Vorsetuzumab mafodotin

Discontinued

SGN-75; anti-CD70-MMAF

Target

CD70 · CD70

Sponsor

Seagen

Indication

CD70+ RCC/NHL

Target family

Other

RP2D dose

3 mg/kg Q3W

Q3WRP2D

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

8 adverse-event terms

Ocular

Any-grade

57%

G3+

23%

RP2D

sagittal schematic · Reversible

↳

Tissues shaded by reported adverse-event rate.

Cornea

15%

Express.

0.82%

Limbus

Express.

Conjunctiva

Express.

0.64%

Lens

Express.

Retina / RPE

Express.

0 nTPM

Off-target signature

15% corneal toxicity, yet the CD70 target is detected in only 0.82% of central cornea - toxicity is not explained by target expression.

Dominant tissue

Cornea

Surface subtype

Corneal (off-target)

Reversibility

Reversible

Reported ocular events

Ocular adverse events (any type, composite)57%

n=47

Dry eye32%

n=47

Ocular adverse events (grade >=3, composite)23%

G3+n=47

Vision blurred - WEEKLY schedule18%

Corneal epitheliopathy15%

n=47

Vision blurred11%

n=47

Keratitis9%

n=47

IridocyclitisG2 observed-

low grade

Per-trial detail

Adverse events by trial

SGN-75 Phase 1 first-in-human (NCT01015911) — Q3Wk schedulePhase 10.3-4.5 mg/kg (all doses pooled; MTD 3 mg/kg, RCC expansion at 3 mg/kg) IV every 3 weeks (Q3Wk)n=47CTCAE 4.0PooledBto verify

Tannir et al., Invest New Drugs 2014;32(6):1246-57 PMID 25142258

34 adverse-event terms · 11 systems · expand a system below

GI6

Gastrointestinal disorders

60%G3+ 11%

28/47

Nausea

30%G3+ 0%

14/47

Constipation

23%G3+ 0%

11/47

Abdominal pain

19%G3+ 4%

9/47

Diarrhea

13%G3+ 0%

6/47

Vomiting

11%G3+ 0%

5/47

Ocular4

Eye disorders

57%G3+ 23%

27/47

Dry eye

32%G3+ 6%

15/47

Corneal epithelium defect

15%G3+ 9%

7/47

Vision blurred

15%G3+ 4%

7/47

Pulmonary4

Hematologic3

General3

Metabolic3

Musculoskeletal3

Neurologic (other)3

Neoplasms2

Renal2

Other1

Construct

Molecular anatomy

Antibody

IgG1

Humanized

Linker

Non-cleavable

DAR

Payload

Cys-mcMMAF

Tubulin inhibitor

Linker structureC10H13NO4

O=C(O)CCCCCN1C(=O)C=CC1=O

Payload structureC52H83N7O13S

drag · scroll to zoom

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)C(=O)CCCCCN3C(=O)CC(C3=O)SC[C@@H](C(=O)O)N

Antibody

Antibody & Fc engineering

Antibody

h1F6 (vorsetuzumab)

Isotype

IgG1

Origin

Humanized

Fc modifications

None^inferred

Glycoengineering

Standard^inferred

Effector silencing

None^inferred

FcγR binding

Retained

C1q binding

Retained^inferred

Linker & conjugation

Linker chemistry

Linker profile

Linker

mc (non-cleavable)

Class

Non-cleavable

Cleavage

Non-cleavable

Attachment

Cysteine (interchain)

Conjugation

Conventional interchain Cys

Symmetry

Symmetric

DAR (mean)

DAR homogeneity

Heterogeneous

Plasma t½

10.0 d

Cleavage trigger

Non-cleavable

Release control

Unconditional

Hydrophilicity mask

None^inferred

DAR distribution

DAR 2, 4, 6, 8 evaluated preclinically; DAR4^contradicted

Formula

C10H13NO4

Linker MW

211.217 Da

Linker TPSA

74.68 Å²

Linker xLogP

0.5564

ADCdb linker

LIN0TAFAV

In-vitro stability

Stability note

Inherited from mc-MMAF class (depatux-m 10 d, AGS-16C3F 8.3 d, denintuzumab 14 d, belantamab 13 d). Tannir 2014 Phase 1 N=47 R/R RCC/NHL paper does not separately tabulate t½ in d in open figures; Ph1 trial closed before MTD reached

Payload

Payload & physicochemistry

Payload profile

Payload

Cys-mcMMAF

Class

Auristatin

Mechanism

Tubulin inhibitor

Released catabolite

Cys-mcMMAF

Mechanistic subtype

Tubulin-auristatin

Stereochem / salt

Bystander

No / minimal

PAMPA rank

1046.3 Da

XLogP3

1.4

logD₇.₄

-1

TPSA

301 Å²

pKa

3.5 pKa

Charge pH 7.4

-1

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C52H83N7O13S

PubChem CID

86278355

ADCdb payload

PAY0QLDVX

Hydrophobicity · logD₇.₄

hydrophilic −2-1+4 lipophilic

Bioactivity note

ADCdb payload page (PAY0QLDVX, MMAF) reports microtubule-inhibitor IC50 values: HT-29 10 nM; SK-BR-3 5.3 nM; Hep-G2 7 nM; BT474-M1 8.8 nM. MMAF is an antimitotic tubulin-polymerization inhibitor; its C-terminal phenylalanine carboxylate attenuates membrane permeability relative t

Dosing & regimen

Dosing

RP2D dose

3 mg/kg Q3W

Schedule

Q3W

Route

Fractionated

n at RP2D

Dose basis

TBW

Trial phase

Phase 1

Dose-OAE available

Tox summary basis

RP2D

ADA rate (%)

21 %

Ocular & expression

Ocular profile & eye-tissue target expression

Target profile

OAE any-grade

57 %

OAE grade 3+

23 %

OAE data status

reported

Severity (weighted)

33.2

Keratopathy

15 %

Conjunctival

Dry eye

32 %

Blurred vision

11 %

Dominant tissue

Cornea

Surface subtype

Corneal (off-target)

Grading scale

CTCAE v4.0

Reversibility

Reversible

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

Cornea (central)

0.82 %

Cornea (limbal)

1 %

Conjunctiva

0.64 %

RPE

Retina (HPA)

0 nTPM

Cross-trial comparability · source-verified

Ascertainment: Symptom-driven reportingScale: UnknownDenominator: RP2D⚠ Not comparable: symptom-driven ascertainment + grading scale not documented

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

0.6 mg/kg

18%

0.3 or 0.6 mg/kg (escalation terminated; no MTD reached)

IV Days 1,8,15 of 28-day cycle (weekly)

n=11 · SGN-75 Phase 1 first-in-human

3 mg/kg (MTD; cohort pooled 0.3-4.5 mg/kg Q3W)

Every 3 weeks (Q3W), IV

15%

n=47 · SGN75-001

0.3-4.5 mg/kg (all doses pooled; MTD 3 mg/kg, RCC expansion at 3 mg/kg)

IV every 3 weeks (Q3Wk)

15%

n=47 · SGN-75 Phase 1 first-in-human

0.3-4.5 mg/kg (all doses pooled; MTD 3 mg/kg, RCC expansion at 3 mg/kg)

IV every 3 weeks (Q3Wk)

n=47 · SGN-75 Phase 1 first-in-human

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

vorsetuzumab-mafodotin

Approval status

Discontinued

Approval year

UniProt

P32970

ADCdb ADC

DRG0XPPOZ

ADCdb antibody

ANI0ESDXP

ADCdb target

PATR0CXRBX

Trial (NCT)

NCT01015911

Primary source

Tannir Invest New Drugs 2014^{no such source}

Aliases & development codes

SGN-75; anti-CD70-MMAF

Notes

MMAF-driven OAE on eye-absent CD70 target. V3.1: n_rp2d 35→47 (Q3W cohort); G3+ OAE 23% (prev blank, per review PMC4677113); blurred vision 18→11% (Q3W; 18 was weekly). PMID corrected 25169121→25142258.^{no such source}