1997: Rituximab: First Anti-Cancer Monoclonal Antibody (1997)

Thirty years after Paul Ehrlich coined the "magic bullet" concept—a drug that would selectively
target and destroy cancer cells—monoclonal antibody technology made it possible to engineer such
a molecule. Rituximab (Rituxan, MabThera), a chimeric human/murine anti-CD20 IgG1 antibody,
was approved by the FDA on 26 November 1997 for the treatment of relapsed or refractory
low-grade or follicular B-cell non-Hodgkin lymphoma.

CD20 was identified by Ronald Levy's group at Stanford University as a surface antigen expressed
exclusively on mature B cells and on the vast majority of B-cell lymphomas, but absent from
pluripotent haematopoietic stem cells—making it an ideal tumour-selective target. Idec
Pharmaceuticals and Genentech developed the chimeric antibody using recombinant DNA technology
to replace the murine constant regions with human sequences, reducing immunogenicity while
retaining CD20 binding. Rituximab depletes B cells via complement-dependent cytotoxicity (CDC),
antibody-dependent cell-mediated cytotoxicity (ADCC), and direct induction of apoptosis.

Clinical trials in follicular lymphoma demonstrated overall response rates of ~48% in
pre-treated patients—remarkable for a single agent in a haematological malignancy. Subsequent
trials established rituximab as part of the standard CHOP-R regimen (cyclophosphamide,
doxorubicin, vincristine, prednisone + rituximab) for diffuse large B-cell lymphoma, improving
survival substantially.

Rituximab also demonstrated efficacy in rheumatoid arthritis (approved 2006), as a bridge to
other B-cell-mediated autoimmune diseases, founding a broader principle that B-cell depletion
is therapeutically useful beyond cancer. By 2017, rituximab biosimilars were entering the market
globally, reducing costs and expanding access.