Loncastuximab tesirine

FDA-approved

Zynlonta; ADCT-402

Target

CD19 · CD19

Sponsor

ADC Therapeutics

Indication

CD19+ DLBCL

Target family

Immunoglobulin superfamily

RP2D dose

0.15 mg/kg x2 then 0.075 mg/kg

Q3WRP2D

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

12 adverse-event terms

Ocular

Any-grade

G3+

RP2D

sagittal schematic · Reversible

↳

Tissues shaded by reported adverse-event rate.

Cornea

Express.

Limbus

Express.

Conjunctiva

Express.

Lens

Express.

Retina / RPE

Express.

0.05%

0 nTPM

Dominant tissue

Surface subtype

None

Reversibility

Reversible

Reported ocular events

Conjunctivitis7.35%

non-seriousn=136

Vision blurred2.94%

non-seriousn=136

Conjunctival haemorrhage2.86%

non-seriousn=35

Eye pain2.86%

non-seriousn=35

Eye pruritus2.86%

non-seriousn=35

Dry eye2.73%

non-seriousn=183

Periorbital oedema2.44%

non-seriousn=41

Ocular hyperaemia2.21%

non-seriousn=136

Visual impairment1.64%

non-seriousn=183

Eye infection1.47%

non-seriousn=136

Cataract0.74%

non-seriousn=136

Swelling of eyelid0.74%

non-seriousn=136

Per-trial detail

Adverse events by trial

Safety and Efficacy Study of Loncastuximab Tesirine + Ibrutinib in Diffuse LargePHASE1|PHASE2real-worldn=136CTCAE NR (ClinicalTrials.govPooledC

ClinicalTrials.gov NCT03684694 posted results, adverse events module (non-serious; 33/136 pooled across arms)

197 adverse-event terms · 21 systems · expand a system below

Infections31

Pneumonia viral

4.41%serious

6/136

Corona virus infection

3.68%serious

5/136

Oral candidiasis

3.68%non-serious

5/136

Sinusitis

3.68%non-serious

5/136

Bronchitis

2.21%non-serious

3/136

Oral herpes

2.21%non-serious

3/136

Pharyngitis

2.21%non-serious

3/136

Rhinitis

2.21%non-serious

3/136

Clostridium difficile colitis

1.47%non-serious

2/136

Furuncle

1.47%non-serious

2/136

Herpes zoster

1.47%non-serious

2/136

Lung infection

1.47%non-serious

2/136

Oral fungal infection

1.47%non-serious

2/136

Pneumonia

1.47%serious

2/136

Pneumonia fungal

1.47%serious

2/136

Sepsis

1.47%serious

2/136

Upper respiratory tract infection

1.47%non-serious

2/136

Urinary tract infection

1.47%serious

2/136

Bacteraemia

0.74%serious

1/136

Campylobacter infection

0.74%serious

1/136

Citrobacter infection

0.74%serious

1/136

Enterococcal infection

0.74%serious

1/136

Erysipelas

0.74%non-serious

1/136

Escherichia sepsis

0.74%serious

1/136

Folliculitis

0.74%serious

1/136

Genital infection fungal

0.74%non-serious

1/136

Pneumocystis jirovecii infection

0.74%serious

1/136

Pneumonia parainfluenzae viral

0.74%serious

1/136

Progressive multifocal leukoencephalopathy

0.74%serious

1/136

Urinary tract infection bacterial

0.74%serious

1/136

Urosepsis

0.74%serious

1/136

Dermatologic22

GI20

General16

Cardiac13

Metabolic13

Investigations12

Pulmonary12

Hematologic9

Musculoskeletal6

Ocular6

Conjunctivitis

7.35%non-serious

10/136

Vision blurred

2.94%non-serious

4/136

Ocular hyperaemia

2.21%non-serious

3/136

Eye infection

1.47%non-serious

2/136

Cataract

0.74%non-serious

1/136

Swelling of eyelid

0.74%non-serious

1/136

Psychiatric6

Vascular6

Hepatic5

Injury5

Neurologic (other)5

Renal4

Neoplasms3

Ear1

Endocrine1

Immune1

Construct

Molecular anatomy

Antibody

IgG1

Humanized

Linker

Cleavable

2.3

DAR

Payload

SG3199 (PBD dimer)

DNA cross-linker

Linker structureC41H65N5O15

[H]OC([H])([H])c1c([H])c([H])c(N([H])C(=O)[C@@]([H])(N([H])C(=O)[C@@]([H])(N([H])C(=O)C([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])N([H])C(=O)C([H])([H])C([H])([H])N2C(=O)C([H])=C([H])C2=O)C([H])(C([H])([H])[H])C([H])([H])[H])C([H])([H])[H])c([H])c1[H]

Payload structureC33H36N4O6

CC1=CN2[C@@H](C1)C=NC3=CC(=C(C=C3C2=O)OC)OCCCCCOC4=C(C=C5C(=C4)N=C[C@@H]6CC(=CN6C5=O)C)OC

Antibody

Antibody & Fc engineering

Antibody

hRB4v1.2 (loncastuximab)

Isotype

IgG1

Origin

Humanized

Fc modifications

None^inferred

Glycoengineering

Standard^inferred

Effector silencing

None^inferred

FcγR binding

Retained

C1q binding

Retained^inferred

Epitope / domain

CD19 extracellular domain^silent

Linker & conjugation

Linker chemistry

Linker profile

Linker

VA dipeptide (tesirine)

Class

Cleavable

Cleavage

Cleavable

Attachment

Cysteine (interchain)

Conjugation

Conventional interchain Cys

Symmetry

Symmetric

DAR (mean)

2.3

DAR homogeneity

Heterogeneous

Plasma t½

20.8 d

Cleavage trigger

Cathepsin B (Val-Ala)^unver.

Release control

Conditional

Hydrophilicity mask

Discrete-PEG-spacer^unver.

Platform

Tesirine^unver.

Cell line

CHO

Formula

C41H65N5O15

Linker MW

867.991 Da

Linker TPSA

247.85 Å²

Linker xLogP

-0.2829

ADCdb linker

LIN0YRUBS

In-vitro stability

Stability note

Conjugated antibody steady-state t½ 20.6 d after ~15 weeks (Hamadani Blood 2021 LOTIS-2 popPK); 2-compartment linear model with time-dependent CL → t½ at C1 ≈ 13 d, increases on multiple dosing. PBD released as stable DNA-guanine adduct, not free drug; warhead toxicity not driven by free-drug circulating^locator?

Payload

Payload & physicochemistry

Payload profile

Payload

SG3199 (PBD dimer)

Class

PBD dimer

Mechanism

DNA cross-linker

Released catabolite

SG3199 (pyrrolobenzodiazepine [PBD] dimer)

Mechanistic subtype

DNA-crosslinker-PBD

Stereochem / salt

(11aS,11a'S)-configured PBD dimer (single defined stereoisomer); free base (no salt)

Bystander

Partial

PAMPA rank

584.7 Da

XLogP3

2.8

logD₇.₄

2.5

TPSA

102 Å²

pKa

5 pKa

Charge pH 7.4

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C33H36N4O6

PubChem CID

90132565

ADCdb payload

PAY0LZRXU

Potency IC50 (nM)

0.1515

CAS no.

1595275-62-9^unver.

Plasma protein binding (%)

95 %

Hydrophobicity · logD₇.₄

hydrophilic −2+2.5+4 lipophilic

Bioactivity note

SG3199 is a sequence-selective DNA minor-groove interstrand crosslinking PBD dimer; ADCdb lists its molecular target as human DNA (hDNA). No numeric IC50 reported on the ADCdb ADC page or the PubChem record.

Dosing & regimen

Dosing

RP2D dose

0.15 mg/kg x2 then 0.075 mg/kg

Schedule

Q3W

Route

Fractionated

n at RP2D

145

Dose basis

TBW

Trial phase

Approved

Dose-OAE available

Tox summary basis

RP2D

ADA rate (%)

2 %

Pharmacology

Clinical pharmacokinetics

By analyte · FDA label §12.3 + Drugs@FDA clinical-pharmacology reviews

	Intact ADC	Total antibody	Free payload
Cmax	2911 (geometric mean; CV 35.3%)ng/mL+4	—	—
AUC	21665 (AUCtau; geometric mean; CV 54.1%)ng*day/mL+4	—	—
Tmax	near end of infusion (approx end of 30-min IV infusion)	—	—
t½	20.8 (mean; SD 7.06)days+1	—	—
CL	0.499 (geometric mean; CV 89.3%; total CL after single dose)L/day+2	0.218 (typical patient; linear CL, common with conjugated antibody in popPK model)L/day	1.9 (popPK estimate CLSG; RSE 16.6%; BSV 124.9%)L/day
Vd	7.11 (geometric mean steady-state Vss; CV 26.6%)L+1	—	0.0492 (popPK estimate V5; RSE 23.0%)L

FDA label §12.3 Drugs@FDA reviewhover a value for dose / population / source · “+N” marks additional reported values

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

Conjunctival

Dry eye

Blurred vision

Dominant tissue

Surface subtype

None

Grading scale

CTCAE v4.0

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: CTCAE v4Denominator: RP2D⚠ Not comparable: symptom-driven ascertainment

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

90 μg/kg

Q3W

25%

n=4 · ADCT-402 Ph1 B-ALL

15 μg/kg

Q3W

25%

n=4 · LOTIS-1 (ADCT-402 Ph1 B-NHL)

75 µg/kg

25%

n=4 · LOTIS-3 (Lonca + Ibrutinib)

120 μg/kg

Q3W

20%

n=5 · ADCT-402 Ph1 B-ALL

30 μg/kg

Q3W

14.3%

n=7 · ADCT-402 Ph1 B-ALL

120 μg/kg

Q3W

12.5%

n=16 · LOTIS-1 (ADCT-402 Ph1 B-NHL)

see line_context

10%

n=10 · LOTIS-3 (Lonca + Ibrutinib)

—

7.35%

n=136 · Safety and Efficacy Study of Loncastuximab Tesirine + Ibrutinib in Diffuse Large

see line_context

6.7%

n=30 · LOTIS-3 (Lonca + Ibrutinib)

see line_context

5.9%

n=17 · Lonca-R, untreated DLBCL (Ph2)

—

5.71%

n=35 · Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Acute L

200 μg/kg

Q3W

5.6%

n=36 · LOTIS-1 (ADCT-402 Ph1 B-NHL)

150 μg/kg

Q3W

5.3%

n=19 · LOTIS-1 (ADCT-402 Ph1 B-NHL)

—

4.92%

n=183 · Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Non Hod

150 μg/kg

Q3W

4.3%

n=69 · LOTIS-1 (ADCT-402 Ph1 B-NHL)

60 µg/kg

2.7%

n=37 · LOTIS-3 (Lonca + Ibrutinib)

—

2.44%

n=41 · LOTIS-9

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

loncastuximab-tesirine

Approval status

FDA-approved

Approval year

2021

UniProt

P15391

ADCdb ADC

DRG0TKVCB

ADCdb antibody

ANI0AWZRF

ADCdb target

TAR0EBTXG

Primary source

FDA Zynlonta label; Caimi LOTIS-2 Lancet Oncol 2021

Aliases & development codes

Zynlonta; ADCT-402

Notes

PBD warhead released as DNA-guanine adduct, not free drug