Inotuzumab ozogamicin: a CD22 mAb–drug conjugate for adult relapsed or refractory B-cell precursor acute lymphoblastic leukemia

Abstract

Despite improved rates of remission and cure in newly diagnosed adult acute lymphoblastic leukemia (ALL), the prognosis for patients with relapsed or refractory disease remains poor and the 5-year overall survival rate after relapse is under 10%. A recent paradigm shift has focused on the promise of targeted immunotherapy rather than standard chemotherapy, as ALL blast cells express a variety of antigens, and monoclonal antibodies may be developed to identify and destroy the leukemic cells. Inotuzumab ozogamicin is a CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin. CD22 expression is detected on leukemic blasts in over 90% of patients with ALL. Based on promising results from preclinical studies, inotuzumab ozogamicin was tested in Phase 1/2 and Phase 3 clinical trials and it demonstrated improved complete remission rates, progression-free survival and overall survival in relapsed or refractory adult ALL compared to standard therapy. Ongoing studies are evaluating the value of inotuzumab ozogamicin when given in combination with chemotherapy as part of upfront treatment. This review discusses the drug’s biochemical properties and mechanism of action, preclinical research outcomes, clinical trial results, adverse events and toxicities, drug approval and ongoing investigations.

Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long‐term survival follow‐up from the randomized, phase 3 INO‐VATE study

“…Inotuzumab ozogamicin (InO) is a recently introduced targeted therapy for adults with R/R CD22‐positive B‐cell precursor (BCP) ALL . InO is an antibody‐drug conjugate composed of a humanized anti‐CD22 monoclonal antibody conjugated to the cytotoxic agent calicheamicin .…”

“…1,6 Inotuzumab ozogamicin (InO) is a recently introduced targeted therapy for adults with R/R CD22-positive B-cell precursor (BCP) ALL. 7,8 InO is an antibody-drug conjugate composed of a humanized anti-CD22 monoclonal antibody Cancer July 15, 2019 conjugated to the cytotoxic agent calicheamicin. 9,10 It binds with high affinity to CD22, a cell-surface antigen expressed by >90% of B-cell blasts in nearly all patients with B-cell ALL.…”

Development of Kinetic Modeling to Assess Multi-functional Vascular Response to Low Dose Radiation in Leukemia

“…However, at high leukemic burden, vascular remodeling results in collapsed vessels, reduced perfusion, and reduced vascular surface area, which lowers K trans back to values similar to those of control mice. Increased K trans values in low burden ALL may indicate a therapeutic window of enhanced delivery for ALL antibody-based therapies such as those targeting CD19 or CD22 which are similar in size to 150 KDa dextran [19,20]. However, differences in vascular transport mechanisms of dextran and therapeutic antibodies make further assessments of antibody delivery kinetics necessary [21].…”

CD22 Expression in B-Cell Acute Lymphoblastic Leukemia: Biological Significance and Implications for Inotuzumab Therapy in Adults

“…After targeting CD22 + by InO in ALL blasts, preclinical and phase 1-2 studies showed that antibody ligation was rapidly followed by internalization of the complex into lysosomes, where calicheamicin is released. This drug binds to the DNA groove, leading to double-strand cleavage and subsequent apoptosis [28]. These studies also highlighted that the levels of unconjugated calicheamicin were below the limit of quantitation (50 pg/mL) for most patients and at different time points.…”

“…In a recent single-arm, phase 2 study, InO in combination with low-intensity chemotherapy was used for old patients with Ph-negative ALL [28]. The results showed that InO is active in the disease, with a high proportion of patients achieving MRD negativity and improved survival outcomes.…”