Antibody-drug conjugate

An anticancer drug is coupled to an antibody that specifically targets a certain tumor antigen (e.g. a protein that, ideally, is only to be found in or on tumor cells). Antibodies attach themselves to the antigens on the surface of cancerous cells. The biochemical reaction between the antibody and the target protein (antigen) triggers a signal in the tumor cell, which then absorbs or internalizes the antibody together with the linked cytotoxin. After the ADC is internalized, the cytotoxin kills the cancer.[5] This targeting, limits side effects and gives a wider therapeutic window than other chemotherapeutic agents.

ADC technologies have been featured in many publications,[6][7] including scientific journals.

Drugs that would target tumor cells and ignore others was conceived in 1900 by German Nobel laureate Paul Ehrlich.[1]

In 2001 Pfizer/Wyeth's drug Gemtuzumab ozogamicin (trade name: Mylotarg) was approved. However, after a request from the U.S. Food and Drug Administration (FDA), the company withdrew it in June 2010.[8] It was re-introduced into the US market in 2017.[9]

Brentuximab vedotin (trade name: Adcetris, marketed by Seattle Genetics and Millennium/Takeda)[10] was approved for relapsed HL and relapsed sALCL by the FDA on August 19, 2011 and received conditional marketing authorization from the European Medicines Agency in October 2012.

Trastuzumab emtansine (ado-trastuzumab emtansine or T-DM1, trade name: Kadcyla, marketed by Genentech and Roche) was approved in February 2013 for the treatment of people with HER2-positive metastatic breast cancer (mBC) who had received prior treatment with trastuzumab and a taxane chemotherapy.[11][12]

The European Commission approved Inotuzumab ozogamicin[13] as a monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL) on June 30, 2017 under the trade name Besponsa® (Pfizer/Wyeth),[14] followed on August 17, 2017 by the FDA.[15]

The first immunology antibody-drug conjugate (iADC), ABBV-3373, is undergoing clinical trials for participants with moderate to severe rheumatoid arthritis.[16]

In July 2018, Daiichi Sankyo Company, Limited and Glycotope GmbH have inked a pact regarding the combination of Glycotope's investigational tumor-associated TA-MUC1 antibody gatipotuzumab and Daiichi Sankyo's proprietary ADC technology for developing gatipotuzumab antibody drug conjugate.[17]

In 2019 AstraZeneca agreed to pay up to US$6.9 billion to jointly develop DS-8201 with Japan's Daiichi Sankyo. It is intended to replace Herceptin for treating breast cancer. DS8201 carries eight payloads, compared to the usual four.[1]

Eight ADCs have received market approval – all for oncotherapies.

A stable link between the antibody and cytotoxic (anti-cancer) agent is a crucial aspect of an ADC.[22] A stable ADC linker ensures that less of the cytotoxic payload falls off before reaching a tumor cell, improving safety, and limiting dosages.

Linkers are based on chemical motifs including disulfides, hydrazones or peptides (cleavable), or thioethers (noncleavable). Cleavable and noncleavable linkers were proved to be safe in preclinical and clinical trials. Brentuximab vedotin includes an enzyme-sensitive cleavable linker that delivers the antimicrotubule agent monomethyl auristatin E or MMAE, a synthetic antineoplastic agent, to human-specific CD30-positive malignant cells. MMAE inhibits cell division by blocking the polymerization of tubulin. Because of its high toxicity MMAE cannot be used as a single-agent chemotherapeutic drug. However, MMAE linked to an anti-CD30 monoclonal antibody (cAC10, a cell membrane protein of the tumor necrosis factor or TNF receptor) was stable in extracellular fluid. It is cleavable by cathepsin and safe for therapy. Trastuzumab emtansine is a combination of the microtubule-formation inhibitor mertansine (DM-1) and antibody trastuzumab that employs a stable, non-cleavable linker.

The availability of better and more stable linkers has changed the function of the chemical bond. The type of linker, cleavable or noncleavable, lends specific properties to the cytotoxic drug. For example, a non-cleavable linker keeps the drug within the cell. As a result, the entire antibody, linker and cytotoxic (anti-cancer) agent enter the targeted cancer cell where the antibody is degraded into an amino acid. The resulting complex – amino acid, linker and cytotoxic agent – is considered to be the active drug. In contrast, cleavable linkers are detached by enzymes in the cancer cell. The cytotoxic payload can then escape from the targeted cell and, in a process called "bystander killing", attack neighboring cells.[23]

Another type of cleavable linker, currently in development, adds an extra molecule between the cytotoxin and the cleavage site. This allows researchers to create ADCs with more flexibility without changing cleavage kinetics. Researchers are developing a new method of peptide cleavage based on Edman degradation, a method of sequencing amino acids in a peptide.[24] Also under development are site-specific conjugation (TDCs)[25] and novel conjugation techniques[26][27] to further improve stability and therapeutic index, α emitting immunoconjugates,[28] antibody-conjugated nanoparticles[29] and antibody-oligonucleotide conjugates.[30]