The civil rights attorney, blogger, and mother to two young children, Beth Caldwell was diagnosed with breast cancer at age 37 (STAT, 2017).
“There is such a culture of positivity around breast cancer,” she said. “People ask me when I will be done with treatment and I tell them ‘never.’ I will die from this.”
Living with the knowledge of pending death, suffering from astronomical prices for cancer drugs and attendant side effects, every year, there are actually millions of real persons as Beth losing the hope of life after a cancer diagnosis (NIH, 2021). And indeed, though with billions of dollars spent on cancer research over many decades, we have not yet found a way to fundamentally cure cancer.
Why cancer is so hard to cure?
The major difficulty in treating cancer is that it is not a single malignant disease but a group of maladies varying significantly among different patients, occurring in different parts of the body with multifarious causes. Thus, it is extremely hard and unrealistic for companies and research institutions to spend substantial amounts of money on various technical routes of therapeutic development for all the types of cancers. Especially, they are demoralized for developing drugs for rare cancers that only affect a small percentage of the population.
Can we develop a strategy that may potentially cure all cancers?
In 2001, Pfizer/Wyeth's drug Gemtuzumab ozogamicin was approved by the Food and Drug Administration (FDA) for treating acute myeloid leukemia (Bross et al. 2001), marking the emergence of a relatively new and important class of biopharmaceuticals, antibody-drug conjugates (ADCs).
ADC is a vector-based chemotherapy that relies on the use of a monoclonal antibody (mAb) linked to an anticancer cytotoxic drug (DeCarvalho et al.1964). ADCs target malignant cells thanks to the specificity of antibody-antigen interactions and release their payload inside cancer cells inducing cell death. Different from current conventional chemotherapy methods, ADCs can selectively target only diseased cells, thereby minimizing collateral damage to healthy tissue and avoiding redundant toxicity.
Adapted from “Antibody-Drug Conjugate Mechanism of Action” by BioRender.com (2020). Retrieved from https://app.biorender.com/biorender-templates
Antibody-drug conjugates (ADCs) bind to surface antigens on cancer cells and are internalized through receptor-mediated endocytosis. ADCs are processed through the endosome-lysosome pathway leading to the release of the cytotoxic payload, which lead to cancer cell death by inducing DNA damage or affecting microtubule structure (Ponziani et al. 2020).
Theoretically, if investigators can identify suitable antigens that exclusively exist on cancer cells, antibodies could be used to direct effective cytotoxic drugs to kill a broad range of cancer types. However in practice, numerous obstacles have been encountered during ADC development and many hurdles related to antigen binding and drug release remain to limit broader use of ADCs.
What are some challenges of ADC based therapies?
ADCs based therapies rely on precise administration of a complex mAb-linker-payload system. In this strategy, the first contacts between ADCs and cancer cells are of great importance, without which, none of the subsequent steps can be carried out.
To induce ADC activity, the antigens selected as tumor markers must have relative high level of expression on cancer cells and low or no expression on healthy ones. Moreover, they should have an extracellular domain (ECD) which should not be shed into the circulation so that the antibodies can bind with them on the targeted cancer cells rather than to the shed circulating EDC outside the tumor. Other desirable properties of the selected antigen include high affinity and avidity for antibody recognition and internalization capability, which all limit the antigen options (AJMB, 2019).
With regard to selecting the ideal antibody for antigen binding, one of the main considerations has been making sure that they can reach the target site. However, mAbs, based on which all current ADCs are constructed, are limited by their large size and do not easily penetrate the tumor microenvironment, especially that of solid tumors. Therefore, the limited penetration could compromise ADCs effectiveness. Additionally, it’s also challenging to find an ideal linker with sufficient stability, which is needed to ensure that the mAbs can safely circulate through the bloodstream, and eventually reach the tumor cells.
Once mAbs bind to antigens on the cell, the efficacy of ADCs relies on favorable intracellular trafficking to reach the lysosome, where their degradation determines controlled payload release. Hence, defective lysosomal degradation of ADCs could lead to reduced drug release into the cytosol, and might have a significant impact on the efficacy of ADCs.
Two types of ADC linkers are commonly used: cleavable and non-cleavable linkers. Cleavable linkers are those containing a conditional cleavage site allowing fast release of the drug after tumor cell endocytosis, thus ensuring efficient drug release at target sites while sparing non-target tissues. However, cleavable linkers are known to be unstable during plasma circulation. In contrast, noncleavable linkers are more stable in the blood as they all involve a non-reducible bond with an amino acid residue in a mAb. Nevertheless, this type of linkers depend on lysosomal degradation of the mAb, which releases the payload and is sensitive to lysosomal conditions (proteases, acidity, and a reducing medium).
The state of ADCs at the Clinic
There are currently nine ADCs approved as cancer treatments by the FDA and hundreds of clinical trials are on-going investigating their efficacy in treatingblood, breast, brain, lung and other numerous cancers (Nature Reviews Clinical Oncology, 2021). However, as the majority of ADC candidates are undergoingn Phase I evaluation, it’s still a long road ahead to understand the impact of ADCs in cancer treatment.
Despite their growing success, most of the current ADCs in clinical use are in the form of a heterogeneous mixture, meaning variable numbers of chemical drugs are loaded on the mAb of choice in one manufacturing process. The naked antibody may be a competitive inhibitor, conjugates with few drugs have poor efficacy and those with too many payloads are rapidly eliminated in plasma, compromising their ADC therapeutic index. In order to broaden the therapeutic utility of ADCs, site-specific chemical conjugation of proteins has been invastigated for several years. Encouragingly, a research team from the University of Southern California has demonstrated a new approach for generatingsite-specific ADCs that ensures fast release of the drugs into target cells (Science Advances, 2020).
A great deal of effort has also been made by the pharmaceutical companies and research institutes to overcome other technological barriers associated with ADCs. As technology advances, ADCs will continue to iterate, and the choice of targets, linkers, and cytotoxic payloads will be gradually expanded. I won’t be surprised if I wake up one morning and see a breaking news on CNN.com titled “No cancers left behind by ADCs”.
What happened to Beth Caldwell?
Four years after diagnosis of breast cancer, Beth Caldwell died in 2017 at the age of 41 while struggling with the last posts on her blog (The Cult of Perfect Motherhood, 2017).
“I’ve watched so many friends die, and it’s never been remotely OK,” Caldwell wrote:
“And now, y’all have to watch me die. But, that’s life. It’s shorter than it should be, and it comes with horrible things — pain, fatigue, wheezing, inability to walk more than 20 feet… But you know what? For now, I’m alive. I get to watch my kids dress up in costumes. I get to watch them play with our new dog (her name is Nova and she’s perfect). This is the life I have, and I’m going to enjoy it.”
“I’ve come to terms with what’s happening to me, that my end is coming, and that I can’t be what I’ve been to all of you. I hope eventually you’ll be OK with that, or not OK really, that’s the wrong word. What I mean is I hope you’ll be able to take how you feel about me and my death, and put those feelings into action.”
Just like the lengthy fruitless siege during the Trojan War of the ancient Greek, we had been fighting against cancer with every possible means for a relatively long time, however, we had not reach a satisfactory end point as of 2017. And now, another four years have elapsed since Beth’s death, probably,
it’s time for our “Trojan Horse” to be pulled into the “city”, and hopefully soon after that, no one will suffer from the fear of cancer any more.
Cruz et al. Monoclonal antibody therapy of solid tumors: clinical limitations and novel strategies to enhance treatment efficacy. Biologics: targets & therapy 13, 33-51 (2019). doi: 10.2147/BTT.S166310
Dai et al. Synthesis of site-specific antibody-drug conjugates by ADP-ribosyl cyclases. Science Advances 6.23 eaba6752 (2020). doi.org/10.1126/sciadv.aba6752
DeCarvalho et al. Coupling of Cyclic Chemotherapeutic Compounds to Immune Gamma-Globulins. Nature 202, 255–258 (1964). doi.org/10.1038/202255a0
Drago et al. Unlocking the potential of antibody–drug conjugates for cancer therapy. Nat Rev Clin Oncol (2021). doi.org/10.1038/s41571-021-00470-8
Nejadmoghaddam et al. Antibody-drug conjugates: possibilities and challenges. Avicenna journal of medical biotechnology 11.1, 3-32 (2019). PMID: 30800238.
Ponziani, S. et al. Antibody-drug conjugates: The new frontier of chemotherapy. Int. J. Mol. Sci. (2020) doi:10.3390/ijms21155510.