Abstract
Unmodified antibodies (abs) have been successful in the treatment of hematologic malignancies, but less so for the treatment of solid tumors. They trigger anti-tumor effects through their Fc-domains, and one way to improve their efficacy is to optimize their interaction with the effectors through Fc-engineering. Another way to empower abs is the design of bispecific abs and related fusion proteins allowing a narrower choice of effector cells. Here we review frequently chosen classes of effector cells, as well as common trigger molecules. Natural Killer (NK)- and T-cells are the most investigated populations in therapeutical approaches with bispecific agents until now. Catumaxomab, the first bispecific ab to receive drug approval, targets the tumor antigen Epithelial Cell Adhesion Molecule (EpCAM) and recruits T-cells via a binding site for the cell surface protein CD3. The next generation of recombinant ab-derivatives replaces the broadly reactive Fc-domain by a binding domain for a single selected trigger. Blinatumomab is the first clinically successful member of this class, targeting cancer cells via CD19 and engaging T-cells by CD3. Other investigators have developed related recombinant fusion proteins to recruit effectors, such as NK-cells and macrophages. The first such agents currently in preclinical and clinical development will be discussed.
Highlights
Antibodies (Abs) have evolved primarily for the defense against infectious agents, but not against spontaneous tumors of non-viral origin in mammals and man
A second large class of ab-derivatives attempts to recruit the body’s own cells as effectors for the elimination of cancer cells. This approach offers several unique advantages, including a reduced immunogenicity and a greater ease of manufacture, and appears attractive for the following reason: Often, some cancer cells resist the treatment with ab-drug conjugates (ADCs), and these may be either cancer stem cells (CSCs) with an intrinsic resistance to the drug, or cells with an increased resistance acquired by mutation
T-cells are activated by the interaction of the T cell receptor (TCR) with specific peptides loaded onto major histocompatibility (MHC) proteins present on other cells
Summary
Antibodies (Abs) have evolved primarily for the defense against infectious agents, but not against spontaneous tumors of non-viral origin in mammals and man. A third way to improve efficacy of therapeutic abs is to optimize their Fc-domain for stronger binding to Fc-receptors (FcRs) on effector cells by Fc-engineering This can be achieved either through introduction of point mutations at critical positions known to be important for the contact between. Due to stronger binding of optimized Fc-domains to FcRs, the competition of therapeutic abs with plasma Ig should be greatly reduced, and a greater fraction of the injected dose should reach the FcRs and mediate the desired effects [19] It is currently expected, that Fc-engineered abs will show improved therapeutic efficacy in upcoming clinical trials. We will emphasize ab-derivatives which deliberately recruit a chosen class of effector cells by engaging a trigger molecule present only on the desired subset of effectors, rather than relying on the broad range of effectors engaged by the reaction of abs still carrying an entire Fc-domain
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