BMS-986148

Discontinued

BMS 986148; Mesothelin-ADC

Target

Mesothelin (MSLN) · MSLN

Sponsor

Bristol Myers Squibb

Indication

Mesothelin-expressing advanced solid tumors (mesothelioma, ovarian, pancreatic, gastric, NSCLC)

Target family

GPI-anchored

RP2D dose

1.2 mg/kg q3w (MTD; de facto RP2D for monotherapy)

Every 3 weeks (q3w); a once-weekly monotherapy schedule and a 0.8 mg/kg + nivolumab 360 mg q3w combination arm also testedRP2D

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

4 adverse-event terms

Ocular

Any-grade

10%

G3+

1.7%

RP2D

sagittal schematic · Reversible

↳

Tissues shaded by reported adverse-event rate.

Cornea

Express.

13.34%

Limbus

Express.

19.42%

Conjunctiva

Express.

55.48%

Lens

Express.

Retina / RPE

Express.

0.6 nTPM

Dominant tissue

Cornea

Surface subtype

Mixed

Reversibility

Reversible

Reported ocular events

Ophthalmic adverse events (any)10%

Keratopathy-

G3+ 1.7%

Visual acuity reduced-

G3+ 1.7%

Cataract (bilateral)-

G3+ 1.7%

Construct

Molecular anatomy

Antibody

IgG1

Human

Linker

Peptide

Cleavable

DAR

Payload

Tubulysin (proprietary tubulysin analog)

Microtubule destabilizer; inhibits tubulin polymerization (binds vinca domain of beta-tubulin)

Linker structureC21H33N5O7

[H]OC(=O)[C@@]([H])(N([H])C(=O)[C@]([H])(N([H])C(=O)C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])N1C(=O)C([H])=C([H])C1=O)C([H])(C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])C([H])([H])N([H])C(=O)N([H])[H]

Payload structureC44H67N5O9S

CC[C@H](C)[C@@H](C(=O)N(COC(=O)CC(C)C)[C@H](C[C@H](C1=NC(=CS1)C(=O)N[C@@H](CC2=CC=C(C=C2)C)C[C@H](C)C(=O)O)OC(=O)C)C(C)C)NC(=O)[C@H]3CCCCN3C

Antibody

Antibody & Fc engineering

Antibody

BMS-986021

Isotype

IgG1

Origin

Human

Fc modifications

Glycoengineering

Effector silencing

None reported; native fully human IgG1 Fc (no silencing mutations disclosed)

FcγR binding

Retained

C1q binding

Retained

Linker & conjugation

Linker chemistry

Linker profile

Linker

Mc-Val-Cit (maleimidocaproyl-valine-citrulline)

Class

Peptide

Cleavage

Cleavable

Attachment

Cysteine (interchain)

Conjugation

Cysteine (interchain thiol) conjugation via maleimidocaproyl (Mc) maleimide; stochastic

Symmetry

Symmetric

DAR (mean)

DAR homogeneity

Heterogeneous

Plasma t½

Cleavage trigger

Cathepsin B (lysosomal cysteine protease); valine-citrulline dipeptide substrate

Release control

Conditional

Hydrophilicity mask

Formula

C21H33N5O7

Linker MW

467.523 Da

Linker TPSA

188 Å²

Linker xLogP

-0.3695

ADCdb linker

LIN0UVPJN

In-vitro stability

Payload

Payload & physicochemistry

Payload profile

Payload

Tubulysin (proprietary tubulysin analog)

Class

Tubulysin

Mechanism

Microtubule destabilizer; inhibits tubulin polymerization (binds vinca domain of beta-tubulin)

Released catabolite

Free tubulysin (active payload) following cathepsin-mediated Val-Cit cleavage

Mechanistic subtype

Tubulin-other

Stereochem / salt

Bystander

Yes

PAMPA rank

842.1 Da

XLogP3

5.4

logD₇.₄

TPSA

213 Å²

pKa

Charge pH 7.4

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C44H67N5O9S

PubChem CID

52945681

ADCdb payload

PAY0PCTOE

Bioactivity note

ADCdb payload page (PAY0PCTOE / PubChem CID 52945681, tubulysin) reports cytotoxicity IC50 2.2 nM (A2780 ovarian) and 2.5 nM (LNCaP prostate); mechanism is inhibition of tubulin polymerization into microtubules. Clinically, BMS-986148 MTD was 1.2 mg/kg IV q3w with ORR ~2-23% acro

Dosing & regimen

Dosing

RP2D dose

1.2 mg/kg q3w (MTD; de facto RP2D for monotherapy)

Schedule

Every 3 weeks (q3w); a once-weekly monotherapy schedule and a 0.8 mg/kg + nivolumab 360 mg q3w combination arm also tested

Route

Fractionated

n at RP2D

59 (1.2 mg/kg q3w cohort); total treated N=126 (84 monotherapy q3w, 12 monotherapy qw, 30 + nivolumab)

Dose basis

TBW

Trial phase

Other

Dose-OAE available

Yes

Tox summary basis

RP2D

Ocular & expression

Ocular profile & eye-tissue target expression

Target profile

OAE any-grade

10 %

OAE grade 3+

1.7 %

OAE data status

reported

Severity (weighted)

4.19

Keratopathy

Conjunctival

Dry eye

Blurred vision

Dominant tissue

Cornea

Surface subtype

Mixed

Grading scale

CTCAE v4

Reversibility

Reversible

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

Cornea (central)

13.34 %

Cornea (limbal)

19.42 %

Conjunctiva

55.48 %

RPE

Retina (HPA)

0.6 nTPM

Cross-trial comparability

Ascertainment: Systematic eye examsScale: CTCAE v4Denominator: RP2D

Identity & registry

Identifiers, registry & notes

ADC id

bms-986148

Approval status

Discontinued

Approval year

UniProt

Q13421

ADCdb ADC

DRG0VYGGK

ADCdb antibody

ANI0TIQFA

ADCdb target

PATR0CXRBX

Primary source

Rottey S, et al. Phase I/IIa Trial of BMS-986148, an anti-mesothelin ADC, alone or with nivolumab. Clin Cancer Res 2022;28(1):95-105 (PMID 34615718; PMC9401510); NCT02341625 (CA008-002)

Aliases & development codes

BMS 986148; Mesothelin-ADC

Notes

COMPOSITION/CHEMISTRY: Anti-mesothelin (MSLN) fully human IgG1 ADC. Antibody = BMS-986021 (ADCdb ANI0TIQFA); target MSLN (TAR0NEZUA). Linker Mc-Val-Cit (ADCdb LIN0UVPJN), cathepsin-B-cleavable Val-Cit dipeptide with maleimidocaproyl (cysteine/thiol) attachment; linker physchem from ADCdb (C21H33N5O7, MW 467.523, TPSA 188, xLogP -0.3695, SMILES recorded). Payload = tubulysin (PAY0PCTOE), a microtubule destabilizer (vinca-domain tubulin inhibitor); average DAR 3 (heterogeneous, stochastic cysteine conjugation). Sponsor Bristol Myers Squibb; ADCdb DRG0VYGGK; TTD D03TBD. Development discontinued (not approved). CLINICAL SOURCE (single): Rottey et al. Clin Cancer Res 2022;28(1):95-105 (PMID 34615718; PMC9401510). Phase I/IIa CA008-002 / NCT02341625, international, N=126 treated: 84 monotherapy q3w (0.1-1.6 mg/kg), 12 monotherapy once-weekly, 30 BMS-986148 0.8 mg/kg + nivolumab 360 mg q3w. MTD/de facto RP2D = 1.2 mg/kg IV q3w. Tumors: pleural/peritoneal mesothelioma, ovarian, pancreatic, gastric, NSCLC. OCULAR (qualifying reason): Ophthalmic AEs in <10% of BMS-986148-treated patients, majority low grade and topical-managed. Documented grade 3 ocular events ALL in the 1.2 mg/kg q3w cohort (n=59): one patient with G3 keratopathy + G3 reduced visual acuity (not reported resolved), and a separate patient with G3 bilateral cataract (resolved after dose delay + surgery). Additional ophthalmic terms reported but NOT quantified -> not given pct rows: dry eyes (managed with saline drops) and microcystic epitheliopathy (managed with dexamethasone drops). CTCAE v4.03. Subtype = Mixed (corneal epitheliopathy/keratopathy + lens cataract + visual acuity). Authors propose a possible antigen-dependent mechanism (mesothelin expressed on corneal/conjunctival epithelium) and a potential ADC class effect. ocular{} group oae_any_pct kept as the verbatim "<10%"; the toxicity_rows "any ophthalmic" row uses pct=10 as the documented upper bound (tier D). OTHER TOXICITY: Dominant toxicity is HEPATIC transaminitis (AST 49%/G3-4 24%; ALT 46%/G3-4 20%); hepatic TRAEs caused discontinuation in 8% and included 3 grade 4 events; this was the dose-limiting toxicity. One treatment-related death (pneumonitis). Fatigue 40% (G3/4 7%) is the most common non-hepatic TRAE but has no matching organ_system enum, so omitted from toxicity_rows. NOTABLY: no peripheral neuropathy and no infusion-related reactions reported among TRAEs (atypical for a tubulin-inhibitor ADC) -> no Neurologic-PN or Infusion rows created (absence was not stated as an explicit 0). Hematologic toxicity minimal: only one serious grade >=3 anaemia; no neutropenia/thrombocytopenia among TRAEs. PAYLOAD PHYSCHEM: numeric properties (MW/xLogP3/logD7.4/TPSA/pKa/charge) left BLANK because the specific BMS tubulysin analog structure is proprietary/undisclosed; assigning parent Tubulysin A (PubChem CID 12134544, C43H65N5O10S) would be speculative. Only class-level payload_bystander = Yes recorded (tubulysin conjugates retain bystander activity per payload-class literature; tier C). Systemic AE percentages are from the pooled monotherapy q3w safety population (n=84, doses 0.1-1.6 mg/kg, which includes the MTD); ocular G3 events are dose-specific to 1.2 mg/kg (n=59). line_context="RP2D" applied to the primary monotherapy q3w cohort rows and the 1.2 mg/kg MTD ocular rows.