Antibody-Drug Conjugates

Antibody Drug Conjugates (ADCs) have emerged as a novel and effective modality in cancer therapeutics. ADCs are Monoclonal Antibodies (mAbs) to which cancer drugs are chemically attached.[1] The idea is to take advantage of the specificity provided by monoclonal antibodies to achieve targeted delivery of the drug to cancer cells.  ADCs have been used at the lab level for decades, but some are now entering clinical use.  Increasingly, these drugs herald a new modus operandi in the management of patients with cancer.

Pfizer’s Mylotarg™ (gemtuzumab ozogamicin) was the first ADC approved for therapeutic use in 2000; it was later pulled from the market but reapproved in 2017. [1, 2, 7]  It was designed for the treatment of CD33 positive Acute Myeloid Leukemia (AML). The voluntary withdrawal followed confirmatory (Phase IV) clinical trials which demonstrated no improvement in overall survival rates in patients undergoing therapy with gemtuzumab. However, when more data cane in and showed benefits, the FDA again approved gemtuzumab.  The European Medicines Agency has also approved us of this drug. [7]

How do ADCs Work?

ADCs have been compared to target-bound missile systems to which a drug payload has been attached. [4] Indeed, they are sometimes called armed antibodies or empowered antibodies.  The human immune system creates antibodies in response to microorganisms and other triggers, the body recognizes cancer cells ‘s immune system produces unique antibodies against cancer cells and the biochemical mediators they synthesize. These antibodies coat the surfaces of the cancer cells where they initiate complex cascades of reactions to kill the cancer cells [1] The concept of ADC rests on the fact that the specificity offered by monoclonal antibodies can be utilized to deliver payloads of cytotoxic cancer drugs mainly to the cancer cells. Once the ADC is inside the cancer cells, the cytotoxic drug payloads are cleaved off or released and subsequently exert their cell-killing effects. [1, 4]

Therapeutic Advantages of ADCs

ADCs are truly targeted. Conventional cancer drugs produce a wide arrays of side effects. This is because conventional chemotherapy agents kill rapidly proliferating cells, irrespective of whether the cells are malignant or healthy. Adverse effects such as neutropenia, anemia, and thrombocytopenia result from damage to the bone marrow. The effect on follicular cells in the scalp results in hair loss. The major difference between ADCs and conventional cancer drugs is specificity. [5, 6, 7] Unlike conventional cancer drugs, ADCs target only the cancer cells. The monoclonal antibodies bind specifically to the malignant cells. Since only the malignant cells are targeted, ADCs produce fewer side effects compared to conventional drugs.  The dose per cancer cell can be high because there is less worry about side effects.

ADCs available for cancer treatment

PDF List of Conjugates.

Polatuzumab vedotin

Brand/Trade Names: Polivy

Formula: C6670H10317N1745O2087S40

Antibody Origin: Humanized G1

Mechanism: Binds to CD30

Toxin: Auristatin, a microtubule destabilizer also called vedotin.

Administration: Intravenous

Notes: Approved by the FDA in 2019.  Used for treatment of large B-cell lymphoma.

Enfortumab vedotin-ejfv

Brand/Trade Names: Padcev

Formula:

Antibody Origin: Human G1

Mechanism: anti-Nectin-4

Toxin: Auristatin, a microtubule destabilizer

Administration: Intravenous

Notes: Approved by the FDA in 2019.  Used for treatment of bladder cancer (urothelial cancer).

Fam-trastuzumab deruxtecan-nxki

Brand/Trade Names: Enhertu

Formula:

Antibody Origin: Humanized

Mechanism: anti-HER2

Toxin: topoisomerase I inhibitor

Administration: Intravenous

Notes: Approved by the FDA in 2019.  Used for treatment of breast cancer.

Gemtuzumab ozogamicin

Brand/Trade Names: Mylotarg, Gemtuzumab Ozogamicin

Formula:

Antibody Origin: Humanized G4

Mechanism: Binds to C33

Toxin: calicheamicin (antibiotic)

Administration: Intravenous

Notes:  Approved by FDA in 2017.  Used for treatment of acute myeloid leukemia.

Brentuximab vedotin

Brand/Trade Names: Adcetris

Formula: C6476H9930N1690O2030S40 (C68H105N11O15)3–5

Antibody Origin: Chimera (human/mouse) G1

Mechanism: Binds to CD30

Administration: Intravenous

Notes: 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.

Tisotumab vedotin-tftv

Brand/Trade Names: Tivdak

Formula:

Origin: Human

Mechanism: Binds to CD142

Toxin: Auristatin, a microtubule destabilizer

Administration: Intravenous

Notes: Approved by the FDA in 2021 for treatment of cervical cancer.  First approved drug that targets tissue factor.

Ado-Trastuzumab emtansine

Brand/Trade Names: Kadcyla, Ado-Trastuzumab emtansine

Formula: C6448H9948N1720O2012S44·(C47H62ClN4O13S)n

Antibody Origin: Humanized G1

Mechanism: anti-HER2

Toxin:   Mertansine, a microtubule inhibitor also called DM1.

Administration: Intravenous

Notes: Approved by the FDA in 2019. First ADC ever approved by the FDA for the treatment of a solid tumor. Used for treatment of HER2 positive metastatic breast cancer. [1, 7]

Inotuzumab ozogamicin

Brand/Trade Names: Besponsa

Formula: C6518H10002N1738O2036S42

Antibody Origin: Humanized G4

Mechanism: Binds to CD22

Toxin: calicheamicin derivative, N-acetyl-gamma-calicheamicin dimethylhydrazide

Administration: Intravenous

Notes: Approved by FDA in August 2017.  Used for the treatment B-cell non-Hodgkin lymphoma.

Denileukin diftitox

Brand/Trade Names: Ontak

Formula: C2560H4042N678O799S17

Antibody Origin: N/A

Mechanism: Binds to CD22.

Toxin: Diphtheria toxin (DT388)

Administration: Intravenous

Notes:  Approved by the FDA in 1999.  Used for treatment of leukemia and lymphoma.  No longer marketed in the US.

Tagraxofusp-erzs

Brand/Trade Names: Elzonris

Formula:

Antibody Origin: N/A

Mechanism: Binds to CD123/interleukin 3 (IL-3) receptor α (IL-3Rα)

Toxin: Diphheria toxin (DT388)

Administration: Intravenous

Notes: Interleukin 3 (IL-3) fused to diphtheria toxin.  Approved by the FDA in 2018.  Used for treatment of blastic plasmacytoid dendritic cell neoplasm.

Sacituzumab govitecan-hziy

Brand/Trade Names: Trodelvy

Formula: C76H104N12O24S

Antibody Origin: Humanized G1

Mechanism: anti-TROP-2

Toxin: topoisomerase 1 inhibitor SN38

Administration: Intravenous

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

Moxetumomab pasudotox-tdfk

Brand/Trade Names: Lumoxiti

Formula: C2804H4339N783O870S14

Origin: Mouse G1

Mechanism: Anti-CD22

Toxin: PE38 (fragment of Pseudomonas exotoxin A)

Administration: Intravenous

Notes: Approved in Sept 2018 under FDA fast-track designation. Orphan drug status.  Used for treatment of hairy cell leukemia.

Loncastuximab tesirine

Brand/Trade Names: Zynlonta

Formula: C6544H10048N1718O2064S52

Origin: Humanized G1

Mechanism: Anti-CD19

Toxin: pyrrolobenzodiazepine dimer

Administration: Intravenous

Notes: Approved in 2021 for treatment of lymphoma.

Conjugates for Radioimmunotherapy

Radioimmunotherapy for cancer involves use of an antibody connected with a radionuclide.  The antibody has a specificity for the tumor cells. This strategy delivers a radioactive atom to the malignant cell, where it is hoped the radiation will kill the cell.  The atoms used emit Beta radiation, which can kill a cell at close range, but it not as destructive to the tissue as Gama radiation.  These combinations are sometimes called radioconjugates.

Like other medical treatment, radioimmunotherapy exploits something that is different about the diseased tissues, in this case malignant cells.  When the tumor cells express an antigen that healthy cells do not, there is an opportunity for an immunotherapy approach.

Three radioimmunotherapy conjugates were approved, and two are still on the market.

Bexxar was a conjugate of tositumomab and Iodine-131.  It was approved by the FDA in 2003 and withdrawn in 2014.  Zevalin is a conjugate of Ibritumomab and Yttrium-90.  The newest radioummunotherapy conjugate, Lutathera, is a conjugate of Lutetium-77 and dotatate.  It was approved by the FDA in 2018.

Ibritumomab tiuxetan

Brand/Trade Names: Zevalin

Formula:

Antibody Origin: Mouse G1

Mechanism: Binds to CD20

Toxin: radioactive Yttrium-90 or Indium-111

Administration: Intravenous

Notes:   Approved by the FDA in 2002.  Used for treatment of B-cell non-Hodgkin’s lymphoma.  Indium-111 (111In) has a half-life of 2.8 days, while Yttrium-90 (90Y) has a half-life of 2.7 days.

Lutetium Lu 177 Dotatate

Brand/Trade Names: Lutathera

Formula: C85H90N14O19S2

Antibody Origin: N/A

Mechanism: Binds to Somatostatin receptors

Toxin: radioactive Lutetium-177, aka 177Lu

Administration: Intravenous

Notes:  Approved by the FDA in 2018.  Used for treatment of gastroenteropancreatic neuroendocrine tumors.  Investigated for treatment of hepatocellular carcinoma.

Tositumomab

Brand/Trade Names: Bexxar

Formula: C6416H9874N1688O1987S44

Antibody Origin: Mouse

Mechanism: Binds to CD22

Toxin: I-131 radioactive isotope, aka 131I

Administration: Intravenous

Notes: Approved by the FDA in 2003.  Later withdrawn from market and no longer used.  Used to treat lymphoma.  I-131 has a half-life of 8 days and emits Beta radiation.

Common Conjugates

Vedotin is Monomethyl auristatin E (MMAE) – C39H67N5O7.  This works in M-phase of the cell cycle and stops division.

The calicheamicins are antibiotics from nature.  One is ozogamicin.

Emtansine is Mertansine (aka DM1).  Mertansine is a tubulin inhibitor, meaning that it also works in the M-phase and inhibits the division of the cell nucleus.

References

  1. H.L. Perez, et al., Antibody-drug conjugates: current status and future directions, Drug Discov Today (2013), http://dx.doi.org/10.1016/j.drudis.2013.11.004
  2. FDA Approval For Gemtuzumab Ozogamicin: Reintroduction Based on Favorable Risk, ADC Reviews (September 2017), https://adcreview.com/news/fda-approval-gemtuzumab-ozogamicin-reintroduction-based-favorable-riskbenefit-profile/
  3. Antibody-Drug Conjugates: Technologies and Global Markets, ( June 2017), https://www.reportlinker.com/p02042686/Antibody-Drug-Conjugates-Technologies-and-Global-Markets.html#utm_source=prnewswire
  4. Ojima Iwao, Guided Molecular Missiles for Tumor-Targeting Chemotherapy—Case Studies Using the Second-Generation Taxoids as Warheads, (2008), https://pubs.acs.org/doi/abs/10.1021/ar700093f
  5. Reichert J.M., Dhimolea E. The future of antibodies as cancer drugs. Drug. Discov. Today. 2012;17:954–963. Doi :10.1016/j.drudis.2012.04.006 https://www.researchgate.net/publication/224914425_The_future_of_antibodies_as_cancer_drugs
  6. Schrama D., Reisfeld R.A., Becker J.C. Antibody targeted drugs as cancer therapeutics. Nat. Rev. Drug Discov.,(2006) https://www.ncbi.nlm.nih.gov/pubmed/16424916
  7. What are Antibody-Drug Conjugates? ADC Reviews (2017), https://adcreview.com/adc-university/adcs-101/antibody-drug-conjugates-adcs/
  8. Mukherjee Sy, The FDA Just Approved a New Pfizer Cancer Drug for a rare, Vicious Leukemia, Fortune (2017), http://fortune.com/2017/08/18/fda-leukemia-pfizer-besponsa