CMC-544 (inotuzumab ozogamicin), an anti-CD22 immuno-conjugate of calicheamicin, alters the levels of target molecules of malignant B-cells

Takeshita, Akira; Yamakage, Nozomi; Shinjo, Kaori; Ono, Takaaki; Hirano, Isao; Nakamura, Shuichi; Shigeno, Kazuyuki; Tobita, Tadasu; Maekawa, Masato; Kiyoi, Hitoshi; Naoe, Tomoki; Ohnishi, Kazunori; Sugimoto, Yoshikazu; Ohno, R

doi:10.1038/leu.2009.77

Cited by 29 publications

(17 citation statements)

References 25 publications

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“…Our in vitro study suggested that the combination use of GO and MDR modifiers may be an ideal therapeutic approach for P-gp-expressing leukemia cells, assuming that the hematologic and non-hematologic toxicities are not worsened. Interestingly, similar results were obtained in studies using inotuzumab ozogamicin, a calicheamicinconjugated anti-CD22 antibody, for lymphoid malignancies [53,54].…”

Section: Drug Resistancesupporting

confidence: 66%

Efficacy and resistance of gemtuzumab ozogamicin for acute myeloid leukemia

Takeshita

2013

Int J Hematol

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Seventy to 80 % of patients with acute myeloid leukemia (AML) achieve complete remission following intensive chemotherapy, but more than 50 % of patients in remission subsequently relapse, which is often associated with clinical drug resistance. Therapy based on monoclonal antibodies (mAbs) has been developed to increase the selectivity of cytotoxic agents by conjugating them with a mAb. Gemtuzumab ozogamicin (GO) is a conjugate of a cytotoxic agent, a calicheamicin derivative, linked to a recombinant humanized mAb directed against the CD33 antigen, which is expressed on leukemia cells from more than 90 % of patients with AML. This conjugated mAb was introduced following promising results from phase I and II studies. However, the initial phase III study did not confirm the efficacy of GO in combination with conventional chemotherapies. Several subsequent phase III studies have shown the efficacy of GO in favorable and intermediate risk AML. Several resistance mechanisms against GO have been reported. Multidrug resistant (MDR) P-glycoprotein (P-gp), a trans-membrane glycoprotein that pumps out many anti-leukemic agents from cells, also affects GO. For this reasons, GO has been used in combination with MDR modifiers, such as cyclosporine, and in cases without P-gp. Several investigators have reported successful results of the use of GO in acute promyelocytic leukemia (APL). GO has also been described as effective in cases relapsed after treatment with all-trans retinoic acid (ATRA), arsenic acid and conventional chemotherapeutic agents. The efficacy of GO will be studied mainly in a favorable risk of AML, such as core binding factor leukemia and APL. In addition, suitable combinations with other chemotherapies and administration schedules should be discussed.

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Section: Drug Resistancesupporting

confidence: 66%

Efficacy and resistance of gemtuzumab ozogamicin for acute myeloid leukemia

Takeshita

2013

Int J Hematol

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“…The toxin or drug moieties of these biotherapeutic agents are delivered into target leukemia cells together with the targeted CD22 molecules by antibody-mediated endocytosis (56)(57)(58)(59). Antibody-mediated internalization of CD22 is dependent on its physical interaction with the clathrin-associated AP-2 adapter complex via tyrosinebased specific internalization motifs within its cytoplasmic domain (59,60).…”

Section: Resultsmentioning

confidence: 99%

CD22 EXON 12 deletion as a pathogenic mechanism of human B-precursor leukemia

Uckun

Goodman

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Here, we report that primary leukemic cells from infants with newly diagnosed B-precursor leukemia express a truncated and functionally defective CD22 coreceptor protein that is unable to transmit apoptotic signals because it lacks most of the intracellular domain, including the key regulatory signal transduction elements and all of the cytoplasmic tyrosine residues. Expression of this structurally and functionally abnormal CD22 protein is associated with a very aggressive in vivo growth of patients' primary leukemia cells causing disseminated overt leukemia in SCID mice. The abnormal CD22 coreceptor is encoded by a profoundly aberrant mRNA arising from a splicing defect that causes the deletion of exon 12 (c.2208-c.2327) (CD22ΔE12) and results in a truncating frameshift mutation. The splicing defect is associated with multiple homozygous mutations within a 132-bp segment of the intronic sequence between exons 12 and 13. These mutations cause marked changes in the predicted secondary structures of the mutant CD22 pre-mRNA sequences that affect the target motifs for the splicing factors hnRNP-L, PTB, and PCBP that are up-regulated in infant leukemia cells. Forced expression of the mutant CD22ΔE12 protein in transgenic mice perturbs B-cell development, as evidenced by B-precursor/B-cell hyperplasia, and corrupts the regulation of gene expression, causing reduced expression levels of several genes with a tumor suppressor function. We further show that CD22ΔE12-associated unique gene expression signature is a discriminating feature of newly diagnosed infant leukemia patients. These striking findings implicate CD22ΔE12 as a previously undescribed pathogenic mechanism in human B-precursor leukemia.

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“…When administered to xenograft models, CMC-544 prevents engraftment, but also induces dose-dependent tumor regression in mice presenting with leukemia. Whereas the level of CD22 expression is significantly reduced after incubation with CMC-544, the CD20 level can be increased (Takeshita et al, 2009). Therefore, sequential administration of rituximab increases the cytotoxic effect and supports the rationale for a combination with other antibodies.…”

Section: Cd22 Immunoconjugatesmentioning

confidence: 87%

Novel Therapeutic Targets in ALL Therapy

Crazzolara¹

2011

Novel Aspects in Acute Lymphoblastic Leukemia

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CMC-544 (inotuzumab ozogamicin), an anti-CD22 immuno-conjugate of calicheamicin, alters the levels of target molecules of malignant B-cells

Cited by 29 publications

References 25 publications

Efficacy and resistance of gemtuzumab ozogamicin for acute myeloid leukemia

Efficacy and resistance of gemtuzumab ozogamicin for acute myeloid leukemia

CD22 EXON 12 deletion as a pathogenic mechanism of human B-precursor leukemia

Novel Therapeutic Targets in ALL Therapy

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