One hundred years ago, Paul Ehrlich*, a German biochemist and Nobel laureate who created the field of chemotherapy, coined the term “magic bullet.” He envisioned that a drug could specifically target a particular pathogen without affecting normal host cells. Antibody drug conjugates (ADCs) are the realization of Ehrlich’s vision for therapies that target tumor cells with precision and specificity.
ADCs are made up of a monoclonal antibody (mAB), a chemical linker, and a drug payload. Unlike conventional chemotherapy treatments, which can harm all tissues surrounding a tumor, ADCs target specific proteins or receptors found on certain types of cells, including cancer cells. The payload is delivered via a linker attached to an mAB that binds to a specific target. Once attached to the target, the complex is internalized, and the linker can release the payload into the cell.
While it may be efficacious, traditional chemotherapy is a nonselective approach that can also damage healthy normal tissues. ADCs combine the selectivity of targeted therapy with the high potency of chemotherapy. They are bioengineered to help reduce systemic exposure to cytotoxic agents that cause side effects, leading to potentially improved tolerability, enhanced therapeutic efficacy and sustained treatment. However, while ADCs are a kind of targeted chemotherapy, toxicity and adverse side effects have been reported and understanding their toxicologic characteristics is critical.
Harnessing the Bystander Effect
The three components of ADCs all have different properties that can impact clinical efficacy and safety. Optimizing each one, while enhancing the functionality of the ADC as a whole, has been one of the major considerations of ADC design and development. Linkers play a key role in determining the overall success of treatment. A well-designed ADC linker can help the antibody to selectively deliver and accurately release the drug at tumor sites.
There are two main categories of linkers in current ADC drugs: cleavable linkers and non-cleavable linkers. In contrast to the non-cleavable linker, the cleavable linker has a chemical trigger in its structure that can be severed to release the cytotoxic payload into the tumor. When a cleavable linker is used in an ADC, it is posited that something called the ‘bystander effect’ may occur – when the payload and mAB of an ADC are separated inside a targeted antigen-positive cancer cell, the released payload also affects neighboring antigen-negative cancer cells and the component cells of the tumor microenvironment. Further investigation is needed to evaluate if the bystander effect may help improve outcomes when treating with ADCs.
Tailoring Treatment with ADCs
Understanding which patients are most likely to benefit from ADC therapy is another critical factor for success. Optimal tumor targets are antigens that are highly expressed on the surface of the tumor, have low expression in normal tissues and can internalize the ADC effectively. The search for better target antigens, particularly for solid tumors, is ongoing, as are efforts to develop better linkers and payloads for ADCs. ADCs are continuing to evolve as a potential treatment option with different linkers and payloads.
What’s Next for ADCs
Next-generation ADC development has rapidly taken off in recent years.11 Today, more than 10 ADCs are approved for use in the U.S. or European Union. Most of these approved ADCs are for treatment of hematological cancers, however, their use has been expanding into solid tumors, and there are now approved ADC treatments for HER2-positive breast, stomach, bladder and cervical cancer.
In addition, the number of investigational agents has more than tripled over the past 10 years, and today there are more than 80 ADCs in development worldwide. Novel ADCs are generating excitement in several arenas, including in rare gynecologic cancers such as ovarian carcinosarcoma, uterine serous carcinoma and ovarian clear cell adenocarcinoma, all of which have limited treatment options and are associated with cell proliferation and drug resistance resulting in poor overall survival for patients. As ADCs continue to gain traction, we expect this approach will continue to deliver a positive impact.
Our Vision for ADCs
At Eisai, everything we do is guided by a simple principle: patients and people come first. We call this human health care, or hhc. As part of that mission, we are working with other organizations to share technologies and grow together to create an ecosystem that enables us to deliver health-related solutions that matter to people across the continuum of their lives. We know we can achieve more by building on our strengths and the strengths of others, and we do this through effective collaborations, such as ones we have with Bristol-Myers Squibb for the ADC, farletuzumab ecteribulin (FZEC), formerly known as MORAb-202, and most recently with Bliss Biopharmaceuticals (Bliss Bio) for another ADC, BB-1701.
In our collaboration with Bristol Myers Squibb, Eisai is investigating the use of FZEC, a folate receptor alpha (FRα)-targeting ADC, in FRα-positive solid tumors including: a Phase 1/2 clinical study in the United States and Europe for solid tumors including endometrial cancer, a Phase 2 clinical study in the United States and Europe for non-small cell lung cancer, and a Phase 2 clinical study in the United States, Europe and Japan for ovarian cancer, peritoneal cancer and fallopian tube cancer. Based on the data from pre-clinical studies, FZEC has the potential to elicit a bystander effect through an enzymatically cleavable linker that releases a payload, eribulin, from the antibody, therefore acting not only on the FRα-positive cancer cells, but also the FRα-negative neighbor cells surrounding the FRα-positive cancer cells. Eribulin, Eisai’s anticancer agent, is a tubulin inhibitor that induces immunogenic cell death. Insights from preclinical research were recently published.
In addition, in May 2023 Eisai entered into a clinical trial collaboration agreement with Bliss Bio for BB-1701, an ADC composed of Eisai’s in-house developed anticancer agent eribulin and an anti-HER2 antibody. The proprietary technology platform of the linker-eribulin payload was developed by our Biologics Discovery Center, Epochal Precision Anti-Cancer Therapeutics, which has been testing the platform on various antibodies. BB-1701 will aim to target breast, lung and other solid tumors that express HER2. A Phase 2 clinical trial will first be conducted by Eisai in breast cancer, with other areas to potentially be investigated in the future. Bliss Bio is currently conducting Phase 1/2 trials in the U.S. and China for HER2-expressing solid tumors.
As more research is conducted into improving target selection, cytotoxic drug potency, innovative linkers, and drug resistance, ADCs could become the future of targeted cancer therapy.
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*Featured image: Paul Ehrlich (1854-1915), a Nobel Prize-winning German physician and scientist who worked in the fields of hematology, immunology, and antimicrobial chemotherapy at work in his laboratory (M0013265). He coined the term “magic bullet” (Zauberkugel), a concept formed by Ehrlich who assumed that it could be possible to kill specific microbes (such as bacteria) without harming the body itself. Photo courtesy: Wellcome Library, London. Wellcome Image (Creative Commons Attribution only license CC BY 4.0).
How to cite:
Toshimitsu Uenaka, Ph.D. 1
Unlocking the Potential of Antibody-Drug Conjugates – J. ADC. September 26, 2023. DOI: 10.14229/jadc.2023.09.26.020.
1 Eisai Co., Ltd
Last Editorial Review: September 26, 2023