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

Notes: FDA expands approval of Adcetris for first-line treatment of Stage III or IV classical Hodgkin lymphoma

 

 

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.