M-9140

Investigational

Precemtabart tocentecan; M9140; Precem-TcT

Target

Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5 / CEA) · CEACAM5

Sponsor

Merck KGaA / EMD Serono

Indication

Metastatic colorectal cancer (irinotecan-refractory)

Target family

CEA family / Ig-CAM

RP2D dose

2.4 and 2.8 mg/kg Q3W (recommended doses for expansion); MTD 2.8 mg/kg Q3W

Every 3 weeks (Q3W)Pooled

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

1 adverse-event term

Ocular

Any-grade

G3+

Pooled

sagittal schematic · Reversible

↳

Tissues shaded by reported adverse-event rate.

Cornea

Express.

0.03%

Limbus

Express.

0.7%

Conjunctiva

Express.

10.55%

Lens

Express.

Retina / RPE

Express.

0 nTPM

Dominant tissue

Hematologic

Surface subtype

None

Reversibility

Reversible

Reported ocular events

Any ocular toxicity (explicitly assessed and absent)0%

Per-trial detail

Adverse events by trial

PROCEADE-CRC-01Phase 10.6-3.2 mg/kg (pooled) Q3W (every 3 weeks), 30-min IV, 21-day cyclesn=40CTCAE 5.0PooledBto verify

Kopetz S, et al. Nat Med 2025;31:3504-13 (PROCEADE-CRC-01) PMID:40739424; PMC12532702; DOI:10.1038/s41591-025-03843-z

22 adverse-event terms · 6 systems · expand a system below

Investigations7

Investigations (SOC)

60%

24/40

White blood cell count decreased

42.5%

17/40

Neutrophil count decreased

42.5%

17/40

Platelet count decreased

35%

14/40

Lymphocyte count decreased

17.5%

7/40

Alanine aminotransferase increased

12.5%

5/40

Aspartate aminotransferase increased

10%

4/40

GI5

Hematologic3

Metabolic3

General2

Dermatologic2

Construct

Molecular anatomy

Antibody

IgG1

Human

Linker

Peptide (glucuronide)

Cleavable

DAR

Payload

Exatecan

DNA topoisomerase I (TOP1) inhibitor

Linker structureC22H25N3O12

O=C(CCN1C(=O)C=CC1=O)NCC(=O)Nc1cc(CO)ccc1O[C@@H]1O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O

Payload structureC24H22FN3O4

CC[C@@]1(C2=C(COC1=O)C(=O)N3CC4=C5[C@H](CCC6=C5C(=CC(=C6C)F)N=C4C3=C2)N)O

Antibody

Antibody & Fc engineering

Antibody

Undisclosed anti-CEACAM5 monoclonal antibody

Isotype

IgG1

Origin

Human

Fc modifications

Fc protein engineering to limit FcgammaR binding and prevent C1q interaction

Glycoengineering

Yes

Effector silencing

Fc engineered to limit FcgammaR binding and prevent C1q interaction (effector-attenuated)

FcγR binding

Reduced

C1q binding

Abolished

Linker & conjugation

Linker chemistry

Linker profile

Linker

Mal-glucuronide-PABC (beta-glucuronide-exatecan)

Class

Peptide (glucuronide)

Cleavage

Cleavable

Attachment

Cysteine (interchain)

Conjugation

Random cysteine conjugation (reduced interchain disulfides)

Symmetry

Symmetric

DAR (mean)

DAR homogeneity

DAR = 8; cleavable beta-glucuronide

Plasma t½

5.7 d

Cleavage trigger

beta-glucuronidase (lysosomal)

Release control

Conditional

Hydrophilicity mask

Sugar

Formula

C22H25N3O12

Linker MW

523.451 Da

Linker TPSA

232.26 Å²

Linker xLogP

-3.1803

ADCdb linker

LIN0DIGYN

In-vitro stability

Stability note

Total and conjugated antibody PK profiles overlapped, indicating linker-payload stability in circulation

Payload

Payload & physicochemistry

Payload profile

Payload

Exatecan

Class

Topoisomerase I inhibitor

Mechanism

DNA topoisomerase I (TOP1) inhibitor

Released catabolite

Exatecan

Mechanistic subtype

TopoI

Stereochem / salt

Bystander

Yes

PAMPA rank

435.5 Da

XLogP3

1.5

logD₇.₄

TPSA

91.7 Å²

pKa

Charge pH 7.4

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C24H22FN3O4

PubChem CID

151115

ADCdb payload

PAY0LEIGJ

Potency IC50 (nM)

0.09

Bioactivity note

Cell-line IC50: SK-CO-1

Dosing & regimen

Dosing

RP2D dose

2.4 and 2.8 mg/kg Q3W (recommended doses for expansion); MTD 2.8 mg/kg Q3W

Schedule

Every 3 weeks (Q3W)

Route

Fractionated

n at RP2D

Dose basis

TBW

Trial phase

Phase 1

Dose-OAE available

Tox summary basis

dose-escalation

ADA rate (%)

2.5 %

HNSTD / NOAEL

NOAEL 24 mg/kg; MTD 30 mg/kg

Target prevalence (%)

90 %

Ocular & expression

Ocular profile & eye-tissue target expression

Target profile

OAE any-grade

0 %

OAE grade 3+

0 %

OAE data status

documented-absent

Severity (weighted)

Keratopathy

0 %

Conjunctival

Dry eye

Blurred vision

Dominant tissue

Hematologic

Surface subtype

None

Grading scale

CTCAE v5.0

Reversibility

Reversible

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

Cornea (central)

0.03 %

Cornea (limbal)

0.7 %

Conjunctiva

10.55 %

RPE

0 %

Retina (HPA)

0 nTPM

Cross-trial comparability · source-verified

Ascertainment: Systematic eye examsScale: CTCAE v5Denominator: RP2D

Ocular AE grading reference — interspecialty consensus · 6 scales + dose modification

Identity & registry

Identifiers, registry & notes

ADC id

m-9140

Approval status

Investigational

Approval year

UniProt

P06731

ADCdb ADC

DRG0VIUMF

ADCdb antibody

ADCdb target

TAR0MKNCY

Primary source

Nature Medicine 2025;31:3504-3513 (PROCEADE-CRC-01 Ph1)

Aliases & development codes

Precemtabart tocentecan; M9140; Precem-TcT

Notes

M-9140 = precemtabart tocentecan (Precem-TcT; formerly M9140), an anti-CEACAM5 IgG1 ADC with a cleavable Mal-glucuronide-PABC (beta-glucuronide) linker, exatecan TOP1i payload, DAR 8, random-cysteine conjugation, and Fc engineering to limit FcgammaR binding/prevent C1q interaction. Sponsor Merck KGaA/EMD Serono. PROCEADE-CRC-01 phase 1 dose escalation (N=40, irinotecan-refractory mCRC, IV Q3W, dose levels 0.6-3.2 mg/kg); RDEs 2.4 and 2.8 mg/kg Q3W, MTD 2.8 mg/kg. 7/40 DLTs (febrile neutropenia, sepsis, neutrophil/platelet decreased, anemia), one treatment-related death (sepsis). Confirmed explicit-zero ocular: 'no cases of ILD or ocular toxicities were reported' / 'no interstitial lung disease or ocular toxicity' (abstract, Safety Overview, Discussion). Safety is heme-dominant. Grade>=3 TRAE percentages from Nature Medicine Table 3 (these supersede the lower escalation-cohort hint numbers in the working-input file). Exact any-grade % for the heme PTs were not isolated in the fetched table (only grade>=3 given as Table 3 counts), so any-grade heme rows omitted rather than approximated; GI rows are any-grade. Payload physchem are standard PubChem exatecan values (CID 9938202); logD7.4 and pKa not populated to avoid imputation. Linker physchem from ADCdb LIN0DIGYN.