Drug Information

Drug (ID: DG00542) and It's Reported Resistant Information

• Name: Inotuzumab ozogamicin
• Synonyms: Inotuzumab ozogamicin
• Indication:
  In total 1 Indication(s)
  Acute lymphoblastic leukaemia [ICD-11: 2A70]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Acute lymphocytic leukemia [ICD-11: 2B33]; [2]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Mature B-cell neoplasms [ICD-11: 2A8Z]; [3]
• Target: Inotuzumab ozogamicin; CD22_HUMAN; [1]
• DrugBank ID: DB05889

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Mature B-cell neoplasms [ICD-11: 2A8Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine-protein kinase ATM (ATM) [3]

• Resistant Disease: Mature B-cell neoplasms [.]
• Molecule Alteration: Missense mutation; Methylation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: pre-InO and/or post-InO tumor cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: GeneSeq assay; Mutation assay
• Mechanism Description: Multiple mechanisms drive CD22 antigen escape, including epitope loss (protein truncation and destabilization) and epitope alteration.Hypermutation caused by error-prone DNA damage repair may serve as a driver of CD22 mutation and escape.

Key Molecule: Cyclin-dependent kinase inhibitor 2A (CDKN2A) [3]

• Resistant Disease: Mature B-cell neoplasms [.]
• Molecule Alteration: Missense mutation; Activation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: pre-InO and/or post-InO tumor cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: GeneSeq assay; Mutation assay
• Mechanism Description: Multiple mechanisms drive CD22 antigen escape, including epitope loss (protein truncation and destabilization) and epitope alteration.Hypermutation caused by error-prone DNA damage repair may serve as a driver of CD22 mutation and escape.

Key Molecule: B-cell receptor CD22 (CD22) [3]

• Resistant Disease: Mature B-cell neoplasms [.]
• Molecule Alteration: Missense mutation; Amplification
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: pre-InO and/or post-InO tumor cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: GeneSeq assay; Mutation assay
• Mechanism Description: Multiple mechanisms drive CD22 antigen escape, including epitope loss (protein truncation and destabilization) and epitope alteration.Hypermutation caused by error-prone DNA damage repair may serve as a driver of CD22 mutation and escape.

Key Molecule: Tumor protein p53 (TP53) [3]

• Resistant Disease: Mature B-cell neoplasms [.]
• Molecule Alteration: Missense mutation; Methylation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: pre-InO and/or post-InO tumor cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: GeneSeq assay; Mutation assay
• Mechanism Description: Multiple mechanisms drive CD22 antigen escape, including epitope loss (protein truncation and destabilization) and epitope alteration.Hypermutation caused by error-prone DNA damage repair may serve as a driver of CD22 mutation and escape.

Key Molecule: Histone-lysine N-methyltransferase 2D (KMT2D) [3]

• Resistant Disease: Mature B-cell neoplasms [.]
• Molecule Alteration: Missense mutation; Loss
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: pre-InO and/or post-InO tumor cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: GeneSeq assay; Mutation assay
• Mechanism Description: Multiple mechanisms drive CD22 antigen escape, including epitope loss (protein truncation and destabilization) and epitope alteration.Hypermutation caused by error-prone DNA damage repair may serve as a driver of CD22 mutation and escape.

Key Molecule: DNA nucleotidylexotransferase (DNTT) [3]

• Resistant Disease: Mature B-cell neoplasms [.]
• Molecule Alteration: Missense mutation; p.R183W
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: pre-InO and/or post-InO tumor cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: GeneSeq assay; Mutation assay
• Mechanism Description: Multiple mechanisms drive CD22 antigen escape, including epitope loss (protein truncation and destabilization) and epitope alteration.Hypermutation caused by error-prone DNA damage repair may serve as a driver of CD22 mutation and escape.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [3]

• Sensitive Disease: Mature B-cell neoplasms [.]
• Molecule Alteration: Function; C2617T/A; A2063G
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: pre-InO and/or post-InO tumor cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: GeneSeq assay; Mutation assay
• Mechanism Description: Multiple mechanisms drive CD22 antigen escape, including epitope loss (protein truncation and destabilization) and epitope alteration.Hypermutation caused by error-prone DNA damage repair may serve as a driver of CD22 mutation and escape.

Acute lymphocytic leukemia [ICD-11: 2B33]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: B-cell receptor CD22 (CD22) [2]

• Resistant Disease: Relapsed B-acute Lymphoblastic leukaemia [ICD-11: 2B33.3]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Experiment for Molecule Alteration: Flow cytometry assay
• Experiment for Drug Resistance: Enzyme-linked immunosorbent assay (ELISA)
• Mechanism Description: One important escape mechanism at relapse may be modulation of the CD22 antigen expression on leukemic blasts, analogous to antigen loss associated with CD19-directed therapies such as blinatumomab and CD19-CAR T-cell therapies.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: B-cell receptor CD22 (CD22) [1]

• Resistant Disease: Relapsed B-acute Lymphoblastic leukaemia [ICD-11: 2B33.3]
• Molecule Alteration: Missense mutation; p.V238 frameshift
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Experiment for Molecule Alteration: Whole genome sequencing assay; Whole transcriptome RNA-sequencing assay
• Experiment for Drug Resistance: Bone marrow biopsy assay; Flow cytometry assay
• Mechanism Description: Decreased surface CD22 expression and receptor density have been reported as mechanisms of acquired@resistance to InO and CD22 CAR-T in some patients relapsing with B-lineage acute leukaemia. Truncating CD22 mutation with concomitant loss of the receptor from the cell surface represents a new mechanism of leukaemic cell escape

References

• Ref 1: Inotuzumab ozogamicin resistance associated with a novel CD22 truncating mutation in a case of B-acute lymphoblastic leukaemiaBr J Haematol. 2020 Oct;191(1):123-126. doi: 10.1111/bjh.16949. Epub 2020 Jul 9.
• Ref 2: LincHOTAIR epigenetically silences miR34a by binding to PRC2 to promote the epithelial-to-mesenchymal transition in human gastric cancer Cell Death Dis. 2015 Jul 2;6(7):e1802. doi: 10.1038/cddis.2015.150.
• Ref 3: Genomic determinants of response and resistance to inotuzumab ozogamicin in B-cell ALL. Blood. 2024 Jul 4;144(1):61-73.