SAR-566658

Discontinued

SAR566658; huDS6-DM4; huDS6-SPDB-DM4; anti-CA6-DM4 immunoconjugate

Target

CA6 sialoglycotope (MUC1-associated tumor carbohydrate antigen) -- NOTE: not carbonic anhydrase 6 · MUC1 (CA6 epitope carried on MUC1)

Sponsor

Sanofi (ImmunoGen-originated)

Indication

CA6-positive advanced solid tumors (Phase 1); CA6+ metastatic triple-negative breast cancer (Phase 2, terminated)

Target family

Mucin

RP2D dose

90 mg/m2 (on D1 and D8, q3w)

D1, D8 every 3 weeks (fractionated); alternative explored 120 mg/m2 q2wRP2D

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

13 adverse-event terms

Ocular

Any-grade

36%

G3+

7.9%

RP2D

sagittal schematic · Reversible

↳

Tissues shaded by reported adverse-event rate.

Cornea

Express.

Limbus

Express.

Conjunctiva

Express.

Lens

Express.

Retina / RPE

Express.

Dominant tissue

Cornea

Surface subtype

Corneal (off-target)

Reversibility

Reversible

Reported ocular events

Keratopathy35.3%

G3+ 7.9%

Keratitis32.4%

G3+ 5.9%

Dry eye27.3%

Vision blurred18.2%

Photophobia18.2%

Abnormal sensation in eye9.1%

Diplopia9.1%

Halo vision9.1%

Vitreous floaters9.1%

Xerophthalmia9.1%

Corneal epithelial microcysts8.3%

Corneal opacity8.3%

Periorbital oedema8.3%

Construct

Molecular anatomy

Antibody

IgG1

Humanized

Linker

Disulfide

Cleavable

3.5

DAR

Payload

DM4 (ravtansine)

Microtubule/tubulin polymerization inhibitor (anti-mitotic)

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 structureC38H54ClN3O10S

C[C@@H]1[C@@H]2C[C@]([C@@H](/C=C/C=C(/CC3=CC(=C(C(=C3)OC)Cl)N(C(=O)C[C@@H]([C@]4([C@H]1O4)C)OC(=O)[C@H](C)N(C)C(=O)CCC(C)(C)S)C)\C)OC)(NC(=O)O2)O

Antibody

Antibody & Fc engineering

Antibody

huDS6 (humanized DS6)

Isotype

IgG1

Origin

Humanized

Fc modifications

Glycoengineering

Effector silencing

None reported (conventional humanized IgG1; no Fc-silencing mutations)

FcγR binding

Retained

C1q binding

Retained

Linker & conjugation

Linker chemistry

Linker profile

Linker

SPDB (N-succinimidyl 4-(2-pyridyldithio)butanoate / N-succinimidyl-4-(2-pyridyldithio)butyrate)

Class

Disulfide

Cleavage

Cleavable

Attachment

Lysine

Conjugation

Random lysine (amide coupling via SPDB NHS ester)

Symmetry

Symmetric

DAR (mean)

3.5

DAR homogeneity

Heterogeneous

Plasma t½

Cleavage trigger

Reductive disulfide cleavage (intracellular thiol/glutathione-mediated); non-enzymatic. Lysosomal proteolysis of the lysine-linked conjugate precedes disulfide reduction.

Release control

N/A

Hydrophilicity mask

None

Formula

C13H14N2O4S2

Linker MW

326.399 Da

Linker TPSA

76.57 Å²

Linker xLogP

2.2093

ADCdb linker

LIN0VZYER

In-vitro stability

Payload

Payload & physicochemistry

Payload profile

Payload

DM4 (ravtansine)

Class

Maytansinoid

Mechanism

Microtubule/tubulin polymerization inhibitor (anti-mitotic)

Released catabolite

DM4 and S-methyl-DM4 (DM4-Me), the lipophilic bystander-active metabolite; lysine-Nepsilon-SPDB-DM4 intermediate catabolite

Mechanistic subtype

Tubulin-maytansinoid

Stereochem / salt

DM4 free-thiol payload (no salt form)

Bystander

Yes

PAMPA rank

780.4 Da

XLogP3

3.2

logD₇.₄

TPSA

157 Å²

pKa

Charge pH 7.4

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C38H54ClN3O10S

PubChem CID

11686439

ADCdb payload

PAY0GTSVM

Bioactivity note

Payload DM4 is a maytansinoid antimitotic that inhibits tubulin polymerization / microtubule assembly via the vinca-alkaloid binding site. SAR566658 binds tumor-associated CA6 sialoglycotope on MUC1, internalizes via receptor-mediated endocytosis, traffics to lysosomes; released

Dosing & regimen

Dosing

RP2D dose

90 mg/m2 (on D1 and D8, q3w)

Schedule

D1, D8 every 3 weeks (fractionated); alternative explored 120 mg/m2 q2w

Route

Fractionated

Yes

n at RP2D

17 (90 mg/m2 D1,D8 q3w cohort; total study N=114)

Dose basis

BSA

Trial phase

Phase 1

Dose-OAE available

Yes

Tox summary basis

Ocular & expression

Ocular profile & eye-tissue target expression

Target profile

OAE any-grade

36 %

OAE grade 3+

7.9 %

OAE data status

reported

Severity (weighted)

16.33

Keratopathy

Conjunctival

Dry eye

Blurred vision

Dominant tissue

Cornea

Surface subtype

Corneal (off-target)

Grading scale

CTCAE (unversioned)

Reversibility

Reversible

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

Cornea (central)

Cornea (limbal)

Conjunctiva

RPE

Retina (HPA)

Cross-trial comparability · source-verified

Ascertainment: Systematic eye examsScale: CTCAE (unversioned)Denominator: RP2D

Identity & registry

Identifiers, registry & notes

ADC id

sar-566658

Approval status

Discontinued

Approval year

UniProt

P15941

ADCdb ADC

DRG0GZGHN

ADCdb antibody

ANI0JBOMV

ADCdb target

TAR0VNYPU

Primary source

Gomez-Roca/Boni et al. ASCO 2016, JCO 2016;34(15_suppl):2511 (Phase 1, NCT01156870 / TED10499); Eaton et al. ocular-AE review PMC4677113; ADCdb DRG0GZGHN + linker LIN0VZYER; MCT 2020;19(8):1660; PubChem CID 11686439 (DM4)

Aliases & development codes

SAR566658; huDS6-DM4; huDS6-SPDB-DM4; anti-CA6-DM4 immunoconjugate

Notes

SAR-566658 (huDS6-DM4) is an anti-CA6 maytansinoid ADC; ocular (corneal) toxicity is the dose-limiting, qualifying AE. KEY CORRECTIONS to ADCdb: (1) ADCdb lists the target as "Carbonic anhydrase 6 (CA6)" -- this is a misannotation. The actual target is the CA6 sialoglycotope, a MUC1-associated tumor carbohydrate antigen recognized by the DS6 antibody (confirmed by MCT 2020;19(8):1660, "An Antibody-Drug Conjugate Targeting MUC1-Associated Carbohydrate CA6"). target_gene set to MUC1. (2) ADCdb lists DAR=1 (default/placeholder); peer-reviewed literature reports average DAR ~3.5 DM4 per IgG1. (3) ADCdb DAR/isotype not given; isotype IgG1 from secondary sources. OCULAR (priority): Phase 1 NCT01156870 (TED10499, N=114, CA6+ solid tumors). Most common AE = reversible grade 2/3 keratopathy 41/114 (36%), grade 3 in 9 (7.9%). Dose-stratified keratopathy: 240 mg/m2 75% (6/8); 190 mg/m2 65% (15/23); 150 mg/m2 36% (12/33); 90 mg/m2 D1,D8 35% (6/17); 120 mg/m2 q2w 13% (2/16). Keratitis 11/34 (32%) at 150 mg/m2, 2 grade 3 (PMC4677113). DLTs at 240 mg/m2 = grade 3 diarrhea + grade 3 keratitis. Classic off-target corneal (ocular-surface) DM4 maytansinoid toxicity; reversible; prophylactic vasoconstrictor + steroid eye drops prevented keratopathy in 8 pts on alternative schedules. ocular_surface_subtype = Corneal (off-target). RP2D = 90 mg/m2 on D1 and D8 q3w (fractionated), chosen via PK/safety simulation to preserve exposure while limiting keratopathy (alternative 120 mg/m2 q2w had lowest keratopathy at 13%). Initial RD 190 mg/m2 abandoned due to high cycle-2 keratopathy. Program discontinued (Phase 2 NCT02984683 in CA6+ mTNBC terminated). DATA GAPS / CAVEATS: GI (nausea 29%, abdominal pain 26%, diarrhea 25%) and peripheral neuropathy 31.6% (also fatigue 32.6%, not in the organ-system enum) are study-wide pooled rates extracted from the ASCO 2016 abstract via secondary search summary -> tier D; the primary abstract (JCO 2016;34:15_suppl:2511) is paywalled (HTTP 403). Hematologic events described only qualitatively ("a few hematological events") and not quantified -> no hematologic rows. Hepatic, pulmonary, and infusion-reaction rates not reported in accessible sources -> left blank. CTCAE version not stated. Linker physchem (SMILES/formula/MW 326.4/TPSA 76.57/xLogP 2.21) is for the SPDB linker reagent (ADCdb LIN0VZYER). DM4 payload physchem from PubChem CID 11686439 (ravtansine): MW 780.4, formula C38H54ClN3O10S, XLogP 3.2, TPSA 157, HBD 3, HBA 11, neutral (charge 0); DM4 is bystander-active via S-methyl-DM4. (Note: PubChem CID 11343137 is mertansine/DM1, NOT DM4 -- do not use.) payload_logd_7_4 and payload_pka left blank (not PubChem-computed; DM4 is neutral so logD7.4 approximates XLogP ~3.2).