Coltuximab ravtansine

Investigational

SAR3419; huB4-DM4

Target

CD19 · CD19

Sponsor

Sanofi

Indication

CD19+ DLBCL

Target family

Immunoglobulin superfamily

RP2D dose

55 mg/m² weekly x4 then Q2W (alt: 160 mg/m² Q3W)

Q1W x4 then Q2WRP2D

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

11 adverse-event terms

Ocular

Any-grade

25%

G3+

RP2D

sagittal schematic · Reversible

↳

Tissues shaded by reported adverse-event rate.

Cornea

1.6%

Express.

Limbus

Express.

Conjunctiva

Express.

Lens

Express.

Retina / RPE

Express.

0.05%

0 nTPM

Off-target signature

1.6% corneal toxicity, yet the CD19 target is detected in only 0% of central cornea - toxicity is not explained by target expression.

Dominant tissue

Cornea

Surface subtype

Corneal (off-target)

Reversibility

Reversible

Reported ocular events

Eye disorders25%

G3+ 0%n=61

Vision blurred23%

Eye disorders extra-corneal (extracorneal eye disorders)21.3%

Eye disorders extra-corneal (extracorneal events)17%

Lacrimation disorder (lacrimal events)6%

Dry eye3.3%

n=61

Keratitis1.6%

n=61

Optic neuropathy-

Corneal microcystic epitheliopathy / keratopathy (microcystic epithelial corneal changes, corneal deposits)-

Eye disorders (composite) / extra-corneal / corneal — combination cohort-

Keratitis (combination and ALL cohorts) and other corneal terms (conjunctivitis, diplopia, eye irritation, scotoma, uveitis)-

Per-trial detail

Adverse events by trial

STARLYTE Phase II (NCT01472887) - Trneny 2018Phase 255 mg/m2 IV weekly x4, then biweekly (q2w) x4n=61CTCAE 4.03Bto verify

Trneny Haematologica 2018, text [1 grade 3-4 febrile neutropenia] PMID 29748443

33 adverse-event terms · 7 systems · expand a system below

Hematologic18

Anaemia

87%G3+ 7%

53/61

Lymphopenia

67%G3+ 21%

41/61

Leukopenia

64%G3+ 15%

39/61

Thrombocytopenia

57%G3+ 10%

35/61

Neutropenia

52%G3+ 25%

32/61

Asthenia/fatigue

30%G3+ 2%

18/61

Nausea

23%G3+ 2%

14/61

Diarrhoea

20%G3+ 0%

12/61

Cough

18%G3+ 0%

11/61

Vomiting

13%G3+ 0%

8/61

Decreased appetite

13%G3+ 0%

8/61

Disease progression

13%G3+ 5%G5 8%

8/61

Back pain

11%G3+ 2%

7/61

Abdominal pain

11%G3+ 3%

7/61

Dyspnoea

10%G3+ 2%

6/61

Constipation

10%G3+ 0%

6/61

Peripheral oedema

10%G3+ 0%

6/61

Febrile neutropenia

—G3+ 1.6%G5 1.6%

Hepatic5

Overall/Summary4

Ocular2

Eye disorders (AE of special interest)

25%G3+ 0%

15/61

Extracorneal eye disorders

21.3%

13/61

Neurologic (other)2

Immune1

Injury1

Construct

Molecular anatomy

Antibody

IgG1

Humanized

Linker

Cleavable

3.5

DAR

Payload

DM4 (free)

Tubulin inhibitor

Linker structureC13H14N2O4S2

[H]c1nc(SSC([H])([H])C([H])([H])C([H])([H])C(=O)ON2C(=O)C([H])([H])C([H])([H])C2=O)c([H])c([H])c1[H]

Payload structureC39H56ClN3O10S

C/C/1=C\CC=C\[C@H]([C@]2(C[C@@H](C([C@H]3[C@@](O3)([C@H](CC(=O)N(C4=C(C(=CC(=C4)C1)OC)Cl)C)OC(=O)[C@H](C)N(C)C(=O)CCC(C)(C)S)C)(C)C)OC(=O)N2)O)OC

Antibody

Antibody & Fc engineering

Antibody

huB4 (coltuximab)

Isotype

IgG1

Origin

Humanized

Fc modifications

None

Glycoengineering

Standard

Effector silencing

None

FcγR binding

Retained

C1q binding

Retained

Target KD (nM)

0.15

Linker & conjugation

Linker chemistry

Linker profile

Linker

SPDB

Class

Cleavable

Cleavage

Cleavable

Attachment

Lysine

Conjugation

Conventional Lys (SPDB)

Symmetry

Asymmetric

DAR (mean)

3.5

DAR homogeneity

Heterogeneous

Plasma t½

7 d

Cleavage trigger

GSH/reductive (disulfide)

Release control

Conditional

Hydrophilicity mask

None

Platform

SPDB hindered-disulfide maytansinoid

Formula

C13H14N2O4S2

Linker MW

326.399 Da

Linker TPSA

76.57 Å²

Linker xLogP

2.2093

ADCdb linker

LIN0VZYER

In-vitro stability

Stability note

Inherited from SPDB-DM4 class (anetumab 5.5 d, mirvetuximab 5–7 d, tusamitamab 6–8 d); Trneny Haematologica 2018 Ph2 does not tabulate explicit t½ in the open-access version

Payload

Payload & physicochemistry

Payload profile

Payload

DM4 (free)

Class

Maytansinoid

Mechanism

Tubulin inhibitor

Released catabolite

DM4 and S-methyl-DM4 (primary lysosomal catabolite lysine-Nε-SPDB-DM4)

Mechanistic subtype

Tubulin-maytansinoid

Stereochem / salt

Bystander

Yes

PAMPA rank

780.4 Da

XLogP3

3.2

logD₇.₄

TPSA

157 Å²

pKa

10.3 pKa

Charge pH 7.4

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C39H56ClN3O10S

PubChem CID

46926355

ADCdb payload

PAY0GTSVM

Permeability (Papp)

Yes

Hydrophobicity · logD₇.₄

hydrophilic −2+3+4 lipophilic

Bioactivity note

DM4 is a tubulin-targeting maytansinoid: binds the vinca site on tubulin, inhibits microtubule polymerization, causing mitotic (G2/M) arrest. Sub-nanomolar antiproliferative potency typical of maytansinoids. ADCdb page does not list a specific numeric IC50 for this ADC/payload en

Dosing & regimen

Dosing

RP2D dose

55 mg/m² weekly x4 then Q2W (alt: 160 mg/m² Q3W)

Schedule

Q1W x4 then Q2W

Route

Fractionated

n at RP2D

Dose basis

BSA

Trial phase

Phase 2

Dose-OAE available

Tox summary basis

RP2D

ADA rate (%)

1 %

Ocular & expression

Ocular profile & eye-tissue target expression

Target profile

OAE any-grade

25 %

OAE grade 3+

0 %

OAE data status

reported

Severity (weighted)

7.5

Keratopathy

1.6 %

Conjunctival

Dry eye

3.3 %

Blurred vision

25 %

Dominant tissue

Cornea

Surface subtype

Corneal (off-target)

Grading scale

CTCAE v4.03

Reversibility

Reversible

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

Cornea (central)

0 %

Cornea (limbal)

0 %

Conjunctiva

0 %

RPE

0.05 %

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

55 mg/m2

IV weekly x4, then biweekly (q2w) x4

21.3%

n=61 · STARLYTE Phase II

55 mg/m2

21.3%

55 mg/m²

Weekly x4 then every 2 weeks (4 weekly + 4 biweekly)

1.6%

n=61 · STARLYTE

10-270 mg/m2 (MTD 160 mg/m2)

IV q3w, up to 6 cycles

43.6%

n=39 · Phase I q3w

270 mg/m2

41%

—

17%

—

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

coltuximab-ravtansine

Approval status

Investigational

Approval year

UniProt

P15391

ADCdb ADC

DRG0MHAHZ

ADCdb antibody

ANI0OCCUD

ADCdb target

TAR0EBTXG

Primary source

Trneny Haematologica 2018

Aliases & development codes

SAR3419; huB4-DM4

Notes

DM4 cleavable; CD19 absent from eye but 25% OAE from bystander. V3.1: Trneny 2018 Haematologica PMID corrected 29704412→29748443.