According to the World Health Organization (WHO), one in six deaths are cancer related. In 2020, about 10 million people died from cancer. Usually, the treatment for cancer includes surgery, radiotherapy, chemotherapy, hormonal, and in some cases, targeted biological therapies. Despite the diversity of treatments available on the market, management of their adverse effects remains challenging. Improved understanding of cancer biology has, however, contributed to the emergence of new technologies that surpass conventional treatments. One notable example is antibody-drug conjugates (ADCs), a new class of drugs that combine the ability of antibodies to target specific antigens on tumor cells with a payload of cytotoxic drugs, allowing the targeted killing of tumor cells.

Structurally, an ADC is composed of three main components: a monoclonal antibody (mAb), a connecting linker, and an antitumor cytotoxic agent, also known as the payload. The correct choice of those components and the way they interact with the tumor are vital for efficacy. Briefly, the mechanism of ADC action involves first the selective binding of the antibody with a specific antigen on tumor cells. After binding, the ADC-antigen complex is internalized, degraded by lysosomal proteases, and the cytotoxic payload is released, leading to cell death.

How the tumor cells are destroyed will depend on the cytotoxic agent used. The payloads most commonly used today are auristatins, calicheamicins, and maytansinoids:

• Auristatins promote changes in the structure of microtubules after binding to the beta subunit of tubulin dimers, leading to the uncontrolled growth of these structures.
• Calicheamicins bind to DNA and lead to double-strand breakage.
• Maytansinoids block tubulin dimers and break down the dynamic instability of microtubules.

Based on the mechanism of action, an ideal ADC must have a monoclonal antibody that is selective for the tumor antigen, and the cytotoxic agent must exert its effects only after being internalized by tumor cells; thus, the connecting linker must have the stability that allows the drug to reach the target without being degraded in the circulation.

What are the advantages and disadvantages of antibody-drug conjugates compared to conventional drug delivery therapies?

The main reason for the development of antibody-drug conjugates was centered on the need for a selective delivery system that allows cytotoxic agents to reach tumor cells without causing toxic effects to healthy cells. The ability of mAbs to specifically recognize tumoral antigens combined with the cytotoxic effects of payloads represents the main advantage of ADCs over conventional therapies. 

Early oncological treatments involved small-molecule chemotherapeutics that primarily targeted dividing cancer cells. Because they are nonspecific molecules, healthy cells were also affected, causing side effects that limited the amount of drug administered, thus reducing the therapeutic window for these drugs. With the development of ADCs, the possibility to have more specific drugs that preserve the healthy cells from toxicity effects has emerged, and an increase in the therapeutic window is expected.

However, when comparing the therapeutic windows of ADCs with conventional mAbs, the differences are still small, which shows that improvements in ADC design are necessary. The development of methodologies that allow site-specific conjugation has led to an increase in the stability of ADCs and the elimination of the heterogeneity of these molecules, improving their therapeutic window. In addition, because ADCs are specific molecules, there is the possibility of using a payload of highly toxic drugs that would generally be unsuitable for traditional chemotherapeutic treatments.

Despite the advances and benefits of ADCs for cancer treatment, some disadvantages and technical challenges are still present. Although ADCs are designed to have high specificity, the fact that tumor antigens can also be present in normal cells, even in small amounts, can still contribute to the toxicity of these molecules. Also, as the mAbs that make up the ADCs are large molecules, the internalization of these molecules by tumor cells can prove challenging. Measuring the exact amount of ADCs in patients is not a trivial process, with studies using labeled antibodies and mathematical models suggesting that a small fraction of ADCs reach the tumor, so more potent cytotoxic agents will be needed to achieve the therapeutic effect.

Even if ADC drug resistance mechanisms are described based on in vitro experiments, drug resistance is also a problem for ADCs and can lead to failure or reduced effectiveness. The mechanisms of resistance in ADCs are diverse and remain poorly understood. They consist of changes in the levels of the antigen recognized by the antibody, defects in pathways that lead to or that internalize ADCs, damage to lysosomal function, and changes in the structure and complexes of proteins responsible for the efflux of the ADCs.

Development state and clinical application of ADCs:

The possibility of using antibodies as carriers of toxic drugs was first explored by Paul Ehrlich in the early 1900s, but only by the 1980s were the first clinical studies to evaluate the effect of antibody-drug conjugates in the treatment of cancer patients initiated.

Currently, eleven antibody-drug conjugates are approved for cancer treatment, and more than 100 molecules are in preclinical and clinical studies. The first FDA-approved ADC was gentuzumab ozogamicin (Mylotarg – Wyeth/Pfizer), indicated for acute myeloid leukemia. This drug is composed of a recombinant humanized anti-CD33 mAb covalently linked to calicheamicin, a payload that breaks the DNA double-strand, leading to apoptotic cell death. Some years after its approval, the drug was withdrawn from the market because clinical studies showed high toxicity. Despite problems in 2017, the FDA reapproved its use after readjusting the dose regimen to improve the safety profile.

Several technical parameters were adjusted after the approval of the first ADC, including the modification of a cytotoxic payload by a more potent one to overcome low penetration of ADC to the tumor site, and an increase of drug-to-antibody ratio (DAR, corresponding to amount of cytotoxic payload per antibody) to enhance therapeutic activity. These modifications were applied on the second FDA-approved ADC, Adcetris (brentuximab vedotin, Seagen/Seattle Genetics), to treat Hodgkin lymphoma. The company used a more potent payload (monomethyl auristatin E) and added approximately four cytotoxic payload molecules per antibody. 

In 2019, Kadcyla (ado-trastuzumab emtansine, Genentech/Roch), the first ADC for solid tumors indicated for HER2+ breast cancer, was approved by the FDA. This ADC presented a revolution in the ADC field because the treatment of solid tumors involves several challenges due to biological barriers of the tumor microenvironment. 

In the last three years, another seven antibodies received FDA approval for cancer treatment. Four of them — Padcev (enfortumab vedotin-ejfv,  Stellas Pharma), Enhertu (fam-trastuzumab deruxtecan-nxki, Daichi Sankyou/AstraZeneca), Trodelvy (sacituzumab govitecan-hziy, Gilead), and Tivak (tisotumab vedotin-tftv, Seagen/Genmab) — are for solid tumors, while two of them — Polivy (polatuzumab vedotin-piiq, Genentech/Roche) and Zynlonta (loncastuximab tesirinelpyl, ADC Therapeutics) — are for B-cell lymphoma, and Blenrep (belantamab mafodotin-blmf, GlaxoSmithKline) is for myeloma. 

Market research shows that by 2026, the sales of ADCs reached more than US$16 billion, with Enhertu alone reaching $6.2 billion. Enhertu is an anti-HER2 antibody linked to cytotoxic payload DXd (novel exatecan derivative) that inhibits topoisomerase I, a DNA-relaxing enzyme; as a result, DNA damage and consequent cell death of tumor cells are observed. The high value generated by the sale of Enhertu stems from its applicability to several subtypes of breast cancer.

In addition to cancer treatment, academic and industry researchers have worked on the possibility of using ADCs to treat other diseases including atherosclerosis, autoimmune diseases, and bacterial infections. An example of ADCs for nononcological diseases is ABBV-3373, developed by Abbvie for rheumatoid arthritis. ABBV-3373 combines the anti-TNF-ɑ adalimumab with a dexamethasone derivative (glucocorticoid receptor modulator) to deliver an adequate amount of glucocorticoid directly to the cells of the immune system that express TNF, leading to a decrease in inflammation and side effects generated by glucocorticoids. Phase IIa clinical studies that evaluated the safety, tolerability, and efficacy of this drug confirmed its clinical efficacy.

Another example is DSTA4637S, an antibody-antibiotic conjugate (AAC) developed by Genentech to treat bacterial infections caused by Staphylococcus aureus. This AAC is composed of an anti–S. aureus thiomab human immunoglobulin G1 mAb linked to a rifamycin-class antibiotic (dmDNA31). The mechanism of action involves the internalization of the AAC by phagocytic cells, followed by cleavage of the linker by intracellular cathepsins, and release of the antibiotic, leading to bacterial death. Phase I clinical studies show that the drug is well tolerated and has a pharmacokinetic and safety profile that supports the further development for bacterial infections caused by S. aureus.

Developments underway and the future of antibody-drug conjugates:

Antibody-drug conjugates are powerful biopharmaceuticals whose use has grown rapidly in recent years due to the interest of big pharmaceutical industries and the distinct advantages over conventional therapies. After years of research, knowledge of the chemical composition and mechanisms of action of this class of therapeutics has contributed significantly to the development of ADCs. However, several challenges and technical issues must still be overcome to achieve highly potent drugs that bring broader and more significant benefits to patients. 

Although the structure of the ADCs seems apparent, a detailed optimization of each component must be carried out to create an efficient and safe drug. Strategic changes to each of the components of the ADCs are being explored by several research groups.

For example, one approach to improve specificity involves bispecific antibodies that recognize two distinct antigens in the construction of ADCs, as demonstrated using a bispecific ADC antibody that targets HER2 and prolactin receptor (PRLR). In 2017, researchers from Regeneron Pharmaceuticals conjugated PRLR and HER2 antibodies to the maytansine derivative DM1 via a noncleavable, hetero-bifunctional linker (HER2xPRLR bsADC). The data showed that HER2xPRLR bsADC was more potent in decreasing cell viability than either HER2-ADC and PRLR-ADC in breast cancer cell lines, suggesting that targeting two different antigens can improve the efficacy of ADCs.

As mAbs are large molecules, the internalization of ADCs in some tumor tissues can be limited. Thus, the replacement of conventional mAbs by small molecules, such as peptide fragments, can facilitate the internalization of cytotoxic payloads in some tumor tissues. This approach is being investigated using PEN-221, a peptide-drug conjugate constructed to target small cell lung cancer (SCLC) via the somatostatin receptor 2. Results from in vitro and in vivo studies showed that PEN-221 was able to penetrate tumor cells and inhibit the cell cycle, demonstrating that this drug can be effective in the treatment of patients with SCLC. The efficacy of PEN-221 is being evaluated in patients through phase I and II clinical trials.

Other strategies, such as targeting antigens in the tumor microenvironment and the search for new payloads, are currently under development to increase the portfolio of ADCs. Four new classes of cytotoxic payloads divided into DNA-damaging agents, apoptosis inducers, amantinis, and immunomodulatory agents are components of the ADCs under review by the FDA.

Although many challenges still lie ahead, the future of antibody-drug conjugates looks very promising. Efforts to optimize the development of these new biopharmaceuticals are moving fast and will bring many benefits in the future, especially for patients who do not respond to conventional therapies.

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