Targeted therapies in hematological malignancies using therapeutic monoclonal antibodies against Eph family receptors

Abstract

The use of monoclonal antibodies (mAbs) and molecules derived from them has achieved considerable attention and success in recent years, establishing this mode of therapy as an important therapeutic strategy in many cancers, in particular hematological tumors. mAbs recognize cell surface antigens expressed on target cells and mediate their function through various mechanisms such as antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, or immune system modulation. The efficacy of mAb therapy can be improved when they are conjugated to a highly potent payloads, including cytotoxic drugs and radiolabeled isotopes. The Eph family of proteins has received considerable attention in recent years as therapeutic targets for treatment of both solid and hematological cancers. High expression of Eph receptors on cancer cells compared with low expression levels in normal adult tissues makes them an attractive candidate for cancer immunotherapy. In this review, we detail the modes of action of antibody-based therapies with a focus on the Eph family of proteins as potential targets for therapy in hematological malignancies.

Tyrosine kinase Eph receptor A6 sensitizes glioma‐initiating cells towards bone morphogenetic protein‐induced apoptosis

“…Because EPHA6 kinase activity was not shown to be a prerequisite for apoptosis, we further examined the function of EPHA6 binding to ephrin‐A ligands by using EPHA6‐Fc consisting of the N‐terminal ephrin‐binding domain conjugated to IgG1. EPHA6 could bind to all ephrin‐A ligands (A1‐A5) and EPHA6‐Fc has been used to block endogenous ephrin‐A ligands in the mouse brain . In TGS‐01 cells, EPHA6‐Fc treatment minimally affected BMP‐2‐induced apoptosis compared to the IgG‐Fc control ().…”

Lymph node fine‐needle cytology in the era of personalised medicine. Is there a role?

“…The main targets are cluster designation (CD) proteins that are usually highly expressed on malignant cells in specific NHLs. The chimeric anti‐CD20 MA (Rituximab) was the first and the most clinically used and studied among the target drugs . Afterwards several other MA unconjugates, or radioconjugates (iodine‐131 anti‐D20, yttrium‐90 anti‐CD20), have been produced.…”

“…The main targets of MAs are cluster designation (CD) proteins, each of them addressed against specific antigens with one or more specific entities as clinical target; namely: blinatumomab (anti‐CD19) in B‐cell precursor anaplastic large cell lymphoma, obinutuzumab (anti‐CD20) in FL and CLL, ofatumumab (anti‐CD20) in CLL, rituximab (anti‐CD20) in CD20 positive FL, CLL and DLBCL, epratuxumab (anti‐CD22), inotuzumab (anti‐CD22) in B‐cell precursor anaplastic large cell lymphoma, moxetumomab (anti‐CD22) in HCL, brentuximab (anti‐CD30) in cHL, ALCL, CD30+ MF and systemic ALCL, daratumumab (anti‐CD38) in multiple myeloma (MM), alemtuzumab (anti‐CD52) in CLL and T‐cell NHL. Other monoclonal antibodies are addressed against different antigens such as apolizumab (antiHLA‐DR), alentuzumab (Campat‐1H) and anti‐CD40 . Table provides a list of the most used monoclonal antibodies, either in untreated or previously treated patients, with molecular target(s), clinical indications and Food and Drug Administration approvals.…”

Introductory Chapter: Advances in Hematologic Malignancies

“…Targeted epigenetic therapies may be particularly attractive as long-term treatment in post remission period, if they could target certain subclones once standard chemotherapy has produced targeted cytoreduction to induce remission of acute leukemia [12]. Personalized targeted therapy have just upset treatment results in some HMs, especially, chronic myeloid leukemia (CML), non-Hodgkin's lymphoma (NHL), multiple myeloma (MM) and acute promyelocytic leukemia (APL) [12,13].…”