Evolution and Emergence of Therapeutic Monoclonal Antibodies

The concept of using antibodies for the treatment of disease dates back to the 1890s, when Emil Adolf von Behring discovered the ability of small doses of diphtheria or tetanus toxin to produce transferable immunity between animals via serum1 (later attributed to the presence of antibodies). However, it was not until the early 1960s that structural characteristics of antibodies were described,2,3 with the following decade marking the discovery of methods for producing monoclonal antibodies (mAbs), including the hybridoma technique.4,5 In 1986, the first mAb, muromonab-CD3, was approved5 for treating steroid-resistant acute allograft rejection in renal transplant recipients. The first fully human mAb (adalimumab) was approved for treating rheumatoid arthritis in 2002.5 As of March 2012, the number of US Food and Drug Administration–approved, actively marketed therapeutic mAbs for use in oncology/hematology, immunomodulatory settings, and other miscellaneous conditions is approaching 30 (Table 1). Most of the recently approved biologics are fully human mAbs, and cancer and immunologic disorders continue to be the focus of investigational therapeutic mAbs6 (estimated at >500 across various stages of development).7View this table:Table 1. Marketed Therapeutic Monoclonal Antibodies With Food and Drug Administration–Approved Indications* (as of December 2012)This review provides an overview of the emergence and use of mAbs as therapeutics, including a discussion of their mechanism of action, delivery, clearance, and overall safety. Key differentiating aspects between mAbs and small-molecule therapeutics are also highlighted, along with a brief summary on the use of mAbs in the cardiology arena. Antibody Structure and FunctionAntibodies, also known as immunoglobulins (Igs), are B-cell–produced molecules composed of 4 polypeptide chains (2 heavy and 2 light chains) that come together to form their characteristic Y shape (Figure 1).8 They can circulate in soluble form or can be bound to the B-cell membrane as …