Antibody-Drug Conjugates

The use of Antibody Drug Conjugates (ADCs) has emerged as a novel and effective modality in cancer therapeutics. ADCs are Monoclonal Antibodies (mAbs) to which cancer drugs are attached with the help of biochemical linkers.[1] The idea is to take advantage of the specificity provided by monoclonal antibodies to achieve targeted delivery of the drug to cancer cells. Pfizer’s Mylotarg™ (gemtuzumab ozogamicin) was the first ADC approved for therapeutic use in 2001; it was later pulled from the market but reapproved in 2017. [1, 2, 7] Currently, there are four approved ADCs available for cancer treatment. [3] With sales projected at a compound annual growth rate of 25.5%, the global market for ADCs is expected to pass $4.2 billion by 2021.[3] Increasingly, these drugs herald a new modus operandi in the management of patients with cancer.

ADCs have been around at the lab level for decades, but some are now entering clinical use.

Gemtuzumab was the first ADC to be approved by US Food and Drug Administration (FDA). [1, 3, 7] It was designed for the treatment of CD33 positive Acute Myeloid Leukemia (AML). First approved in 2000, it was later withdrawn by its manufacturer, Pfizer. 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 in 2017.  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. Just as in its response to microorganisms and other triggers, the body’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 damages to the rapidly dividing cells of the bone marrow. The effect on follicular cells in the scalp results in hair loss, which is possibly the commonest sign a patient is undergoing chemotherapy. The major difference between ADCs and conventional cancer drugs is specificity. [5, 6, 7] Unlike conventional cancer drugs, ADCs target only the cancer cells. This is made possible with the help of monoclonal antibodies that bind specifically to the malignant cells. Since only the malignant cells are targeted, ADCs produce reduced side effects compared to other cancer drugs. Because of this and other benefits, ADCs are generating excitement as a better modality in cancer therapeutics.

Commercially Available ADCs

Nearly 200 ADCs are being developed. [7]

Polatuzumab vedotin

Brand/Trade Names: Polivy

Formula: C6670H10317N1745O2087S40

Mechanism:

Class: Conjugate

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:

Mechanism:

Class: Conjugate

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:

Mechanism:

Class: Conjugate

Administration: Intravenous

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

Gemtuzumab ozogamicin

Brand/Trade Names: Mylotarg, Gemtuzumab Ozogamicin

Formula:

Mechanism:

Class: Conjugate

Administration: Intravenous

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

Brentuximab

Brand/Trade Names: Adcetris, Brentuximab vedotin

Formula: C6476H9930N1690O2030S40 (C68H105N11O15)3–5

Mechanism:

Class: Conjugate

Administration: Intravenous

Notes: Approved by the FDA in 2011.   Used for treatment of Hodgkin’s disease and anaplastic large cell lymphoma.

Trastuzumab emtansine

Brand/Trade Names: Kadcyla, Ado-Trastuzumab emtansine

Formula: C6448H9948N1720O2012S44·(C47H62ClN4O13S)n

Mechanism: An anti-HER2 monoclonal antibody combined with a microtubular inhibitor.

Class: Conjugate

Administration: Intravenous

Notes: Approved by the FDA in 2013. 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

Brand/Trade Names: Besponsa, Inotuzumab ozogamicin

Formula: C6518H10002N1738O2036S42

Mechanism:

Class: Conjugate

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

Mechanism: Diphtheria toxin plus Interleukin-2

Class: Conjugate

Administration: Intravenous

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

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.  These are sometimes called radioconjugates.

Like other medical treatment, RIT 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.  Lutathera is a conjugate of Lutetium-77 and dotatate.  It was approved by the FDA in 2018.

Ibritumomab

Brand/Trade Names: Zevalin

Formula:

Origin: Mouse

Mechanism: Linked with radioactive Yttrium-90.

Administration: Intravenous

Notes:   Approved by the FDA in 2002.  Used for treatment of B-cell non-Hodgkin’s lymphoma.

Lutetium Lu 177 Dotatate

Brand/Trade Names: Lutathera

Formula: C85H90N14O19S2

Mechanism: Linked with radioactive Lutetium-77.

Class: radioconjugate

Administration: Intravenous

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

Tositumomab

Brand/Trade Names: Bexxar

Formula: C6416H9874N1688O1987S44

Origin: Mouse

Class:

Administration: Intravenous

Notes: Approved by the FDA in 2003.  Later withdrawn from market and no longer used.  Used to treat lymphoma.

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/