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

1 adverse-event term

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

Blindness unilateral (serious AE)-

G3+ 0.6%

Per-trial detail

Adverse events by trial

Besponsa Post Marketing Surveillance StudyNA (observational)real-worldn=107B

CT.gov NCT04307134 posted results (other AEs; MedDRA27.1) NCT04307134

112 adverse-event terms · 19 systems · expand a system below

Infections23

Pneumonia klebsiella

0.9%

1/107

Anal abscess

0.9%

1/107

Atypical pneumonia

0.9%

1/107

Bacteriuria

0.9%

1/107

Bronchiolitis

0.9%

1/107

Clostridium difficile infection

0.9%

1/107

Conjunctivitis

0.9%

1/107

Herpes dermatitis

0.9%

1/107

Herpes simplex

0.9%

1/107

Large intestine infection

0.9%

1/107

Meningitis

0.9%

1/107

Oral candidiasis

0.9%

1/107

Oral herpes

0.9%

1/107

Otitis externa

0.9%

1/107

Otitis media chronic

0.9%

1/107

Parainfluenzae virus infection

0.9%

1/107

Pathogen resistance

0.9%

1/107

Periodontitis

0.9%

1/107

Pharyngitis

0.9%

1/107

Pneumonia pneumococcal

0.9%

1/107

Pulpitis dental

0.9%

1/107

Tinea pedis

0.9%

1/107

Tonsillitis

0.9%

1/107

GI12

Musculoskeletal9

Pulmonary8

Ocular7

Blepharitis

0.9%

1/107

Chalazion

0.9%

1/107

Keratitis

0.9%

1/107

Retinal exudates

0.9%

1/107

Retinal haemorrhage

0.9%

1/107

Vision blurred

0.9%

1/107

Vitreous floaters

0.9%

1/107

Investigations7

Dermatologic7

General5

Hematologic4

Metabolic4

Neoplasms4

Neurologic (other)4

Hepatic3

Injury3

Psychiatric3

Other3

Ear2

Endocrine2

Immune2

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

Glycoengineering

Standard

Effector silencing

None

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

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

—

16.7%

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

—

9.1%

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

—

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)

—

3.7%

n=107 · Besponsa Post Marketing Surveillance Study

—

1.6%

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

—

1.4%

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

—

0.9%

n=107 · Besponsa Post Marketing Surveillance Study

—

0.6%

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

—

0.6%

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

—

0.6%

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