Advances in Fc-based Biotherapeutics: Fusion Proteins, Engineering, and Emerging Conjugation Strategies

Once considered primarily a structural component of antibodies, the fragment crystallizable (Fc) domain of immunoglobulin G (IgG) has emerged as a versatile platform in modern biotherapeutic design. A principal factor underlying this transition is the interaction of the Fc domain with the neonatal Fc receptor (FcRn), which enables pH-dependent recycling and extends circulation time. This property has made Fc-based approaches especially useful for improving pharmacokinetics. In this mini-review, we examine recent developments in the medicinal chemistry of Fc-fusion proteins and Fc-derived constructs, with particular attention to how structural design influences in vivo behavior. Design features such as linker composition, methods of payload attachment, and Fc glycosylation all play a role in shaping stability, biological activity, and systemic exposure. In addition, strategies to modulate Fc effector function and FcRn binding have made it possible to fine-tune immune engagement while controlling half-life. More recently, Fc-fragmentation approaches have begun to attract attention. These smaller formats can address some of the limitations associated with larger biologics, including restricted tissue penetration and structural complexity, while still retaining useful Fc-mediated properties. Recent clinical examples illustrate a growing interest in tailoring Fc-based designs to specific therapeutic requirements rather than focusing exclusively on half-life extension. Instead of maximizing half-life alone, current designs are tailored to the specific requirements of a given therapeutic context. As a result, the Fc domain is better understood not as a static component, but as a flexible platform that can be adapted to support a range of biologic drug strategies.