Currently, chemotherapy, using cytotoxic small molecules to kill cancer cells, is the predominant conventional cancer treatment. Despite the clinical benefits of this approach, there are several factors, including low selectivity and high toxicity to normal cells, that limit its therapeutic efficacy. Since many powerful anti-cancer drugs are nonspecific, they tend to create adverse side effects and are therefore rendered too toxic for clinical use.
In the era of precision medicine, oncology is transitioning from a universal approach, such as chemotherapy, to treatments tailored to specific molecular profiles and targets. Today, a more in-depth understanding of tumor biology has enabled the classification of patient subpopulations with actionable alterations across cancer types. This has shifted oncology drug development towards tissue-agnostic, biomarker-driven treatments that target specific molecular alterations. And antibody-drug conjugates (ADCs) are a premier example of this personalized approach to cancer treatment.
Over the past few decades, the therapeutic application of monoclonal antibodies (mAbs) has played a significant role in the shift towards tailoring therapies with the highest safety margin to specific patient subgroups. ADCs, one of the fastest growing drug classes in oncology, address the limitations of chemotherapy, or monoclonal antibody therapy, by providing a means of targeting the vulnerability of cancer cells.
ADCs, considered the ‘homing missiles’ of cancer therapy, represent the optimal combination of mAbs and small molecule drugs to create a single, highly specific, and cytotoxic moiety. These missiles comprise three structural components: an mAb directed toward a target antigen expressed on the tumor cell surface, a cytotoxic payload, and a cleavable or non-cleavable chemical linker. Together these components enable selective delivery of toxic chemotherapeutic payloads, which cannot be administered systemically, to preferentially expressed target antigens in tumors.
ADCs are at the forefront of expression-based therapy in oncology, designed to specifically target disease cells without affecting healthy tissues. In the shift towards precision medicine in oncology, antibody-based therapeutics have accelerated the evolution from conventional chemotherapy to molecularly targeted medicine and are constantly evolving with new proof-of-concept formats.
As of last year, there are 14 ADC drugs available worldwide, with many more in preclinical and clinical development. Apart from ADCs, antibody-based therapeutics are also emerging in a wide range of innovative and diverse forms, including bispecific antibodies and nanobodies. The development of bispecific antibodies (BsAbs), antibodies directed against two different antigens or two different epitopes on the same antigen, expands the choice of partner antibodies for ADCs. And bispecific ADCs (BsADCs) could help address issues related to endocytosis, toxicity, and drug resistance of ADC drugs. Currently, there are seven BsADCs approved by the Federal Drug Administration (FDA) and the European Medicines Agency (EMA), with over 200 in preclinical development and clinical trials.
Despite their expanding potential and popularity, there is still a large discrepancy between the number of ADCs in pharmaceutical pipelines and the proportion that actually reach late-stage trials. There are still significant challenges in augmenting their therapeutic value in terms of improving efficacy, assuring safety, and reducing toxicity.
Here’s a quick overview of the 5 key challenges in ADC development:
There are still several complexities and challenges that have to be addressed in the ADC development process before they can be more extensively integrated into clinical treatments. However, given the current pace of research into ADC technology, cancer biology, pharmacology, etc., ADC drugs are already ushering in a new era of precision medicine in oncology.
The next evolutionary step would be to explore the potential of these targeted therapeutics outside the oncological ecosystem. Here again, steady progress is being made to expand the ADCs to non-oncological indications such as autoimmune and infectious diseases
such as atherosclerosis, bacteremia, and inflammatory diseases.
But even as all of this unfolds, it is abundantly clear that ADCs represent a new age in precision drugs for the precision medicine era.