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 purpose is to utilize the specificity provided by monoclonal antibodies to achieve targeted delivery of the drug to cancer cells. Since the approval in 2000 of Pfizer’s Mylotarg™, the first ADC approved for therapeutic use, there has been an interest in these novel medicines. [1, 2, 7] Currently, there are four approved ADCs available for cancer treatment. [3] With a projected 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.

How do ADCs Work?

ADCs have been compared to target-bound missile systems to which a drug payload has been attached. [4] Just as in its response to microorganisms and other triggers of immune response, the body 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

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 the 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. However, their use is limited by their high cost.

Commercially Available ADCs

There are currently four (4) ADCs approved for treating cancer patients, while nearly 200 ADCs are being developed or in different phases of clinical trials. [7]

Gemtuzumab

Brand/Trade Names: Mylotarg, Gemtuzumab Ozogamicin

Formula:

Mechanism:

Class: Monoclonal Antibody

Administration: Intraveneous

Notes: Mylotarg™ is 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 clinical trials which demonstrated no improvement in overall survival rates in patients undergoing therapy with Mylotarg™. However, following a recent improvement in many clinical trials, Mylotarg™ has been re-approved both in the United States and in the European Union. [7]

Brentuximab

Brand/Trade Names: Adcetris, Brentuximab vedotin

Formula: C6476H9930N1690O2030S40 (C68H105N11O15)3–5

Mechanism:

Class: Monoclonal Antibody

Administration: Intraveneous

Notes: Brentuximab vedotin was developed by Seattle Genetics in 2011 and was intended for patients with refractory or relapsed CD 30 positive Hodgkin lymphoma.[1, 7] It has also been approved for patients with Anaplastic Large Cell Lymphoma as a second line treatment.

Trastuzumab

Brand/Trade Names: Kadcyla, Trastuzumab emtansine

Formula: C6448H9948N1720O2012S44·(C47H62ClN4O13S)n

Mechanism:

Class: Monoclonal Antibody

Administration: Intraveneous

Notes: Ado-Trastuzumab emtansine was developed by Roche and Genentech. Approved in 2013, Kadcyla™ was the first ADC ever approved by the FDA for the treatment of a solid tumor. Its use is for HER2 positive metastatic breast cancer. [1, 7]

Inotuzumab

Brand/Trade Names: Besponsa, Inotuzumab ozogamicin

Formula: C6518H10002N1738O2036S42

Mechanism:

Class: Monoclonal Antibody

Administration: Intraveneous

Notes: Produced and marketed by Pfizer, this drug was approved by FDA in August 2017 for the treatment of adults with relapsed or refractory B-cell precursor Acute Lymphoblastic Leukemia. [1, 7, 8]

References