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) Of the 43 new cancer drugs approved by the FDA from 2015 to 2018, 11 are monoclonal antibodies.

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 (MAbs), 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: (1) by activating the body’s immune system, (2) by attaching to biochemical receptors on the external walls of malignant cells, and thereby stopping the receptors from interacting with signaling molecules, or (3) by bringing radioactive materials or toxins to the inside of the cancer cells by attaching to cellular receptors.

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.

Differences between Humanized and Chimeric Antibodies

Humanized antibodies derive from animals (non-human) but they have been changed to make them more amenable to human therapy.

Scientists at biotech companies often work with animal cell lines, especially murine (mouse) cells.  The antibodies developed then are different in some ways from the antibodies that would arise from human cells and antibodies produced in the immune system of a human.  To make the antibody effective and safe for therapeutic use in human patients, the murine antibody is modified, humanized.

Some antibodies in use are chimeric.  Chimera in biology refers to proteins or constructs that derive from a fusion of parts from different origins.  Chimeric antibodies are made from antibody sections that come from two different species. (In ancient mythology a chimera was a creature with parts from more than one animal.)  Many mouse-human chimeric antibodies are used in cancer therapy.

Sometimes chimeric antibodies are made on the way to constructing a humanized antibody; there is further modification of the proteins.  Most chimeric antibodies are not considered fully humanized.

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) is used for the treatment of acute myelogenous leukemia.

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:  Approved by the FDA in 2016.  Approved for small cell lung cancer, urothelial carcinoma, breast cancer, non-small cell lung cancer

Avelumab

Brand/Trade Names: Bavencio

Formula: C6374H9898N1694O2010S44

Origin: Human

Mechanism: anti-PD-L1

Administration: Intravenous

Notes:  Approved by the FDA in 2017.   Approved for treatment of merkel cell carcinoma, renal cell carcinoma, and urothelial carcinoma,

Blinatumomab

Brand/Trade Names: Blincyto

Formula: C2367H3577N649O772S19

Origin: Mouse

Mechanism: BiTE antibody

Administration: Intravenous

Notes:  Approved by the FDA in 2017.   Approved for treatment of B-cell acute lymphoblastic leukemia.

Cemiplimab-rwlc

Brand/Trade Names: Libtayo

Formula: C6380H9808N1688O2000S44

Origin: Human

Mechanism: Checkpoint Inhibitor

Administration: Intravenous

Notes:  Approved by the FDA in 2018. Approved for treatment of cutaneous squamous cell carcinoma.

Daratumumab

Brand/Trade Names: Darzalex

Formula: C6466H9996N1724O2010S42

Origin: Human

Mechanism: Binds to CD38

Administration: Intravenous

Notes:  Approved by the FDA in 2015 for treatment of multiple myeloma.  Sales in 2015 were only $20 million, but industry analysts expect big things from this medicine.

Dinutuximab

Brand/Trade Names: Unituxin, Isquette

Formula: C6422H9982N1722O2008S/sub>48

Origin: Chimeric: Human/Mouse

Mechanism:

Administration: Intravenous

Notes:  Approved by the FDA in 2015.  Approved for treatment of neuroblastoma.

Durvalumab

Brand/Trade Names: Imfinzi

Formula: C6502H10018N1742O2024S42

Origin: Human

Mechanism: Anti-PD-L1

Administration: Intraveneous

Notes:  Approved by the FDA in 2017.  Approved for treatment of non-small cell lung cancer and urothelial carcinoma .

Elotuzumab

Brand/Trade Names: Empliciti

Formula: C6476H9982N1714O2016S42

Origin: Humanized

Mechanism: SLAMF7 blocker

Administration: Intravenous

Notes:  Approved by the FDA in 2015 for treatment of multiple myeloma.

Ibritumomab

Brand/Trade Names: Zevalin

Formula:

Origin: Mouse

Mechanism:

Administration: Intravenous

Notes: linked with radioactive Yttrium-90.  First approved by the FDA in 2002 for B-cell non-Hodgkin’s lymphoma.

Ipilimumab

Brand/Trade Names: Yervoy

Formula: C6742H9972N1732O2004S40

Origin: Human

Mechanism: CTLA-4 blocker

Administration: Intravenous

Notes:  Approved by the FDA in 2011.  Approved for treatment of benal cell carcinoma, melanoma. and colorectal cancer.

Mogamulizumab

Brand/Trade Names: Poteligeo

Formula: C6520H10072N1736O2020S42

Origin: Humanized

Mechanism:

Administration: Intravenous

Notes:  Approved by the FDA in 2018 for treatment of cutaneous T-cell lymphoma.

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.  Approved for treatment of hairy cell leukemia.

Necitumumab

Brand/Trade Names: Portrazza

Formula: C6436H9958N1702O2020S42

Origin: Human

Mechanism: EGFR inhibitor

Administration: Intravenous

Notes:  Approved by the FDA in 2015.  Approved for treatment of squamous non-small cell lung cancer.

Nivolumab

Brand/Trade Names: Opdivo

Formula: C6362H9862N1712O1995S42

Origin: Human

Mechanism: PD-1 blocking antibody

Administration: Intravenous

Notes:  Approved by the FDA in 2014.  Approved for treatment of Hodgkin’s lymphoma, colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer, small cell lung cancer, renal cell carcinoma, melanoma, squamous cell carcinoma of the head and neck, and urothelial carcinoma.  Sales of $1.12 bullion in 2015.

Obinutuzumab

Brand/Trade Names: Gazyva

Formula: C6512H10060N1712O2020S44

Origin: Humanized

Mechanism:

Administration: Intravenous

Notes:  Approved by the FDA in 2013.  Approved for treatment of chronic lymphocytic leukemia and follicular lymphoma.   Sales of $130 million in 2015.

Ofatumumab

Brand/Trade Names: Arzerra

Formula: C6480H10022N1742O2020S44

Origin: Human

Mechanism:

Administration: Intravenous

Notes: Approved by the FDA in 2014.  Used for chronic lymphocytic leukemia.  More about ofatumumab.

Olaratumab

Brand/Trade Names: Lartruvo

Formula: C6554H10076N1736O2048S40

Origin: Human

Mechanism: PDGFR-α blocker

Administration: Intravenous

Notes:  Approved by the FDA in 2016.  Approved for treatment of soft tissue sarcoma.

Panitumumab

Brand/Trade Names: Vectibix

Formula: C6398H9878N1694O2016S48

Origin: Human

Mechanism: EGFR Inhibitor

Administration: Intravenous

Notes:  Approved by the FDA in 2006.  Approved for treatment of colorectal cancer.

Pembrolizumab

Brand/Trade Names: Keytruda

Formula: C6534H10004N1716O2036S46

Origin: Humanized

Mechanism:

Administration: Intravenous

Notes:  Approved by the FDA in 2017.  First cancer drug to get approval that attacks malignant cells based on their genetics rather than organ.  More on this idea.  Approved for treatment of cervical cancer, stomach cancer, Hodgkin’s Disease, merkel cell carcinoma, renal cell carcinoma, non-small cell lung cancer, microsatellite instability-high cancer, melanoma, hepatocellular carcinoma, large B-cell lymphoma, squamous cell carcinoma, and urothelial carcinoma.

Pertuzumab

Brand/Trade Names: Perjeta

Formula:

Origin: Humanized

Mechanism:

Administration: Intravenous

Notes:  Approved by the FDA in 2012.  Approved for treatment of breast cancer.  Sales of $1.5 billion in 2015.

Ramucirumab

Brand/Trade Names: CYRAMZA

Formula: C6374H9864N1692O1996S46

Origin: Human

Mechanism: Angiogenesis Inhibitor

Administration: Intravenous

Notes:  Approved by the FDA in 2014.  Approved for treatment of hepatocellular carcinoma, colorectal cancer, non-small cell lung cancer,  and stomach adenocarcinoma .

Siltuximab

Brand/Trade Names: Sylvant

Formula: C6450H9932N1688O2016S50

Origin: Chimeric: Mouse/Human

Mechanism: interleukin-6 (IL-6) antagonist

Administration: Intravenous

Notes:  Approved by the FDA in 2014.

Trastuzumab

Brand/Trade Names: Herceptin

Formula: C6470H10012N1726O2013S42

Origin: Humanized

Class:

Administration: Intravenous

Notes:  First approved by the FDA in 1998.Heart monitoring a must for breast cancer patients on Herceptin Approved for treatment of breast cancer and stomach adenocarcinoma .  Sales of $6.79 billion in 2015.

Alemtuzumab

Brand/Trade Names: Campath

Formula: C6468H10066N1732O2005S40

Origin: Humanized

Class:

Administration: Intravenous

Notes: Also used to treat multiple sclerosis.  Approved by the FDA in 2014.  Approved for treatment of B-cell chronic lymphocytic leukemia.

Rituximab

Brand/Trade Names: Rituxan

Formula: C6416H9874N1688O1987S44

Origin: Chimeric (mouse/human)

Class:

Administration: Intravenous

Notes: Approved by the FDA in 1997.  Biggest-selling (in dollar terms) chemotherapy drug today.   Approved for treatment of B-cell non-Hodgkin’s lymphona and chronic lymphocytic leukemia.  Sales of $7.39 bullion in 2015.

Cetuximab

Brand/Trade Names: Erbitux

Formula: C6484H10042N1732O2023S36

Origin: Chimeric (mouse/human)

Class: EGFR Inhibitor

Administration: Intravenous

Notes: Approved by the FDA in 2009.  Approved for treatment of colorectal cancer and squamous cell carcinoma of the head and neck.

Bevacizumab

Brand/Trade Names: Avastin

Formula: C6538H10034N1716O2033S44

Origin: Humanized (from mouse)

Mechanism: Angiogenesis inhibitor

Class:

Administration: Intravenous

Notes: Approved by the FDA in 2004. First antiangiogenesis medicine in general use.  Approved for treatment of colorectal cancer, renal cell carcinoma, cervical cancer, glioblastoma, nonsquamous non-small cell lung cancer, and ovarian epithelial cancer.  At one time the leading medicine in the US in terms of sales at the retail level.  2015 sales were $6.95 billion.

Brentuximab vedotin

Brand/Trade Names: Adcentris

Formula: C6476H9930N1690O2030S40

Origin: Chimeric (mouse/human)

Mechanism:

Class:

Administration: Intravenous

Notes: First approved by the FDA in 2011.   Approved for treatment of peripheral T-cell lymphoma, cutaneous T-cell lymphoma, cutaneous anaplastic large cell lymphoma, Hodgkin’s Disease, anaplastic large cell 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.