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.

Atezolizumab

Brand/Trade Names: Tecentriq

Formula: C₆₄₄₆H₉₉₀₂N₁₇₀₆O₁₉₉₈S₄₂

Origin: Humanized

Mechanism: anti-PD-L1

Administration: Intravenous

Notes: Approved by the FDA in 2016. Used to treat 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.  Used for treatment of merkel cell carcinoma, renal cell carcinoma, and urothelial carcinoma,

Belantamab

Brand/Trade Names: Blenrep

Formula: C₆₄₈₄H₁₀₀₀₈N₁₇₂₈O₂₀₃₀S₄₄

Origin: Humanized

Mechanism:

Administration: Intravenous

Notes:  Approved by the FDA in 2020. Approved for treatment of multiple myeloma.

Blinatumomab

Brand/Trade Names: Blincyto

Formula: C₂₃₆₇H₃₅₇₇N₆₄₉O₇₇₂S₁₉

Origin: Mouse

Mechanism: BiTE antibody

Administration: Intravenous

Notes:  Approved by the FDA in 2017.   Used 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.  Used to treat 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.  Used for treatment of multiple myeloma.

Dinutuximab

Brand/Trade Names: Unituxin, Isquette

Formula: C₆₄₂₂H₉₉₈₂N₁₇₂₂O₂₀₀₈S/sub>48

Origin: Chimeric: Human/Mouse

Mechanism:

Administration: Intravenous

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

Durvalumab

Brand/Trade Names: Imfinzi

Formula: C₆₅₀₂H₁₀₀₁₈N₁₇₄₂O₂₀₂₄S₄₂

Origin: Human

Mechanism: Anti-PD-L1

Administration: Intravenous

Notes:  Approved by the FDA in 2017.  Used 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.  Used 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. Used for treatment of melanoma, colorectal cancer, hepatocellular carcinoma, mesothelioma, non-small cell lung cancer, renal cell carcinoma.

Isatuximab-irfc

Brand/Trade Names: Sarclisa

Formula: C₆₄₅₆H₉₉₃₂N₁₇₀₀O₂₀₂₆S₂₄₄

Origin: Chimeric

Mechanism: CD38-directed cytolytic antibody

Administration: Intravenous

Notes:  Approved by the FDA in 2020 for treatment of multiple myeloma.

Mogamulizumab

Brand/Trade Names: Poteligeo

Formula: C₆₅₂₀H₁₀₀₇₂N₁₇₃₆O₂₀₂₀S₄₂

Origin: Humanized

Mechanism:

Administration: Intravenous

Notes:  Approved by the FDA in 2018. Used 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.  Used 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.  Used 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.  Used for treatment of melanoma, lung cancer, renal cell carcinoma, lymphoma, head and neck cancer, colon cancer, and liver cancer.

Obinutuzumab

Brand/Trade Names: Gazyva

Formula: C₆₅₁₂H₁₀₀₆₀N₁₇₁₂O₂₀₂₀S₄₄

Origin: Humanized

Mechanism:

Administration: Intravenous

Notes:  Approved by the FDA in 2013.  Used for treatment of chronic lymphocytic leukemia and follicular lymphoma.

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.  Used 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.  Used 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 tumor-agnostic drug to get approval.   Used 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, urothelial carcinoma.

Pertuzumab

Brand/Trade Names: Perjeta

Formula:

Origin: Humanized

Mechanism:

Administration: Intravenous

Notes:  Approved by the FDA in 2012.  Used for treatment of breast cancer.

Ramucirumab

Brand/Trade Names: Cyramza

Formula: C₆₃₇₄H₉₈₆₄N₁₆₉₂O₁₉₉₆S₄₆

Origin: Human

Mechanism: Angiogenesis Inhibitor

Administration: Intravenous

Notes:  Approved by the FDA in 2014.  Used for treatment of hepatocellular carcinoma, colorectal cancer, non-small cell lung cancer, 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.  Used for treatment of Castleman disease.

Tafasitamab

Brand/Trade Names: Monjuvi

Formula: C₆₅₅₀H₁₀₀₉₂N₁₇₂₄O₂₀₄₈S₅₂

Origin: Humanized from Mouse

Mechanism:

Administration: Intravenous

Notes: Approved by the FDA in 2020 for treatment of diffuse large B-cell lymphoma.

Trastuzumab

Brand/Trade Names: Herceptin

Formula: C₆₄₇₀H₁₀₀₁₂N₁₇₂₆O₂₀₁₃S₄₂

Origin: Humanized

Class:

Administration: Intravenous

Notes:  Approved by the FDA in 1998.   Used for treatment of breast cancer and stomach adenocarcinoma.

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.  Used 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.  Used for treatment of B-cell non-Hodgkin’s lymphona, chronic lymphocytic leukemia.

Cetuximab

Brand/Trade Names: Erbitux

Formula: C₆₄₈₄H₁₀₀₄₂N₁₇₃₂O₂₀₂₃S₃₆

Origin: Chimeric (mouse/human)

Class: EGFR Inhibitor

Administration: Intravenous

Notes: Approved by the FDA in 2009.  Used for treatment of colorectal cancer, non-small cell lung 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, non-small cell lung cancer, and ovarian epithelial cancer.

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.