adverse events by trial

A Study Of PF-06647263 In Patients With Advanced Solid TumorsPHASE1real-worldn=60CTCAE NR (ClinicalTrials.govPooledC

ClinicalTrials.gov NCT02078752 posted results, adverse events module (non-serious; 9/60 pooled across arms)

272 adverse-event terms · 22 systems · expand a system below

Dermatologic40

Rash

18.33%non-serious

11/60

Dry skin

16.67%non-serious

10/60

Nail disorder

15%non-serious

9/60

Skin hyperpigmentation

15%non-serious

9/60

Alopecia

13.33%non-serious

8/60

Pruritus

13.33%non-serious

8/60

Skin discolouration

11.67%non-serious

7/60

Skin lesion

6.67%non-serious

4/60

Erythema

5%non-serious

3/60

Nail discolouration

5%non-serious

3/60

Onychomadesis

5%non-serious

3/60

Palmar-plantar erythrodysaesthesia syndrome

5%non-serious

3/60

Rash maculo-papular

5%non-serious

3/60

Blister

3.33%non-serious

2/60

Dermatitis

3.33%non-serious

2/60

Madarosis

3.33%non-serious

2/60

Night sweats

3.33%non-serious

2/60

Pain of skin

3.33%non-serious

2/60

Skin fragility

3.33%non-serious

2/60

Urticaria

3.33%non-serious

2/60

Dermatitis acneiform

1.67%non-serious

1/60

Dermatitis bullous

1.67%non-serious

1/60

Ecchymosis

1.67%non-serious

1/60

Hair texture abnormal

1.67%non-serious

1/60

Hyperkeratosis

1.67%non-serious

1/60

Nail bed tenderness

1.67%non-serious

1/60

Onychalgia

1.67%non-serious

1/60

Onycholysis

1.67%non-serious

1/60

Papule

1.67%non-serious

1/60

Petechiae

1.67%non-serious

1/60

Photosensitivity reaction

1.67%non-serious

1/60

Pigmentation disorder

1.67%non-serious

1/60

Rash erythematous

1.67%non-serious

1/60

Rash generalised

1.67%non-serious

1/60

Rash macular

1.67%non-serious

1/60

Rash papular

1.67%non-serious

1/60

Rash pruritic

1.67%non-serious

1/60

Scar pain

1.67%non-serious

1/60

Skin disorder

1.67%non-serious

1/60

Telangiectasia

1.67%non-serious

1/60

GI38

General23

Infections20

Pulmonary20

Neurologic (other)17

Metabolic16

Investigations14

Ocular14

Vision blurred

6.67%non-serious

4/60

Conjunctivitis

5%non-serious

3/60

Eye irritation

3.33%non-serious

2/60

Ocular hyperaemia

3.33%non-serious

2/60

Cataract

1.67%non-serious

1/60

Conjunctival haemorrhage

1.67%non-serious

1/60

Diplopia

1.67%non-serious

1/60

Eye discharge

1.67%non-serious

1/60

Eye haemorrhage

1.67%non-serious

1/60

Eye pruritus

1.67%non-serious

1/60

Eye symptom

1.67%non-serious

1/60

Iritis

1.67%non-serious

1/60

Mydriasis

1.67%non-serious

1/60

Vitreous floaters

1.67%non-serious

1/60

Musculoskeletal10

Injury9

Other9

Renal8

Hematologic7

Psychiatric7

Vascular7

Hepatic5

Cardiac3

Neoplasms2

Ear1

Endocrine1

Immune1

Construct

Molecular anatomy

Antibody

IgG1

Humanized

Linker

Cleavable

4.6

DAR

Payload

N-acetyl-gamma-calicheamicin

DNA strand break

Linker structureC12H15NO3

CC(=O)c1ccc(OCCCC(N)=O)cc1

Payload structureC57H76IN3O22S4

CCN([C@H]1CO[C@H](C[C@@H]1OC)O[C@@H]2[C@H]([C@@H]([C@H](O[C@H]2O[C@H]3C#C/C=C\C#C[C@@]4(CC(=O)C(=C3C4=CCSSSC)NC(=O)OC)O)C)NO[C@H]5C[C@@H]([C@@H]([C@H](O5)C)SC(=O)C6=C(C(=C(C(=C6OC)OC)O[C@H]7[C@@H]([C@@H]([C@H]([C@@H](O7)C)O)OC)O)I)C)O)O)C(=O)C

Antibody

Antibody & Fc engineering

Antibody

huE22 (anti-EFNA4)

Isotype

IgG1

Origin

Humanized

Fc modifications

None^inferred

Glycoengineering

Standard^inferred

Effector silencing

None^inferred

FcγR binding

Retained

C1q binding

Retained^inferred

Dev code

E22

Linker & conjugation

Linker chemistry

Linker profile

Linker

AcButDMH (AcBut acid-labile hydrazone + disulfide)

Class

Cleavable

Cleavage

Cleavable

Attachment

Lysine

Conjugation

Conventional Lys (NHS); random lysine

Symmetry

Symmetric

DAR (mean)

4.6

DAR homogeneity

Heterogeneous

Plasma t½

Cleavage trigger

pH/acid (hydrazone) + GSH/reductive (disulfide)

Release control

Conditional

Hydrophilicity mask

None^inferred

DAR distribution

~70-80% of species DAR3-5

Formula

C12H15NO3

Linker MW

221.256 Da

Linker TPSA

69.39 Å²

Linker xLogP

1.5335

ADCdb linker

LIN0KWKDL

In-vitro stability

Unknown

Payload

Payload & physicochemistry

Payload profile

Payload

N-acetyl-gamma-calicheamicin

Class

Calicheamicin

Mechanism

DNA strand break

Released catabolite

N-acetyl-gamma-calicheamicin (active enediyne), released from conjugated N-acetyl-gamma-calicheamicin dimethylhydrazide (N-Ac-gamma-cal-DMH) via acid-labile hydrazone hydrolysis + reductive disulfide cleavage; Garrido-Laguna 2019 states payload is hydrolytically released in the lysosome and generates double-strand DNA breaks

Mechanistic subtype

DNA-strand-break

Stereochem / salt

Unknown

Bystander

Partial

PAMPA rank

1368.4 Da^conflicts

XLogP3

logD₇.₄

TPSA

410 Å²

pKa

Charge pH 7.4

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C57H76IN3O22S4^conflicts

PubChem CID

134819845

ADCdb payload

PAY0RZSDY

Hydrophobicity · logD₇.₄

hydrophilic −2+2+4 lipophilic

Bioactivity note

ADCdb reports clinical objective response rate (ORR) 10.4% across all dose groups (9.1% at 0.015 mg/kg weekly) in the terminated Phase 1; no payload IC50 or ADC binding-affinity values reported. Payload is N-acetyl-gamma-calicheamicin, a DNA-cleaving enediyne (same warhead class

Dosing & regimen

Dosing

RP2D dose

0.015 mg/kg

Schedule

QW (weekly)

Route

Fractionated

n at RP2D

Dose basis

TBW

Trial phase

Phase 1

Dose-OAE available

Yes

Tox summary basis

RP2D

ADA rate (%)

39.6 %

Ocular & expression

Ocular profile & eye-tissue target expression

Target profile

OAE any-grade

8 %

OAE grade 3+

0 %

OAE data status

reported

Severity (weighted)

2.4

Keratopathy

Conjunctival

Dry eye

8 %

Blurred vision

8 %

Dominant tissue

Mixed

Surface subtype

Unknown

Grading scale

CTCAE v4.03

Reversibility

Unknown

Target expression in eye tissues (HCA detection · HPA bulk)

Cornea (central)

Cornea (limbal)

Conjunctiva

RPE

Retina (HPA)

Cross-trial comparability · source-verified

Ascertainment: Symptom-driven reportingScale: CTCAE v4Denominator: RP2D⚠ Not comparable: symptom-driven ascertainment

Dose & schedule → ocular toxicity · ocular AE (any-grade) by cohort

0.01 mg/kg

33.3%

n=3 · NCT02078752

0.015 mg/kg

8.3%

n=12 · NCT02078752

0.015 mg/kg

n=25 · NCT02078752

0.015 mg/kg

7.7%

n=13 · NCT02078752

0.02 mg/kg

14.3%

n=7 · NCT02078752

0.03 mg/kg

Q3W

66.7%

n=3 · NCT02078752

0.03 mg/kg

Q3W

33.3%

n=3 · NCT02078752

0.05 mg/kg

Q3W

11.1%

n=9 · NCT02078752

0.075 mg/kg

Q3W

33.3%

n=3 · NCT02078752

0.1 mg/kg

Q3W

16.7%

n=6 · NCT02078752

0.134 mg/kg

Q3W

50%

n=2 · NCT02078752

0.01-0.134 mg/kg (all cohorts)

Q3W/QW

10%

n=60 · NCT02078752

—

6.67%

n=60 · A Study Of PF-06647263 In Patients With Advanced Solid Tumors

—

1.7%

n=60

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

Identity & registry

Identifiers, registry & notes

ADC id

pf-06647263

Approval status

Investigational

Approval year

UniProt

P52798

ADCdb ADC

DRG0SHGPV

ADCdb antibody

ANI0ONCDU

ADCdb target

TAR0IMOZN

Primary source

ClinicalTrials.gov NCT02078752 (all-causality AE table); Garrido-Laguna et al., Int J Cancer 2019;145(7):1798-1808 (PMID 30680712)

Aliases & development codes

PF-6647263; anti-EFNA4 calicheamicin ADC; huE22-AcButDMH-N-Ac-calicheamicin conjugate; Anti-EFNA4-ADC

Notes

EFNA4 (Ephrin-A4)-targeted ADC; antibody huE22 (humanized IgG1); linker AcButDMH (acid-labile hydrazone + disulfide; ADCdb LIN0KWKDL, the SAME shared calicheamicin linker as gemtuzumab-ozogamicin, inotuzumab-ozogamicin, and CMD-193); payload N-acetyl-gamma-calicheamicin (enediyne, DNA double-strand breaks); DAR 4.6 (ADCdb); random-lysine conjugation; Pfizer. Phase 1 FIH NCT02078752 (Garrido-Laguna et al., Int J Cancer 2019;145(7):1798-1808, PMID 30680712), advanced solid tumors with a metastatic-TNBC dose-expansion; development discontinued (Phase 1 terminated). RP2D 0.015 mg/kg QW; MTD not reached for either Q3W or QW; 1 DLT (thrombocytopenia) on QW. OCULAR — CRITICAL ATTRIBUTION CAVEAT: the ocular AEs are ALL-CAUSALITY events from the ClinicalTrials.gov posted results, NOT treatment-related. The peer-reviewed publication's treatment-related AE tables (Tables 3-4) contain ZERO ocular events. Calicheamicin is not a classically ocular-toxic payload (gemtuzumab/inotuzumab report 0% ocular AEs in their FDA labels). These eye AEs are almost certainly background/incidental in an advanced-cancer population; causal attribution to PF-06647263 is weak. No ocular AE was serious or Grade >=3 (CT.gov serious-AE table has zero eye disorders; the paper lists no ocular event among Grade 3/4 AEs) -> oae_g3plus_pct=0 is a documented zero. CORRECTION to the screening hint: the hint's 'conjunctivitis 5.0%' is NOT an Eye-disorders SOC ocular-surface event -- it is 'Conjunctivitis' under the Infections & infestations SOC (infective conjunctivitis, 3/60: groups EG001/EG007/EG008), not a drug-induced ocular toxicity. The only Eye-disorders conjunctival PT is conjunctival haemorrhage (1/60, 1.7%, a hemorrhagic event likely related to thrombocytopenia). Hence ae_conjunctival_pct is left blank (no on-target conjunctivitis). DENOMINATOR NOTE: the CT.gov AE table is split into 10 dose-level groups (no pooled column). RP2D = 0.015 mg/kg QW = EG001 (Part 1, n=13) + EG009 (Part 2 TNBC expansion, n=12) = n=25. ocular{} summary and all line_context=RP2D rows use this n=25 all-causality slice (tier D, no grade resolution at this cohort). Treatment-related grade data (tier B) live in line_context=dose-escalation rows (Q3W arm n=25; QW arm n=35). Per-group RP2D ocular detail: 0.015 QW Part 1 (n=13) vision blurred 15.4%, dry eye/eye irritation/iritis/mydriasis 7.7% each; 0.015 QW Part 2 (n=12) dry eye/cataract/diplopia 8.3% each. Whole-study pooled all-cause (N=60) ocular: dry eye 10.0%, lacrimation increased 10.0%, vision blurred 6.7%, eye irritation 3.3%, ocular hyperaemia 3.3%; iritis/cataract/diplopia/conjunctival haemorrhage/mydriasis/vitreous floaters/eye discharge/eye haemorrhage/eye pruritus/eye symptom 1.7% each. NON-OCULAR (Garrido-Laguna 2019, treatment-related): dominant toxicities are thrombocytopenia (QW 31.4% any/5.7% G3+; Q3W 44% any/20% G3+ [G3 8% + G4 12%]), GI (nausea/vomiting/diarrhea/mucositis 20-64%; G3+ rare: Q3W vomiting 4%, QW nausea 2.9%, QW gastritis G4 2.9%), and the calicheamicin-class hepatobiliary signal (Q3W Grade-3 hyperbilirubinemia 8%; 1 grade-1 hepatic VOD + 1 nodular regenerative hyperplasia/portal hypertension in the Q3W arm; pooled all-cause VOD 1.7%, blood bilirubin increased 11.7%, AST increased 10%). Neutropenia infrequent (~1.7-5% pooled), consistent with attenuated marrow toxicity in a solid-tumor (non-hematologic-target) setting vs gemtuzumab/inotuzumab. Peripheral neuropathy 10% pooled all-cause/low-grade (not a calicheamicin toxicity). No drug-related ILD/pneumonitis (1 'radiation pneumonitis' = radiotherapy-related) and no infusion-related reactions reported -> pulm_ild and infusion left BLANK (not zero). Linker physchem (SMILES/formula/MW 221.256/TPSA 69.39/xLogP 1.5335) carried from the shared LIN0KWKDL platform (verified on the ADCdb linker page, shared with gemtuzumab/inotuzumab/CMD-193). payload_physchem uses the standard calicheamicin-gamma1 reference values (shared payload) per DB convention. Derived columns (dna_damage subtype, FcgammaR/C1q status, stability conditional/unconditional, severity, HCA/HPA) intentionally left blank for downstream computation.