Paul Ehrlich was the first proponent of using antibodies – the metaphor was “magic bullets” – to target tumor cells (1) and in recent decades, monoclonal antibody (MAb or MAB) drugs have found their way into cancer treatment regimens.(2) Of the 69 new cancer drugs approved by the FDA from 2015 to 2020, 16 are unconjugated monoclonal antibodies and another 5 are conjugates of an MAb and another active drug.

Monoclonal antibodies are sometimes called identical antibodies.  They differ from polyclonal antibodies which derive from multiple cell lineages.  Hybridoma technology for producing MAbs in bulk was developed in the 1970s, and drug designers began introducing MAb drugs in the 1990s.=

Why can’t the body’s own immune cells go after the malignant cells?  They do, but medical intervention can help them.  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: (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.  MAbs are very specific and most target only one receptor.  The body’s immune cells target only one receptor and most man-made drugs also target only one receptor, but some, called bispecific monoclonal antibodies, target more than one.  The bispecific antibodies can be throught of as a soluble T cell receptor fused to an immune effector molecule.

Some 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 a toxin (“conjugated”). Conjugation with a poisonous or radioactive payload is the third way MAbs can fight cancer cells.  The radiation is targeted at a microscopic level.   The specificity increases the chance of a positive outcome and while minimizing non-specific damaging exposure to radiation.  This precise targeting is what Paul Ehrlich had in mind a century ago,

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 to the inside of the cell.  Small molecule drugs have a direct impact on their targets, whereas all that unconjugated 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 to convert them.  Chimeric antibodies are not considered fully humanized.

There is always a risk of a negative reaction from the patient’s body to external MAbs.  Scientists feel that MAbs derived from human cells are the safest, while those from animal cells are the most risky.  Chimeric antibodies are safer than those of purely animal origin, while humanized MAbs are safer than chimeric ones, and human origin MAbs are the least likely to invoke an undesirable reaction.

Common Challenges of Monoclonal Antibody Usage

• Low immunogenicity of xenogeneic antibodies.  In other words, MAbs derived from non-human cells may not provoke the immune response intended.
• Infusion reactions – some patients experience a negative reaction to the medicine.  In extreme cases this can be severe anaphylaxis.
• Antigen shedding when MAbs detach from cancer cells.  They may then cause detrimental “bystander effects” in other cells.
• Unconventional vasculature in the tumor makes targeting through intravenous injection to site of tumor challenging.
• Elevated hydrostatic pressure at the tumor site.  High pressure in this region can damage the immune cells the body produces; hence even if the system works as intended and the natural immune system recognizes the cancer cells, the tumor might still not be 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.

Biosimilars for Cancer

PDF list of unconjugated Monoclonal Antibodies used in treatment of cancer:  Monoclonal Antibodies.

For a list of conjugates used to treat cancer, click here.

Amivantamab

Brand/Trade Names: Rybrevant

Formula: C₆₄₇₂H₁₀₀₁₄N₁₇₃₀O₂₀₂₃S₄₆

Origin: Human G1

Mechanism: anti-MET and anti-EGFR

Administration: Intravenous

Notes: Approved by the FDA in 2021. Used to treat small cell lung cancer. A bispecific antibody.

Atezolizumab

Brand/Trade Names: Tecentriq

Formula: C₆₄₄₆H₉₉₀₂N₁₇₀₆O₁₉₉₈S₄₂

Origin: Humanized G1

Mechanism: checkpoint inhibitor, 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 G1

Mechanism: checkpoint inhibitor, 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 G1

Mechanism: anti-BCMA

Administration: Intravenous

Notes:  First drug ever that targets BCMA (B-cell maturation antigen). Approved by the FDA in 2020. Approved for treatment of multiple myeloma.

Blinatumomab

Brand/Trade Names: Blincyto

Formula: C₂₃₆₇H₃₅₇₇N₆₄₉O₇₇₂S₁₉

Origin: Mouse G1

Mechanism:  Binds to CD19 and C3

Administration: Intravenous

Notes:  A bispecific antibody, and sometimes classified at a BiTE (Bi-specific T-cell engager). Approved by the FDA in 2014.   Used for treatment of B-cell acute lymphoblastic leukemia.

Cemiplimab-rwlc

Brand/Trade Names: Libtayo

Formula: C₆₃₈₀H₉₈₀₈N₁₆₈₈O₂₀₀₀S₄₄

Origin: Human G4

Mechanism: Checkpoint Inhibitor.  Anti-PD-1

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 G1

Mechanism: Binds toCD38

Administration: Intravenous

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

Dinutuximab

Brand/Trade Names: Unituxin, Isquette

Formula: C₆₄₂₂H₉₉₈₂N₁₇₂₂O₂₀₀₈S₄₈

Origin: Chimeric: Human/Mouse G2

Mechanism: Binds to GD2

Administration: Intravenous

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

Dostarlimab-gxly

Brand/Trade Names: Jemperli

Formula: C₆₄₂₀H₉₈₃₂N₁₆₉₀O₂₀₁₄S₄₄

Origin: Humanized G4

Mechanism: Anti PD-1

Administration: Intravenous

Notes:  Approved by the FDA in 2021. Used for treatment of endometrial cancer.

Durvalumab

Brand/Trade Names: Imfinzi

Formula: C₆₅₀₂H₁₀₀₁₈N₁₇₄₂O₂₀₂₄S₄₂

Origin: Human G1

Mechanism: checkpoint inhibitor, 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 G1

Mechanism: SLAMF7 blocker

Administration: Intravenous

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

Ipilimumab

Brand/Trade Names: Yervoy

Formula: C₆₇₄₂H₉₉₇₂N₁₇₃₂O₂₀₀₄S₄₀

Origin: Human G1

Mechanism: Checkpoint inhibitor, 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 – mouse and human G1

Mechanism:  Binds to CD38

Administration: Intravenous

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

Margetuximab

Brand/Trade Names: Margenza

Formula: C₆₄₈₄H₁₀₀₁₀N₁₇₂₆O₂₀₂₄S₄₂

Origin: Chimeric – mouse and human G1

Mechanism: Anti-HER2

Administration: Intravenous

Notes:  Approved by the FDA in 2020. Used for treatment of breast cancer.

Mogamulizumab

Brand/Trade Names: Poteligeo

Formula: C₆₅₂₀H₁₀₀₇₂N₁₇₃₆O₂₀₂₀S₄₂

Origin: Humanized G1

Mechanism: Anti-CCR4

Administration: Intravenous

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

Naxitamab

Brand/Trade Names: Danyelza

Formula: C₆₄₁₄H₉₉₁₀N₁₇₁₈O₁₉₉₆S₄₄

Origin: Humanized G1

Mechanism: Anti-G2

Administration: Intravenous

Notes:  Approved by the FDA in 2020.  Used for treatment of neuroblastoma.

Necitumumab

Brand/Trade Names: Portrazza

Formula: C₆₄₃₆H₉₉₅₈N₁₇₀₂O₂₀₂₀S₄₂

Origin: Human G1

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 G4

Mechanism: checkpoint inhibitor, anti-PD-1

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 G1

Mechanism:  Binds to CD20

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 G1

Mechanism:  Binds to CD20

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 G1

Mechanism: PDGFR-α blocker

Administration: Intravenous

Notes:  Approved by the FDA in 2016.  Withdrawn from market in 2019.  Used for treatment of soft tissue sarcoma.

Panitumumab

Brand/Trade Names: Vectibix

Formula: C₆₃₉₈H₉₈₇₈N₁₆₉₄O₂₀₁₆S₄₈

Origin: Human G2

Mechanism: Anti-EGFR

Administration: Intravenous

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

Pembrolizumab

Brand/Trade Names: Keytruda

Formula: C₆₅₃₄H₁₀₀₀₄N₁₇₁₆O₂₀₃₆S₄₆

Origin: Humanized G4

Mechanism: Checkpoint inhibitor, Anti-PD-1

Administration: Intravenous

Notes:  Approved by the FDA in 2014.  First tumor-agnostic drug to get approval.   Used for treatment of tumors that have high microsatellite instability, including cases of cervical cancer, stomach cancer, Hodgkin’s Disease, Merkel cell carcinoma, renal cell carcinoma, non-small cell lung cancer, melanoma, hepatocellular carcinoma, large B-cell lymphoma, squamous cell carcinoma, and urothelial carcinoma.

Pertuzumab

Brand/Trade Names: Perjeta

Formula:

Origin: Humanized G1

Mechanism: Anti-HER2

Administration: Intravenous

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

Ramucirumab

Brand/Trade Names: Cyramza

Formula: C₆₃₇₄H₉₈₆₄N₁₆₉₂O₁₉₉₆S₄₆

Origin: Human G1

Mechanism: Angiogenesis Inhibitor, anti-VEGFR2

Administration: Intravenous

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

Relatlimab

Brand/Trade Names: Opdualag (when combined with nivolumab)

Formula: C₆₄₇₂H₉₉₂₂N₁₇₁₀O₂₀₂₄S₃₈

Origin: Human G1

Mechanism: LAG-3 Inhibitor

Administration: Intravenous

Notes:  Approved as part of a combination therapy with nivolumab by the FDA in 2022  Used for treatment of prostate cancer.

Siltuximab

Brand/Trade Names: Sylvant

Formula: C₆₄₅₀H₉₉₃₂N₁₆₈₈O₂₀₁₆S₅₀

Origin: Chimeric: Mouse/Human G1

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 G1

Mechanism: Binds to CD19

Administration: Intravenous

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

Tebentafusp-tebn

Brand/Trade Names: Kimmtrak

Formula:

Origin:

Mechanism: Binds to CD3

Administration: Intravenous

Notes: Approved by the FDA in 2022 for treatment of uveal melanoma First approved therapy that uses T cell receptor (TCR) technology. A bispecific MAb.  First bispecific immunotherapy to treat a solid tumor.

Teclistamab-cqyv

Brand/Trade Names: Tecvayli

Formula:

Origin:

Mechanism:

Administration: Intravenous

Notes: Approved by the FDA in 2022 for treatment of multiple myeloma.

Trastuzumab

Brand/Trade Names: Herceptin

Formula: C₆₄₇₀H₁₀₀₁₂N₁₇₂₆O₂₀₁₃S₄₂

Origin: Humanized G1

Mechanism: Anti-HER2

Administration: Intravenous

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

Tremelimumab

Brand/Trade Names: Imjudo

Formula: C₆₅₀₀H₉₉₇₄N₁₇₂₆O₂₀₂₆S₅₂

Origin:

Mechanism:

Administration: Intravenous

Notes:  Approved by the FDA in 2022 for treatment of liver cancer.

Alemtuzumab

Brand/Trade Names: Campath

Formula: C₆₄₆₈H₁₀₀₆₆N₁₇₃₂O₂₀₀₅S₄₀

Origin: Humanized G1

Mechanism: Anti-CD52

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) G4

Mechanism:  Binds to CD20

Administration: Intravenous

Notes: Approved by the FDA in 1997.  Used for treatment of B-cell non-Hodgkin’s lymphoma, chronic lymphocytic leukemia.

Cetuximab

Brand/Trade Names: Erbitux

Formula: C₆₄₈₄H₁₀₀₄₂N₁₇₃₂O₂₀₂₃S₃₆

Origin: Chimeric (mouse/human) G1

Mechanism: 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) G1

Mechanism: Angiogenesis inhibitor.  Anti-VEGF

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.

A note on MAb targets.

Who makes these drugs?

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.