Monoclonal Antibodies in the Treatment of Cancer
Paul Ehrlich was the first proponent of using antibodies or “magic bullets” to target tumor cells (1) and in recent years, monoclonal antibodies found their way into cancer treatment regimens.(2) Why can’t the body’s own immune cells go after the malignant cells? Cancer is clever. The transformed cancer cells evade the immune system through biochemical camouflage.(3) Immunotherapy (monoclonal antibodies and cancer vaccines) can make cancer cells visible to the natural immune system by taking advantage of molecular markers selectively present on cancer cells only.(4) Monoclonal antibodies, engineered in the laboratory and produced either in mice or through advanced hybridoma technology in humanized or chimeric forms, mimic the natural antibodies of the body.(5)
MAbs generally fight cancer in one of three ways.
In addition to re-targeting cancer cells to the immune system (activating the immune system), monoclonal antibodies can also function by attenuating hyperactive growth signals (inhibiting cancer cell multiplication). In other words, the antibodies attach to receptors on the outside of malignant cells to prevent the receptors from interacting with signaling molecules that tell the cell to multiply. Related to this, MAbs act through antiangiogenesis – inhibiting new blood vessel formation, in turn starving cancer cells of nutrition and oxygen supply.(6)
Monoclonal antibodies are either delivered alone (“Unconjugated”) or in combination with other cellular targets (“Chimeric” or “Conjugated”). Conjugation with a “payload” is the third way MAbs can fight cancer cells. For example, a monoclonal antibody can be conjugated to a radioactive particle. This promotes transport of the particle to the cancerous cells and only the cancerous cells. The radiation can thus be targeted at a microscopic level. This precise targeting is what Paul Ehrlich had in mind a century ago and maximizes the chances of positive outcome and while minimizing non-specific damaging exposure to radiation.
Major differences between monoclonal antibodies and small-molecule drugs
The primary difference lies in their mechanisms of action. Small-molecule drugs are usually cell membrane permeable, diffusing into the cells to find their organelle targets.(4,5) In comparison, monoclonal antibodies target unique cell-specific markers on the external surface of the cell (peptide antigens) and do not permeate through the cell. Small molecule drugs have a direct impact on their targets, whereas all that monoclonal antibodies do is re-direct targets to the immune system for resolution. Small molecule drugs are given in oral or intravenous administration while monoclonal antibodies are always administered intravenously (they would be destroyed in the digestive system before making their way to the cancerous cells.)
More on clinical use of monoclonal antibodies.
Common Challenges of Monoclonal Antibody Usage
- Low immunogenicity of xenogeneic antibodies.
- Unscrupulous antigen shedding into circulation causing bystander effects.
- Inordinate vasculature in the tumor making targeting through intravenous injection to site of tumor challenging.
- Elevated hydrostatic pressure at the tumor site. Limited number of effector immune cells in the tumor microenvironment; hence even after recognition by the natural immune system the cells might still not be completely destroyed.
Dosing for monoclonal antibodies
Although doctors’ first instincts are to vary the dose of monoclonal antibodies with patient body size, mathematical simulation of pharmacokinetics suggest this variation may not provide better efficacy. This is in contrast to many drugs – and indeed most chemotherapy drugs – where bigger patients get higher doses. But mAbs are target-specific with a relatively large therapeutic window. The dangers of overdosing are lower than they are for conventional chemotherapy drugs. Some scientists therefore recommend a fixed dose (i.e. everyone gets the same dose) when these drugs are first used in humans, at least until data from real patients indicates a more nuanced approach is preferable.
Some monoclonal antibody agents used to treat cancer
Alemtuzumab (Campath) is used for the treatment of B-cell chronic lymphocytic leukemia (CLL).
Bevacizumab (Avastin) is used for the treatment of breast cancer, colon cancer and lung cancer. It targets VEGF.
Brentuximab vedotin (Adcetris) is used for the treatment of Hodgkin lymphoma.
Cetuximab (Erbitux) is used for the treatment of colon cancer, squamous cell carcinoma, and head and neck cancers. It targets EGFR.
Dinutuximab (Unituxin) is used for the treatment of neuroblastoma.
Gemtuzumab (Mylotarg) was used for the treatment of acute myelogenous leukemia. However, this drug has been withdrawn from the market.
Ibritumomab (Zevalin) is a radioimmunotherapy medicine used for the treatment of non-Hodgkin’s lymphoma. Although this drug is currently on the market, in some patients it is known to cause serious side effects.
Ipilimumab (Yervoy) is used for the treatment of melanoma.
Necitumumab (Portrazza) is used for the treatment of non-small cell lung cancer.
Ofatumumab (Arzerra) is used for the treatment of chronic lymphocytic leukemia.
Panitumumab (Vectibix) is used for the treatment of colon cancer, targets EGFR.
Rituximab (Rituxan) is used for the treatment of hematological cancers.
Tositumomab (Bexxar) was used for the treatment of non-Hodgkin’s lymphoma, but it has been withdrawn from the market.
Trastuzumab (Herceptin) is used for the treatment of breast cancer. It targets HER-2.
Atezolizumab
Brand/Trade Names: Tecentriq
Formula: C6446H9902N1706O1998S42
Origin: Humanized
Mechanism: anti-PD-L1
Administration: Intravenous
Notes:
Avelumab
Brand/Trade Names: Bavencio
Formula: C6374H9898N1694O2010S44
Origin: Human
Mechanism: anti-PD-L1
Administration: Intravenous
Notes:
Blinatumomab
Brand/Trade Names: Blincyto
Formula: C2367H3577N649O772S19
Origin: Mouse
Mechanism: BiTE antibody
Administration: Intravenous
Notes:
Cemiplimab-rwlc
Brand/Trade Names: Libtayo
Formula: C6380H9808N1688O2000S44
Origin: Human
Mechanism: Checkpoint Inhibitor
Administration: Intravenous
Notes:
Daratumumab
Brand/Trade Names: Darzalex
Formula: C6466H9996N1724O2010S42
Origin: Human
Mechanism: Binds to CD38
Administration: Intravenous
Notes:
Dinutuximab
Brand/Trade Names: Unituxin, Isquette
Formula: C6422H9982N1722O2008S/sub>48
Origin: Chimeric: Human/Mouse
Mechanism:
Administration: Intravenous
Notes:
Durvalumab
Brand/Trade Names: Imfinzi
Formula: C6502H10018N1742O2024S42
Origin: Human
Mechanism: Anti-PD-L1
Administration: Intraveneous
Notes:
Elotuzumab
Brand/Trade Names: Empliciti
Formula: C6476H9982N1714O2016S42
Origin: Humanized
Mechanism: SLAMF7 blocker
Administration: Intravenous
Notes:
Ibritumomab
Brand/Trade Names: Zevalin
Formula:
Origin: Mouse
Mechanism:
Administration: Intravenous
Notes: linked with radioactive Yttrium-90
Ipilimumab
Brand/Trade Names: Yervoy
Formula: C6742H9972N1732O2004S40
Origin: Human
Mechanism: CTLA-4 blocker
Administration: Intravenous
Notes:
Mogamulizumab
Brand/Trade Names: Poteligeo
Formula: C6520H10072N1736O2020S42
Origin: Humanized
Mechanism:
Administration: Intravenous
Notes:
Moxetumomab pasudotox-tdfk
Brand/Trade Names: Lumoxiti
Formula: C2804H4339N783O870S14
Origin: Mouse
Mechanism:
Administration: Intravenous
Notes: Approved in Sept 2018 under FDA fast-track designation. Orphan drug status.
Necitumumab
Brand/Trade Names: Portrazza
Formula: C6436H9958N1702O2020S42
Origin: Human
Mechanism: EGFR inhibitor
Administration: Intravenous
Notes:
Nivolumab
Brand/Trade Names: Opdivo
Formula: C6362H9862N1712O1995S42
Origin: Human
Mechanism: PD-1 blocking antibody
Administration: Intravenous
Notes:
Obinutuzumab
Brand/Trade Names: Gazyva
Formula: C6512H10060N1712O2020S44
Origin: Humanized
Mechanism:
Administration: Intravenous
Notes:
Ofatumumab
Brand/Trade Names: Arzerra
Formula: C6480H10022N1742O2020S44
Origin: Human
Mechanism:
Administration: Intravenous
Notes: Used for chronic lymphocytic leukemia. More about ofatumumab.
Olaratumab
Brand/Trade Names: Lartruvo
Formula: C6554H10076N1736O2048S40
Origin: Human
Mechanism: PDGFR-α blocker
Administration: Intravenous
Notes:
Panitumumab
Brand/Trade Names: Vectibix
Formula: C6398H9878N1694O2016S48
Origin: Human
Mechanism: EGFR Inhibitor
Administration: Intravenous
Notes:
Pembrolizumab
Brand/Trade Names: Keytruda
Formula: C6534H10004N1716O2036S46
Origin: Humanized
Mechanism:
Administration: Intravenous
Notes:
Pertuzumab
Brand/Trade Names: Perjeta
Formula:
Origin: Humanized
Mechanism:
Administration: Intravenous
Notes:
Ramucirumab
Brand/Trade Names: CYRAMZA
Formula: C6374H9864N1692O1996S46
Origin: Human
Mechanism: VEGFR2 Inhibitor
Administration: Intravenous
Notes:
Siltuximab
Brand/Trade Names: Sylvant
Formula: C6450H9932N1688O2016S50
Origin: Chimeric: Mouse/Human
Mechanism: interleukin-6 (IL-6) antagonist
Administration: Intravenous
Notes:
Trastuzumab
Brand/Trade Names: Herceptin
Formula: C6470H10012N1726O2013S42
Origin: Humanized
Class:
Administration: Intravenous
Notes: Heart monitoring a must for breast cancer patients on Herceptin
Alemtuzumab
Brand/Trade Names: Campath
Formula: C6468H10066N1732O2005S40
Origin: Humanized
Class:
Administration: Intravenous
Notes:
Rituximab
Brand/Trade Names: Rituxan
Formula: C6416H9874N1688O1987S44
Origin: Chimeric (mouse/human)
Class:
Administration: Intravenous
Notes:
Cetuximab
Brand/Trade Names: Erbitux
Formula: C6484H10042N1732O2023S36
Origin: Chimeric (mouse/human)
Class: EGFR Inhibitor
Administration: Intravenous
Notes:
Alemtuzumab
Brand/Trade Names: Campath
Formula: C6468H10066N1732O2005S40
Mechanism:
Class:
Administration: Intravenous
Notes:
Bevacizumab
Brand/Trade Names: Avastin
Formula: C6538H10034N1716O2033S44
Mechanism:
Class:
Administration: Intravenous
Notes: First antiangiogenesis medicine in general use
Brentuximab vedotin
Brand/Trade Names: Adcentris
Formula: C6476H9930N1690O2030S40 (C68H105N11O15)3–5
Mechanism:
Class:
Administration: Intravenous
References
1. Ehrlich P. Collected studies on immunity. (New York: J. Wiley & Sons, 1906).
2. Old LJ. Immunotherapy for cancer. Sci Am. 1996; 275:136-143.
3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 144:646-674, 2011.
4. Cersosimo RJ. Monoclonal antibodies in the treatment of cancer, Part 1 Am J Health Syst Pharm 60:1531-1548, 2003.
5. Cersosimo RJ. Monoclonal antibodies in the treatment of cancer, Part 2 Am J Health Syst Pharm 60:1631-1641, 2003.
Today’s arsenal of chemotherapy agents includes many different class of medicines. Researchers continue to find and test new drugs Oncologists have many methods of administering medications.