Six Experts Discuss the Development, Innovation, Landscape, R&D, and Manufacturing of ADC/PDC Conjugation Technologies

Conjugation technology has provided a new solution for drug delivery. Small-molecule toxins, which were previously considered undruggable or difficult to drug, are now delivered deep into tumor tissues by carriers such as antibodies or peptides, enabling precise killing of tumor cells. Conjugated drugs, represented by antibody-drug conjugates (ADCs), have taken root and flourished over the past two decades, and have now become a cornerstone in the field of pharmaceuticals.

Recently, VCBeat/VCBeat New Medicine has consecutively hosted multiple salon events related to drug delivery.

[VB Thought Sharing Session] Issue 37: VCBeat/VCBeat New Medicine, in collaboration with Shengshan Capital and Viva Biotech, focused on drug conjugation technology and invitedChen Rulai, Co-founder and Chief Operating Officer of InnoLake Pharma; Zang Xiaoyu, Co-founder & CEO of N1 Life; Wang Guitao, Deputy Director of Tongyi Research Institute and Assistant to the General Manager at Tonsi Pharmaceutical; Cai Jiaqiang, Co-founder & CSO of Elicio Therapeutics; Wang Jun, Senior Director at WuXi XDC; and Dai Han, Chief Business Officer of Viva Biotech and Head of Viva Biotech Innovation Center.

Experts at the salon shared their insights on the latest advancements and industrial development in the fields of ADCs and PDCs. We have excerpted and summarized some of the content as follows:

Analyzed through the lens of the Gartner Hype Cycle, I personally believe that ADC technology is currently positioned squarely in the middle of the "Slope of Enlightenment." The technology has largely matured, having navigated most of the typical pitfalls, setbacks, and barriers encountered during its development. Meanwhile, industrial outcomes are beginning to stabilize, with more than ten products already approved for market launch. Furthermore, given that ADC technology comprises multiple components, each offering potential for optimization and upgrading, thereforeWhen compared horizontally with monoclonal antibody technology, ADC technology has a much larger scope for future innovation, a view echoed by many experts.This is also why InnoLake is interested in entering this field.

Another question is whether ADCs will become as saturated and hyper-competitive as PD-1 inhibitors.

On this topic, I can share my experience: About a decade ago, we frequently traveled to the United States to explore various collaboration opportunities. At that time, there were not many companies working on antibody-drug conjugates (ADCs), but we did come across some ADC-related opportunities. I recall that we engaged in direct discussions with one company, Immunogen. However, the experts on our company’s technical team were largely united in their opposition, considering the technology too complex and unnecessary, as monoclonal antibodies remained the mainstream focus at the time. Moreover, we were already fully occupied with our antibody drug development efforts, so we decided not to pursue this area.

Before 2013 and 2014, biosimilars were the hottest area in China. At that time, many multinational pharmaceutical companies were seeking suitable biosimilar candidates for collaboration, primarily those with strong preclinical process and quality data. After oncology immunotherapies, represented by PD-1 inhibitors, gained momentum, the development of innovative antibody drugs in China began to surge. ADCs emerged slightly later, around 2016–2017, but in the few years since then, China’s pipeline of ADCs under development has already accounted for one-third of the global portfolio.

On one hand, the majority of ADC products under development in China are concentrated on the same targets and similar technologies, leading to intense competition, particularly for the most popular targets such as HER2 and TROP-2; on the other hand, innovative ADC technologies and products have been gradually emerging over the past two years.

Therefore, returning to the issue of “involution,” I believe the focus should not be on involution itself, but on innovation. Genuine innovation can transcend involution and economic cycles. This principle applies not only to the ADC field but also to many other emerging technology sectors.So, what constitutes true innovation? We believe that genuine innovation should not focus on technology for its own sake; rather, it must address practical problems. In the context of drug development, this means solving clinical challenges. For any given disease, if there are unresolved clinical issues and your technological innovation can effectively address them, then that is true innovation.

ADC technology offers numerous avenues for innovation. There is significant room for breakthroughs across various components, including target selection, antibodies, linkers, toxins, and even the choice of indications. For instance, certain toxins that were previously considered undruggable may now become viable therapeutic agents through the ADC platform. Additionally, established targets can still yield novel successes; HER2 is a prime example, having already spawned multiple blockbuster monoclonal antibody and ADC products, demonstrating that “old trees can sprout new branches.” Furthermore, RemeGen’s RC-48 (Disitamab Vedotin) exemplifies this potential: beyond its innovative antibody design, its unique selection of clinical indications has been a critical factor in its success.

Let me first introduce what PDC is. In fact, its structure is similar to that of ADCs, both consisting of three components: a peptide, a linker, and a payload. This field has a rich research history, with over 1,000 publications per year in the past two decades. I have provided a brief summary below.

The primary classification of peptide carriers includes targeting peptides and cell-penetrating peptides.Targeting peptides are further categorized into those targeting cell surface receptors and the emerging class targeting the tumor microenvironment. Cell-penetrating peptides encompass a broader range, including those that penetrate the cell membrane, mitochondrial membrane, blood-brain barrier, blood-ocular barrier, and skin.

The linkers in peptide-drug conjugates (PDCs) are similar to those in antibody-drug conjugates (ADCs), primarily categorized into cleavable linkers and non-cleavable (stable) linkers, which release the drug through different stimuli.

Regarding the effector molecule component, due to the small molecular weight and high flexibility of peptides themselves, they have a broad range of applications; small molecules, macromolecules, peptides, and nucleic acids can all serve as effector molecules.

Compared with ADCs or other drugs, PDCs have their own advantages.

First, in terms of production,PDCs are chemically synthesized, allowing for better control over production costs and batch quality.Another important aspect is that the drug loading efficiency and drug loading capacity are highly deterministic.There will be no shell company ratio.Therefore, as a pharmaceutical product, PDCs offer high assurance of quality and stability.

On the other hand,PDCs are generally non-immunogenic, and the metabolites of their peptide components are mostly endogenous to the human body, resulting in fewer potential safety concerns. Due to the low molecular weight of peptides, PDCs demonstrate significantly superior penetration into tissues and tumors compared to ADCs and protein-based therapeutics.

ADC technology benefits from the specific binding of antibodies to their targets and their long half-life in vivo, which allows for sustained release of effector molecules. However, large-molecule antibodies also present certain challenges, such as poor tissue penetration and some degree of immunogenicity. Therefore,In parallel with ADCs, there are a series of “XDC” technological pathways, such as PDC (peptide-drug conjugates), LDC (drug-liposome conjugates), and SMDC (small-molecule drug conjugates).

Early-generation PDCs, owing to their relatively low molecular weight, effectively addressed issues related to tissue penetration and immunogenicity. However, this came at the cost of reduced target-binding capacity, including specificity. Consequently, many companies currently engaged in PDC drug development are prioritizing the enhancement of PDC specificity and affinity.

Tongyi Medicine approaches this issue from a different perspective. We believe that if one molecule is insufficient, we can employ two to achieve a synergistic effect where 1+1>2. This strategy allows us to enhance the affinity and specificity of the drug while maintaining the strong penetrability characteristic of small molecules and their ability to mediate rapid endocytosis.

Building on this technology, our philosophy is to combine two targets that are not readily druggable, or that have historically underperformed in drug development, into a pair of druggable targets.

The concept of antibody-drug conjugates (ADCs) actually dates back to 1913, although the necessary material foundation was lacking at that time. It was not until the breakthroughs in monoclonal antibody technology during the 1970s and 1980s that a preliminary material basis was truly established. The ADC industry continued to evolve over the subsequent decades, with many early-stage startups emerging during this period. It was not until 2000 that the first ADC drug, Pfizer’s Mylotarg, received regulatory approval for market launch.

In recent years, the ADC industry has experienced rapid growth and achieved significant technological breakthroughs, particularly with the approval of two products—Enhertu and Trodelvy—from Daiichi Sankyo and Immunomedics, respectively.The key distinction between these two companies and previous ADC drug developers lies in their use of low-toxicity compounds.Traditional ADC development has long revolved around highly toxic compounds, resulting in numerous failures. Daiichi Sankyo and Immunomedics have demonstrated that low-toxicity agents can also exhibit relatively favorable performance in clinical applications.

If we disregard the therapeutic effects of the antibody, an antibody-drug conjugate (ADC) is essentially a small-molecule prodrug—a delivery technology that uses antibodies to enable targeted administration of small molecules that are otherwise undruggable. Moreover, compared with conventional small-molecule prodrugs, ADCs demonstrate superior performance in tumor targeting, pharmacokinetics, and cellular penetration.

On the other hand,ADCs also have some drawbacks. Their large molecular weight affects therapeutic efficacy in solid tumors, they cannot be administered orally, and the cost of antibodies is relatively high. However, with the rapid advancement of antibody technologies leading to decreasing antibody costs, coupled with the 2–4 week dosing interval of ADCs, these disadvantages are gradually diminishing.

There are currently 14 ADC drugs on the market, of which 12 truly utilize small-molecule toxins as the payload. Among these, six employ MMAE/MMAF as the payload. Historically, lysine residues were the predominant conjugation sites, but cysteine residues are now more commonly used. Lysine-based conjugation is relatively less stable and results in more heterogeneous products, whereas cysteine-based conjugation offers greater stability and simplicity.

We have categorized ADCs into four generations based on their developmental history.First-generation ADCs utilize murine antibodies., so there are many issues related to immunogenicity and toxicity, with the toxins used exhibiting relatively high toxicity.Second-generation ADCs feature significant modifications to the antibody component, utilizing humanized antibodies.Meanwhile, the toxins used in second-generation antibody-drug conjugates (ADCs) are more diverse than those in first-generation ADCs. Both first- and second-generation ADCs are heterogeneous mixtures with relatively high toxicity. Although a greater number of second-generation ADCs have received regulatory approval, their overall clinical development success rate remains relatively low.The most significant change in third-generation ADCs lies in site-specific, stoichiometric conjugation.First, it addresses the issues associated with previous heterogeneous mixtures; most importantly, third-generation antibody-drug conjugates (ADCs) are designed to enhance the stability of conjugation sites. Conjugation methods for third-generation ADCs include chemical and enzyme-catalyzed approaches, both of which have demonstrated successful cases; however, no products have yet been commercialized.One of the characteristics of fourth-generation ADCs is the use of camptothecin-based topoisomerase I inhibitors as low-toxicity payloads.Fourth-generation ADCs have achieved remarkable success, expanding the horizons for ADC technology and injecting new vitality into global ADC drug development.

From a manufacturing and supply perspective, ADCs involve at least three key components: a large molecule, a small molecule, and their conjugation, resulting in a very long supply chain.Therefore, during the early development of antibody-drug conjugates (ADCs), such as Kadcyla, raw materials were sourced from multiple different suppliers.We provide one-stop services for XDC, eliminating the need for customers to source from multiple suppliers. Our supply chain is short and primarily concentrated in the Yangtze River Delta region.

Currently, cysteine-based conjugation is predominantly employed due to its convenience and lower complexity compared to lysine-based methods, with the drug-to-antibody ratio (DAR) typically around 4.If traditional methods are employed, the drug-to-antibody ratio (DAR) may range from 0 to 8. However, it is well established that an excessively low DAR results in insufficient therapeutic efficacy, while an excessively high DAR leads to a shortened half-life and increased toxicity.

Therefore, to address this issue, XDC has developed two approaches. The first approach employs divalent zinc, which ensures that the occupied sites remain unreduced during the reduction process, achieving a DAR4 proportion of approximately 75%. The second approach involves engineering the antibody, enabling a DAR4 proportion of 85% to even 90%, thereby yielding results comparable to those achieved with site-specific conjugation.

To validate our DAR4 technology, we designed a Trop-2-targeting antibody-drug conjugate (ADC). Trop-2 is currently one of the most commonly used antibodies in the ADC field. Although Trop-2 is expressed on many normal cells, it is highly overexpressed on cancer cells and undergoes rapid internalization. In basic research, Trop-2 has also been found to be associated with poor prognosis in many cancers. We found that this ADC demonstrated favorable safety and potent antitumor activity in animal studies, particularly exhibiting superior cytotoxicity against pancreatic cancer cells compared to other ADCs.

For ADC drug development, the selection of target antigens is a critical step.We aim to identify target antigens that are highly expressed in cancerous tissues but exhibit low or no expression in normal tissues. However, in the actual drug discovery process, target antigens meeting these criteria are exceedingly rare. ThereforeResearchers will conduct more comprehensive evaluations from biological and medical perspectives to screen for targets that meet the required criteria, and even leverage technological platforms to make some suboptimal targets viable.Following the binding of the target antigen to the antibody, internalization of the target antigen facilitates the transport of the antibody-drug conjugate (ADC) into the cell, thereby enabling its therapeutic effect. Consequently, the capacity for internalization is a critical factor in the selection of target antigens. Furthermore, the bystander effect represents another key consideration in ADC development.

As a critical component of antibody-drug conjugates (ADCs), antibodies are responsible for the specific recognition of target antigens; therefore, antibody selection is one of the most crucial factors in ADC design.There are several critical considerations for antibodies in conjugation, such as preserving their intrinsic properties post-conjugation. The affinity of monoclonal antibodies for their targets may be affected after conjugation with linkers and small-molecule drugs, and the internalization efficiency varies for each antibody-antigen pair.

The toxin is the ultimate active ingredient of ADC drugs, possessing highly potent pharmacodynamic effects.Only a small fraction of antibodies injected into the body accumulate in solid tumor tissues, and currentlyThe average drug-to-antibody ratio (DAR) of mainstream ADCs is limited to 3.5–4, resulting in a low amount of drug delivered to tumor cells; therefore, the cytotoxic payloads are required to exhibit high potency.

Furthermore, the linker is not merely a simple connecting element. As an integrated therapeutic agent, the chemical properties of the linker in an antibody-drug conjugate (ADC) directly influence the drug’s toxicity, specificity, stability, and efficacy.