November 8, 2022
What are Antibody-Drug Conjugates (ADCs)?
Antibody-Drug Conjugates (ADCs) are a rather novel class of biopharmaceutical agents with a very high potential to elicit a lasting change in the medical and pharmaceutical landscape. This is reflected by the number of candidates in various preclinical development stages and clinical trials, which is in the hundreds.1
ADCs combine the properties of highly specific monoclonal antibodies (mAbs) and very potent small molecule pharmaceutical agents. Presently, the largest part of ADCs are anticancer drugs that aim to specifically deliver cytotoxic (cell killing) drugs to cancerous cells, thus reducing off-site toxicity, enhancing the therapeutic index and increasing tolerability.
Antibody-Drug Conjugates come with special requirements within their manufacturing process, such as on the controlled freezing of ADCs, but also concerning safety aspects. This article will give you an overview of applications of Antibody-Drug Conjugates, how they work and how they are built up.
Antibody-Drug Conjugates – current and future applications
Each of the eleven Antibody-Drug Conjugates that have already been granted FDA approval is used as a cancer treatment: ado-Trastuzumab emtansine (Kadcyla ®), trastuzumab deruxtecan, sacituzumab govitecan, inotuzumab ozogamicin, enfortumab vedotin, brentuximab vedotin (Adcetris ®), Gemtuzumab ozogamicin (Mylotarg ®).
The diseases which they treat are malignancies such as HER2-positive metastatic breast cancer, refractory or relapsed diffuse large B-cell lymphoma, hodgkin lymphoma, acute myeloid leukemia among others.
There are very promising ongoing efforts to optimize future ADC use in cancer therapy as novel multi-drug combination immunotherapy regimens, as is shown in in vitro as well as in vivo trials. Moreover, new ADCs are developed to expand into other medical fields, such as autoimmune diseases.
In addition to the pharmacological side, key players working with ADCs face challenges regarding process safety during the demanding synthesis and handling of ADC preparations. Innovative companies like Single Use Support offer solutions in the field of fluid management to push future ADC development forward.
ADCs: mechanism of action
The key to ADCs outstanding pharmacology is that they are targeted therapies, sparing healthy cells: the ADC molecule acts as a receptor specific to antigens on the tumor cell surface. Selective binding of the ADC to the membranes of target cells is followed by internalization into the cell, where the cytotoxic drug is released site-specifically and effects apoptosis i.e. cell death. This two-pronged approach is intricately tied to the components and structural properties of ADCs.
Structural properties of Antibody-Drug Conjugates
The aforementioned two-pronged mechanism of action relies on three constituents: a linker that attaches the two active components to each other and is selectively cleaved when the ADC arrives in the tumor, leading to intricate possibilities to modulate pharmacokinetics.2
Currently, linkers are designed to be cleaved by lysosomal enzymes in the lysosome of cancer cells, e.g . cathepsin cleavable peptide linkers, or non-cleavable linkers based on disulfide derivatives that release the cytotoxic agent when the mAb component is digested.
Monoclonal antibodies confer the outstanding specificity to ADCs. Nowadays, mAbs can be designed to have fine-tuned specificity to increase drug delivery into solid tumors and exhibit low immunogenicity. Additionally, they are large enough to carry big payloads (high drug antibody ratio – DAR) of linked small molecule cytotoxins without losing their activity. Their biodegradability in lysosomes allow the use of non-cleavable linkers to modulate off-site activity.
The cytotoxic payload of ADCs is generally from one of the following drug classes:
- Microtubule inhibitors (tubulin polymerization inhibition): e. g. monomethyl auristatin E (MMAE)
- DNA alkylating agents: duocarmycin derivatives, leading to DNA destruction
- DNA binders: enediyne derivatives such as calicheamicin, effecting DNA destruction
- Topoisomerase inhibitors: antitumor activity via DNA destruction
These compounds share the characterization as being extremely poisonous and would exhibit severe side effects due to their indiscriminate toxicity towards cancerous and healthy cells alike, thus preventing any clinical development. However, if used in ADCs, they are transported to cancer cells, where they act specifically to fight malign cells only. The selectivity of the mAb component allows the use of such extremely potent cytotoxins.3
Types of ADCs
Broadly speaking, ADCs can be segmented into several types or classes, depending on the nature of the drug or active component that is conjugated to the antibody.
An important group of ADCs is called small molecule drug conjugates (SMDCs), due to the relatively small size of the component that is linked to the antibody. Some natural product cytotoxins exhibit a rather large molecular weight for a small molecule but they are still tiny compared to an antibody.
Radionuclide antibody conjugates (RACs) are functionally similar to cytotoxic ADCs in the sense that they shuttle a warhead to a malignant target tissue, namely a radioactive isotope. The high energy radiation emitted from the radionuclide is especially harmful to fast dividing cells like cancerous cells. It is bound to the antibody via a chelating agent, thus being concentrated in close vicinity to the antigen. This mechanism reduces the exposure of healthy tissue to radioactivity.
Immune stimulating antibody conjugates (ISACs) are molecular combinations of monoclonal antibodies and compounds that activate the immune system. The underlying concept is the selective highlighting of cancers to the immune system, which would otherwise hide from attacks by immune cells through a variety of mechanisms. Currently, most ISACs carry ligands of the Toll-like receptor, which is a key player in the activation of the innate immune system.
Relatives – other types of immunoconjugates
One of the most promising immunoconjugates closely related to ADCs is the bispecific ADC. Here, the mAb portion is a specific antibody that enables ADCs to exhibit high specificity towards two unrelated antigens. One antigen would be specific to the cancerous cell, while the second antigen would be a receptor that enables fast internalization of the ADC, thus increasing the efficacy of the ADC therapy.
Bispecific ADCs are still rather new biopharmaceutical that come with many challenges in the manufacturing and handling processes that require innovative solutions. Companies like Single Use Support team up with key players in the biopharma sector to push promising approaches.
- Antibody–Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index, http://dx.doi.org/10.1158/1078-0432.CCR-19-0272, Published 2019-04-12
- Development of Anilino-Maytansinoid ADCs that Efficiently Release Cytotoxic Metabolites in Cancer Cells and Induce High Levels of Bystander Killing, http://dx.doi.org/10.1021/acs.bioconjchem.5b00430, Published 2015-09-10
- Antibody–drug conjugates: using monoclonal antibodies for delivery of cytotoxic payloads to cancer cells, http://dx.doi.org/10.4155/tde.10.98, Published 2011-03-09