Monoclonal Antibodies & Immunotherapy in Cancer

Monoclonal Antibodies & Immunotherapy in Cancer

1. Definition, historical context & overview

• A monoclonal antibody (mAb) is an immunoglobulin derived from a single B-cell clone, recognising a single antigen (one epitope) — e.g. an epitope on a growth-factor receptor or a cancer cell-surface protein (G&G 14e Ch.72, p.1416).
• mAbs are large molecules and cell-based therapeutics — distinct from the small-molecule pathway-targeted inhibitors of Ch.71; they are given parenterally, have a long plasma t½ of days to weeks, and require only intermittent dosing (G&G 14e Ch.72, pp.1415–6).
• Four broad cancer-cell eradication mechanisms of a mAb (G&G 14e Ch.72, p.1416):
  • Blocking ligands or function of cell-surface receptors (e.g. cetuximab, trastuzumab).
  • Recruiting immune cells and complement to a formed antigen–antibody complex (ADCC, CDC, ADCP).
  • Modulating immune-cell function (immune-checkpoint inhibitors).
  • Carrying toxins or radionuclides as cytotoxic payloads to target cells (ADCs, radioimmunoconjugates).
• Historical milestones (G&G 14e Ch.72, pp.1416, 1421, 1425, 1427):
  • William B. Coley (1910) — first to propose harnessing the immune system against cancer by injecting bacterial toxins into sarcoma ("Coley's toxins").
  • Köhler & Milstein (1975) — first hybridoma cell lines producing monoclonal antibodies; with Niels Jerne shared the 1984 Nobel Prize in Physiology/Medicine.
  • Paul Ehrlich (1913) — "Zauberkugel" / "magic bullet" concept — selective cytotoxic targeting of cancer without harming healthy tissue (basis of ADCs).
  • Judah Folkman (1971) — hypothesised that solid-tumour growth depends on angiogenesis; blockade of angiogenic factors would treat cancer (basis of anti-VEGF therapy).
  • Tasuku Honjo & James Allison — shared the 2018 Nobel Prize "for discovery of cancer therapy by inhibition of negative immune regulation" (checkpoint inhibition).
  • Rituximab (1997) — first therapeutic antibody approved for oncology (anti-CD20).
  • Trastuzumab — first anti-HER2 mAb (US 1998, Europe 2000).
  • Ipilimumab (2011) — first immune-checkpoint inhibitor approved (anti–CTLA-4).
  • Tisagenlecleucel (2017) — first FDA-approved CD19 CAR T-cell therapy.
• Over 40 antibody-based therapeutics are FDA-approved for cancer, many added in the last 5 years; the WHO "mab" stem encompassed 880 entities by 2021 (G&G 14e Ch.72, pp.1416, 1417).
• Targeted/antibody therapy is frequently combined with classical cytotoxics (Ch.70), pathway-targeted small molecules (Ch.71), or radiotherapy — cell death from these can promote cytotoxic T-cell infiltration, rationalising combination immunotherapy (G&G 14e Ch.72, p.1417).
• KDT framing: targeted drugs are of two types — (i) specific monoclonal antibodies, given parenterally, attacking cell-surface targets/tumour antigens; and (ii) synthetic small-molecule compounds, given orally, penetrating cells to affect cancer-specific enzymes/pathways (KDT 8e Ch.64, pp.928–9).