Inotuzumab: from preclinical development to success in B-cell acute lymphoblastic leukemia

Abstract

Inotuzumab ozogamicin (InO) is a recently US Food and Drug Administration–approved antibody–drug conjugate for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). InO consists of a CD22-targeting immunoglobulin G4 humanized monoclonal antibody conjugated to calicheamicin. Although initially developed for the treatment of non-Hodgkin lymphoma (NHL) because of activity in preclinical models and high response rates in indolent lymphomas, a phase 3 trial was negative and further development focused on CD22+ ALL. Although results in NHL were disappointing, parallel testing in early-phase trials of CD22+ ALL demonstrated feasibility and efficacy. Subsequently, the randomized phase 3 Study Of Inotuzumab Ozogamicin Versus Investigator's Choice Of Chemotherapy In Patients With Relapsed Or Refractory Acute Lymphoblastic Leukemia trial showed that InO was superior to standard of care regimens with a significantly improved complete remission (CR) rate in patients with relapsed/refractory disease (80.7% vs 29.4%, P < .001). Patients achieving CR with InO also had a significantly higher rate of undetectable minimal residual disease compared with chemotherapy (78.4% vs 28.1%, P < .001). InO-specific side effects, including veno-occlusive disease, have been an ongoing area of concern, and consensus guidelines for minimizing toxicities are now available. Ongoing trials are investigating the combination of InO with other agents in the relapse setting and the addition of InO to frontline therapy. This review details the preclinical and clinical development of InO, focusing on how best to use it and future directions for further development.

Antibody-drug conjugates in clinical trials for lymphoid malignancies and multiple myeloma

“…[33]. Calicheamicin has been used in inotuzumab ozogamicin and gemtuzumab ozogamycin [11,[34][35][36].…”

Induction of NK Cell Reactivity against B-Cell Acute Lymphoblastic Leukemia by an Fc-Optimized FLT3 Antibody

“…However, while these drugs exert significant therapeutic effects, their activity is still limited, among others due to resistance mechanisms, which are for example associated with the modulation of their target antigens [23]. Downmodulation of target antigens associated with failure of therapy has been reported for approaches comprising binders of CD19 like the BiTE Blinatumomab and also anti-CD19 CAR-T cells [24,25] as well as the CD22-targeting ADC Inotuzumab ozogamicin [26][27][28]. With our FLT3 binder 4G8, we also observed downmodulation of FLT3 expression on AML and B-ALL cells [12], but even high mAb concentrations did not reduce antigen expression by more than 30%-40%.…”

Antibody–Drug Conjugates for Cancer Therapy

“…This linker connecting the antibody to calicheamicin forms a hydrazone with the hydrazide of the calicheamicin derivative, which is hydrolysed in lysosomal pH, and calicheamicin is released, leading to cell death. However, the acid-sensitive linker has a low plasma stability of 48–72 h [ 56 , 57 , 58 ]. The protease-cleavable linker, e.g., dipeptide valine-citrulline (Val-Cit, V-C), is utilized in brentuximab vedotin to link the monomethylauristatin E (MMAE) payload to the anti-CD30 antibody.…”

“…Inotuzumab ozogamicin (Besponsa) is an ADC composed of anti-CD22 monoclonal antibody linked to a semi-synthetic derivative of calicheamicin Calich-DMH. Calicheamicin is a DNA-damaging cytotoxic agent derived from soil bacterium Micromonospora echinospora [ 58 ].…”