No abstract

The efficacy and specificity of conventional monoclonal antibody (mAb) drugs in the clinic require further improvement. Currently, the development and application of novel antibody formats for improving cancer immunotherapy have attracted much attention. Variable region‐retaining antibody fragments, such as antigen‐binding fragment (Fab), single‐chain variable fragment (scFv), bispecific antibody, and bi/trispecific cell engagers, are engineered with humanization, multivalent antibody construction, affinity optimization and antibody masking for targeting tumor cells and killer cells to improve antibody‐based therapy potency, efficacy and specificity. In this review, we summarize the application of antibody variable region engineering and discuss the future direction of antibody engineering for improving cancer therapies.

Patients with multiple myeloma, an incurable malignancy of plasma cells, frequently develop osteolytic bone lesions that severely impact quality of life and clinical outcomes. Eliglustat, a U.S. Food and Drug Administration-approved glucosylceramide synthase inhibitor, reduced osteoclast-driven bone loss in preclinical in vivo models of myeloma. In combination with zoledronic acid, a bisphosphonate that treats myeloma bone disease, eliglustat provided further protection from bone loss. Autophagic degradation of TRAF3, a key step for osteoclast differentiation, was inhibited by eliglustat as evidenced by TRAF3 lysosomal and cytoplasmic accumulation. Eliglustat blocked autophagy by altering glycosphingolipid composition whilst restoration of missing glycosphingolipids rescued autophagy markers and TRAF3 degradation thus restoring osteoclastogenesis in bone marrow cells from myeloma patients. This work delineates both the mechanism by which glucosylceramide synthase inhibition prevents autophagic degradation of TRAF3 to reduce osteoclastogenesis as well as highlighting the clinical translational potential of eliglustat for the treatment of myeloma bone disease.