Gemtuzumab ozogamicin (Mylotarg) has therapeutic activity against CD33⁺ acute lymphoblastic leukaemias in vitro and in vivo

Abstract

SummaryGemtuzumab ozogamicin (GO) is a humanized anti-CD33 antibody conjugated with the cytotoxic drug calicheamicin and approved for the treatment of relapsed acute myeloid leukaemia. As approximately 18% of acute lymphoblastic leukaemias (ALL) are also CD33 positive, we have investigated the cytotoxic activity of GO on CD33 + ALL cells in vitro and in vivo. 10 ng/ml GO induced 30-95% inhibition of thymidine uptake and 30-70% cell death in four freshly isolated and one in vivo passaged CD33 + ALL-cell cultures. Furthermore, an in vivo model of a CD33 + ALL carrying the Philadelphia chromosome [t(9;22)] was established. 5 · 10 6 ALL-2 cells inoculated in the tail vein of severe combined immunodeficient mice engrafted into haematopoietic organs, reaching a mean of 70%, 61% and 69% human CD45 + cells in bone marrow, spleen and liver, respectively, at 35 d. To test the therapeutic activity of GO, 50 or 100 lg immunotoxin was inoculated i.p. on days 7, 11 and 15 following tumour-cell inoculation. GO treatment dramatically inhibited expansion of ALL-2 cells in all tested organs and increased survival of tumour-injected animals by 28-41 d, relative to controls. These data demonstrated that GO is active both in vitro and in vivo against CD33 + ALL cells.

Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

“…On the basis of the significant TGI obtained in the s.c. implanted HL60 human leukemia model, PHA-848125 efficacy was also explored in two models of human primary disseminated leukemias, which might more closely reflect the pathogenesis of the human disease: ALL-2 derived from a Philadelphia chromosome-positive ALL patient in relapse (33) and AML-ps derived from an AML patient with normal karyotype (34).…”

“…In this assay, specific peptides or protein substrates are transphosphorylated by their specific kinase in the presence of ATP traced with [γ- 33 P]ATP using optimal buffers and cofactors.…”

Therapeutic potential of CD22-specific antibody-targeted chemotherapy using inotuzumab ozogamicin (CMC-544) for the treatment of acute lymphoblastic leukemia

“…26 In contrast, only 18% of the ALL patients were reported to express CD33 on the leukemic blasts. 22,27,28 Patients with CD33 þ ALL responded favorably to the treatment with gemtuzumab ozogamicin. 22,28,29 In a pediatric study conducted in conjunction with gemtuzumab ozogamicin, leukemic blast cells from two patients (55% blasts from one and 88% blasts from the other) were shown to express on their surface both CD22 and CD33.…”

“…22,27,28 Patients with CD33 þ ALL responded favorably to the treatment with gemtuzumab ozogamicin. 22,28,29 In a pediatric study conducted in conjunction with gemtuzumab ozogamicin, leukemic blast cells from two patients (55% blasts from one and 88% blasts from the other) were shown to express on their surface both CD22 and CD33. 22 Given the sensitivity of ALL cells to calicheamicin and potential to express CD22 and CD33, either simultaneous or sequential use of inotuzumab ozogamicin and gemtuzumab ozogamicin may confer greater therapeutic advantage by targeting both CD22 þ and CD33 þ ALL cells.…”

Immunotherapy of hematological malignancies: what is new?

“…In general terms, it is accepted that GO binds the CD33 molecule and is then internalized and allocated into lysosomes [54], where calicheamicin is released and generates oxidative damage of DNA [55,56] and mitochondrial damage leading to apoptosis [57]. One would therefore assume that the degree of susceptibility of AML (and CD33+ ALL [58]) blasts to GO cytolysis depends on the density of CD33 in the surface of the AML blasts. However, no such correlation has ever been found [59,60] and, moreover, some patients with CD33À blasts can still respond to GO [61].…”