![]() ![]() Compared to conventional mAbs, HcAbs consist of just two heavy chains, with a single variable domain (VHH, ~15kDa) as the antigen-binding region. The serendipitous discovery of heavy-chain only antibodies (HcAbs) in camelids sparked the most recent wave of “third generation” antibodies. This prompted the improved “second generation” of utilizing antibody fragments such as the antigen-binding fragment (Fab, ~50kDa) and single-chain variable fragment (scFv, ~30kDa) however, this approach remained limited by a short serum half-life and aggregation-induced immunogenicity ( 2). Despite the clinical potential, their immunogenicity and large size (~150 kDa) became major detriments to their efficacy ( 1). Just under 50 years ago, the “first generation” of therapeutic antibodies consisted of murine-derived, monoclonal antibodies (mAbs), with over 30 mAbs now approved by the Food and Drug Administration (FDA) for clinical use. ![]() This review highlights their various applications in cancer and analyzes their trajectory toward their translation into the clinic. However, the recent discovery of “nanobodies,” the smallest-known functional antibody fragment, has demonstrated significant translational potential in preclinical and clinical studies. With mixed clinical success, mAbs still hold significant shortcomings, as they possess limited tumor penetration, high manufacturing costs, and the potential to develop therapeutic resistance. The development of targeted medicine has greatly expanded treatment options and spurred new research avenues in cancer therapeutics, with monoclonal antibodies (mAbs) emerging as a prevalent treatment in recent years. 3Harvard Stem Cell Institute, Harvard University, Cambridge, MA, United States.2Departments of Neurosurgery, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States. ![]()
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