Fc-engineered antibodies, often referred to in contexts like FcSK (Fc-silent or Fc-modified) antibodies, represent a class of therapeutic antibodies optimized for enhanced specificity and reduced off-target effects. Traditional antibodies comprise two functional regions: the Fab region, which binds antigens, and the Fc region, which interacts with Fc receptors (FcγRs) on immune cells, triggering effector functions like antibody-dependent cellular cytotoxicity (ADCC) or complement activation. While these functions are beneficial in oncology (e.g., tumor cell clearance), they can cause harmful inflammation in autoimmune or inflammatory diseases.
Fc engineering involves modifying the Fc domain to either enhance or suppress its interaction with Fc receptors. For example, Fc-silent antibodies are designed with mutations (e.g., L234A/L235A or N297A) to minimize FcγR binding, thereby reducing immune activation—useful in autoimmune therapies like anti-CD40L for lupus. Conversely, Fc-enhanced antibodies, through glycoengineering or amino acid substitutions (e.g., afucosylation), boost ADCC for cancer applications, as seen in obinutuzumab (anti-CD20).
Recent advances include tuning Fc affinity for specific FcγR subtypes to balance efficacy and safety. Such engineering also improves pharmacokinetics by modulating pH-dependent FcRn binding, extending half-life. FcSK antibodies highlight the shift toward precision biologics, enabling tailored immune modulation across oncology, autoimmunity, and infectious diseases. Ongoing research explores bispecific formats and combination therapies to expand therapeutic potential.