Inotuzumab ozogamicin

FDA-approved

Besponsa; CMC-544

Target

CD22 · CD22

Sponsor

Wyeth/Pfizer

Indication

CD22+ ALL

Target family

Siglec

RP2D dose

1.8 mg/m² cycle 1 (0.8 D1 + 0.5 D8 + 0.5 D15)

D1+D8+D15 Q3-4WRP2D

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

41 adverse-event terms

Ocular

Any-grade

G3+

RP2D

sagittal schematic · Reversible

↳

Tissues shaded by reported adverse-event rate.

Cornea

Express.

0.5%

Limbus

Express.

1.1%

Conjunctiva

Express.

1.64%

Lens

Express.

Retina / RPE

Express.

1.16%

0 nTPM

Dominant tissue

Hepatic

Surface subtype

None

Reversibility

Reversible

Reported ocular events

Ocular GvHD18.52%

non-seriousn=27

Blurred vision9.09%

non-seriousn=22

Eye disorders9.09%

non-seriousn=22

Eye irritation8.4%

non-seriousn=119

Ocular GVHD6.67%

non-seriousn=15

Eye disorder6.67%

non-seriousn=15

CONJUNCTIVITIS5.06%

non-seriousn=79

Periorbital edema4.55%

non-seriousn=22

Lacrimation increased4.2%

non-seriousn=119

Eye pain4.17%

non-seriousn=48

Conjunctival haemorrhage4.17%

non-seriousn=72

Eye disorders-Other4.17%

non-seriousn=48

ABNORMAL VISION3.8%

non-seriousn=79

EYE DISORDER3.8%

non-seriousn=79

Dry eye3.74%

non-seriousn=107

Chronic ocular GvHD3.7%

non-seriousn=27

Cataract3.33%

non-seriousn=90

Dry Eye Syndrome3.33%

non-seriousn=90

DRY EYES2.53%

non-seriousn=79

Visual impairment2.47%

non-seriousn=81

Ocular/Visual Other2.22%

non-seriousn=90

Photophobia2.08%

non-seriousn=48

Watering eyes2.08%

non-seriousn=48

Ocular hyperaemia1.68%

non-seriousn=119

Periorbital oedema1.68%

non-seriousn=119

BLEPHARITIS1.27%

non-seriousn=79

CATARACT SPECIFIED1.27%

non-seriousn=79

CORNEAL LESION1.27%

non-seriousn=79

EYE PAIN1.27%

non-seriousn=79

KERATITIS1.27%

non-seriousn=79

Conjunctivitis0.93%

non-seriousn=107

Vision blurred0.93%

non-seriousn=107

Blepharitis0.93%

non-seriousn=107

Chalazion0.93%

non-seriousn=107

Keratitis0.93%

non-seriousn=107

Leukaemic retinopathy0.93%

non-seriousn=107

Retinal exudates0.93%

non-seriousn=107

Retinal haemorrhage0.93%

non-seriousn=107

Vitreous floaters0.93%

non-seriousn=107

Blindness unilateral (serious AE)0.6%

G3+n=307

Cytomegalovirus chorioretinitis0%

seriousn=164

Per-trial detail

Adverse events by trial

Study Evaluating CMC-544 In B-Cell Non-Hodgkin's LymphomaPHASE1real-worldn=79CTCAE NR (ClinicalTrials.govPooledC

ClinicalTrials.gov NCT00073749 posted results, adverse events module (non-serious; 3/79 pooled across arms)

223 adverse-event terms · 12 systems · expand a system below

GI31

NAUSEA

50.63%non-serious

40/79

ANOREXIA

30.38%non-serious

24/79

CONSTIPATION

24.05%non-serious

19/79

DIARRHEA

20.25%non-serious

16/79

VOMITING

20.25%non-serious

16/79

GAMMA GLUTAMYL TRANSPEPTIDASE INCREASED

11.39%non-serious

9/79

ABDOMINAL DISTENSION

10.13%non-serious

8/79

DRY MOUTH

7.59%non-serious

6/79

DYSPEPSIA

6.33%non-serious

5/79

STOMATITIS

6.33%non-serious

5/79

LIVER FUNCTION TESTS ABNORMAL

5.06%non-serious

4/79

ERUCTATION

3.8%non-serious

3/79

APHTHOUS STOMATITIS

2.53%non-serious

2/79

DYSPHAGIA

2.53%non-serious

2/79

FLATULENCE

2.53%non-serious

2/79

GASTROENTERITIS

2.53%non-serious

2/79

GASTROESOPHAGEAL REFLUX DISEASE

2.53%non-serious

2/79

MUCOSITIS

2.53%non-serious

2/79

GUM HEMORRHAGE

2.53%non-serious

2/79

FECAL INCONTINENCE

1.27%non-serious

1/79

HEPATOMEGALY

1.27%non-serious

1/79

LIVER FATTY DEPOSIT

1.27%non-serious

1/79

MOUTH ULCERATION

1.27%non-serious

1/79

ORAL MONILIASIS

1.27%non-serious

1/79

PANCREAS DISORDER

1.27%non-serious

1/79

RECTAL DISORDER

1.27%non-serious

1/79

RECTAL HEMORRHAGE

1.27%non-serious

1/79

BLOOD IN STOOL

1.27%non-serious

1/79

CHOLELITHIASIS

1.27%non-serious

1/79

GASTROINTESTINAL DISORDER

1.27%non-serious

1/79

NAUSEA AND VOMITING

1.27%non-serious

1/79

Metabolic28

General24

Pulmonary24

Cardiac22

Hematologic21

Neurologic (other)18

Dermatologic15

Renal13

Musculoskeletal11

Ocular9

CONJUNCTIVITIS

5.06%non-serious

4/79

ABNORMAL VISION

3.8%non-serious

3/79

EYE DISORDER

3.8%non-serious

3/79

DRY EYES

2.53%non-serious

2/79

BLEPHARITIS

1.27%non-serious

1/79

CATARACT SPECIFIED

1.27%non-serious

1/79

CORNEAL LESION

1.27%non-serious

1/79

EYE PAIN

1.27%non-serious

1/79

KERATITIS

1.27%non-serious

1/79

Investigations7

Construct

Molecular anatomy

Antibody

IgG4

Humanized

Linker

Cleavable

DAR

Payload

Calicheamicin gamma1

DNA strand break

Linker structureC12H15NO3

CC(=O)c1ccc(OCCCC(N)=O)cc1

Payload structureC55H74IN3O21S4

CCN[C@H]1CO[C@H](C[C@@H]1OC)O[C@@H]2[C@H]([C@@H]([C@H](O[C@H]2O[C@H]3C#C/C=C\C#C[C@@]\4(CC(=O)C(=C3/C4=C\CSSSC)NC(=O)OC)O)C)NO[C@H]5C[C@@H]([C@@H]([C@H](O5)C)SC(=O)C6=C(C(=C(C(=C6OC)OC)O[C@H]7[C@@H]([C@@H]([C@H]([C@@H](O7)C)O)OC)O)I)C)O)O

Antibody

Antibody & Fc engineering

Antibody

G5/44 (inotuzumab)

Isotype

IgG4

Origin

Humanized

Fc modifications

None^inferred

Glycoengineering

Standard^inferred

Effector silencing

None^inferred

FcγR binding

Retained

C1q binding

Reduced

Target KD (nM)

Epitope / domain

CD22 N-terminal Ig domain 1

Linker & conjugation

Linker chemistry

Linker profile

Linker

AcBut hydrazone + disulfide

Class

Cleavable

Cleavage

Cleavable

Attachment

Lysine

Conjugation

Conventional Lys (NHS)

Symmetry

Asymmetric

DAR (mean)

DAR homogeneity

Heterogeneous

Plasma t½

12.3 d

Cleavage trigger

pH/acid (hydrazone) + GSH/reductive (disulfide)

Release control

Conditional

Hydrophilicity mask

None

DAR distribution

2-8

Formula

C12H15NO3

Linker MW

221.256 Da

Linker TPSA

69.39 Å²

Linker xLogP

1.5335

ADCdb linker

LIN0KWKDL

In-vitro stability

Stability note

Terminal t½ 12.3 d in N=234 R/R ALL — much longer than gemtuzumab despite same AcBut chemistry, attributable to higher per-Ab loading (DAR 6 vs 2.5) and IgG4-class pharmacokinetics; calicheamicin metabolite (N-Ac-γ-cal-DMH) below limit of quantitation in serum due to extensive reduction

Payload

Payload & physicochemistry

Payload profile

Payload

Calicheamicin gamma1

Class

Calicheamicin

Mechanism

DNA strand break

Released catabolite

N-acetyl-gamma-calicheamicin dimethylhydrazide

Mechanistic subtype

DNA-strand-break

Stereochem / salt

Bystander

Partial

PAMPA rank

1368.4 Da

XLogP3

logD₇.₄

TPSA

410 Å²

pKa

Charge pH 7.4

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C55H74IN3O21S4

PubChem CID

10953353

ADCdb payload

PAY0RZSDY

Hydrophobicity · logD₇.₄

hydrophilic −2+2+4 lipophilic

Bioactivity note

ADCdb reports ADC in vitro cytotoxicity IC50 from ~5 pM (Daudi) to ~750 pM (HL-60 control); Phase 3 ALL CR ~73.8%. Free calicheamicin gamma1 binds DNA minor groove causing double-strand breaks (sub-nM potency).

Dosing & regimen

Dosing

RP2D dose

1.8 mg/m² cycle 1 (0.8 D1 + 0.5 D8 + 0.5 D15)

Schedule

D1+D8+D15 Q3-4W

Route

Fractionated

Yes

n at RP2D

164

Dose basis

BSA

Trial phase

Approved

Dose-OAE available

Tox summary basis

RP2D

ADA rate (%)

3 %

Pharmacology

Clinical pharmacokinetics

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

	Intact ADC
Cmax	308ng/mL
AUC	100,000ng·h/mL
t½	12.3days+2
CL	0.0333L/h
Vd	~12L+1

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

0 %

Conjunctival

Dry eye

Blurred vision

Dominant tissue

Hepatic

Surface subtype

None

Grading scale

Mixed

Reversibility

Reversible^unver.

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

Cornea (central)

0.5 %

Cornea (limbal)

1.1 %

Conjunctiva

1.64 %

RPE

1.16 %

Retina (HPA)

0 nTPM

Cross-trial comparability

Ascertainment: Symptom-driven reportingScale: MixedDenominator: RP2D⚠ Not comparable: symptom-driven ascertainment + mixed grading scale

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

0.8 mg/m^2

20%

n=5 · Study Evaluating CMC-544 In B-Cell Non-Hodgkin's Lymphoma

1.2 mg/m^2

50%

n=2 · CMC-544 and Allogeneic Transplantation for CD22 Positive-Lymphoid Malignancies

1.6 mg/m^2

8.3%

n=12 · Study Evaluating Inotuzumab Ozogamicin In Acute Lymphocytic Leukemia

1.8 mg/m^2

23.8%

n=21 · CMC-544 and Allogeneic Transplantation for CD22 Positive-Lymphoid Malignancies

1.8 mg/m^2

16.7%

n=6 · Study Evaluating CMC-544 In B-Cell Non-Hodgkin's Lymphoma

1.8 mg/m^2

16.7%

n=6 · Study Evaluating CMC-544 In B-Cell Non-Hodgkin's Lymphoma

1.8 mg/m^2

14.3%

n=7 · Study Evaluating Inotuzumab Ozogamicin [CMC-544] Administered In Combination With Rituximab In Subjects With Non-Hodgkin's Lymphoma (NHL)

1.8 mg/m^2

11.1%

n=9 · Study Evaluating Inotuzumab Ozogamicin In Acute Lymphocytic Leukemia

1.8 mg/m^2

6.7%

n=45 · CMC-544 in Relapsed Refractory Acute Lymphoblastic Leukemia (ALL)

1.8 mg/m^2

5.7%

n=35 · Study Evaluating Inotuzumab Ozogamicin In Acute Lymphocytic Leukemia

1.8 mg/m^2

4.7%

n=43 · Study Evaluating CMC-544 In B-Cell Non-Hodgkin's Lymphoma

1.8 mg/m^2

2.3%

n=43 · Study Evaluating CMC-544 In B-Cell Non-Hodgkin's Lymphoma

2.4 mg/m^2

16.7%

n=6 · Study Evaluating CMC-544 In B-Cell Non-Hodgkin's Lymphoma

375 mg/m^2

11.8%

n=34 · Study Evaluating Inotuzumab Ozogamicin [CMC-544] Administered In Combination With Rituximab In Subjects With Non-Hodgkin's Lymphoma (NHL)

375 mg/m^2

5.9%

n=34 · Study Evaluating Inotuzumab Ozogamicin [CMC-544] Administered In Combination With Rituximab In Subjects With Non-Hodgkin's Lymphoma (NHL)

375 mg/m^2

2.5%

n=40 · Study Evaluating Inotuzumab Ozogamicin [CMC-544] Administered In Combination With Rituximab In Subjects With Non-Hodgkin's Lymphoma (NHL)

—

40%

n=5 · S1312, Inotuzumab Ozogamicin and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Acute Leukemia

—

33.3%

n=3 · Phase I/II Study of Bosutinib in Combination With Inotuzumab Ozogamicin in CD22-positive PC Positive ALL and CML

—

25%

n=4 · Combination Chemotherapy and Inotuzumab Ozogamicin in Treating Patients With B Acute Lymphoblastic Leukemia

—

25%

n=4 · Inotuzumab Ozogamicin and Chemotherapy in Treating Patients With Leukemia or Lymphoma Undergoing Stem Cell Transplantation

—

25%

n=4 · S1312, Inotuzumab Ozogamicin and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Acute Leukemia

—

20%

n=5 · S1312, Inotuzumab Ozogamicin and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Acute Leukemia

—

20%

n=5 · S1312, Inotuzumab Ozogamicin and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Acute Leukemia

—

18.52%

n=27 · CMC-544 and Allogeneic Transplantation for CD22 Positive-Lymphoid Malignancies

—

16.7%

n=6 · Phase I/II Study of Bosutinib in Combination With Inotuzumab Ozogamicin in CD22-positive PC Positive ALL and CML

—

14.58%

n=48 · S1312, Inotuzumab Ozogamicin and Combination Chemotherapy in Treating Patients W

—

9.1%

n=11 · Inotuzumab Ozogamicin and Chemotherapy in Treating Patients With Leukemia or Lymphoma Undergoing Stem Cell Transplantation

—

9.09%

n=22 · Phase I/II Study of Bosutinib in Combination With Inotuzumab Ozogamicin in CD22-

—

8.4%

n=119 · Study Evaluating Inotuzumab Ozogamicin [CMC-544] Administered In Combination Wit

—

7.7%

n=13 · S1312, Inotuzumab Ozogamicin and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Acute Leukemia

—

6.7%

n=15 · Study Comparing Inotuzumab Ozogamicin In Combination With Rituximab Versus Defined Investigator's Choice In Follicular Non-Hodgkin's Lymphoma (NHL)

—

6.67%

n=15 · Study Comparing Inotuzumab Ozogamicin In Combination With Rituximab Versus Defin

—

6.67%

n=15 · Inotuzumab Ozogamicin and Chemotherapy in Treating Patients With Leukemia or Lym

—

4.17%

n=72 · Study Evaluating Inotuzumab Ozogamicin In Acute Lymphocytic Leukemia

—

3.7%

n=107 · Besponsa Post Marketing Surveillance Study

—

3.33%

n=90 · CMC-544 in Relapsed Refractory Acute Lymphoblastic Leukemia (ALL)

—

2.47%

n=81 · Study Evaluating Inotuzumab Ozogamicin (CMC-544) In Indolent Non-Hodgkins Lympho

—

1.6%

n=63 · Treatment of Patients With Diffuse Large B Cell Lymphoma Who Are Not Suitable for Anthracycline Containing Chemotherapy

—

1.59%

n=63 · INCA

—

1.4%

n=72 · Study Evaluating Inotuzumab Ozogamicin (CMC-544) In Indolent Non-Hodgkins Lymphoma

—

1.27%

n=79 · Study Evaluating CMC-544 In B-Cell Non-Hodgkin's Lymphoma

—

0.93%

n=107 · Besponsa Post Marketing Surveillance Study

—

0.9%

n=107 · Besponsa Post Marketing Surveillance Study

—

0.61%

n=164 · A Study Of Inotuzumab Ozogamicin Versus Investigator's Choice Of Chemotherapy In

—

0.6%

n=307

—

0.6%

n=164 · A Study Of Inotuzumab Ozogamicin Versus Investigator's Choice Of Chemotherapy In Patients With Relapsed Or Refractory Acute Lymphoblastic Leukemia

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

inotuzumab-ozogamicin

Approval status

FDA-approved

Approval year

2017

UniProt

P20273

ADCdb ADC

DRG0SXFSY

ADCdb antibody

ANI0RLBTI

ADCdb target

TAR0XTCGM

Primary source

FDA Besponsa label; INO-VATE NEJM 2016

Aliases & development codes

Besponsa; CMC-544

Notes

Hematologic target; VOD/SOS dominant toxicity; 0% ocular AEs in label