World ADC 2022 Highlights: Customized Payload-Linker Platforms and the Rise of Tailored ADC Design

In recent years, the ADC field has seen a surge of major deals and strategic moves, presenting a landscape of intense competition. Just this year, Mersana announced a $1.46 billion licensing collaboration with GSK to jointly develop an immunosynthetic ADC targeting a novel HER2 epitope; Kelun Pharmaceutical issued an announcement that its subsidiary, Kelun-Biotech, reached a $1.4 billion licensing agreement with Merck & Co., licensing an ADC drug to Merck; Daiichi Sankyo explicitly stated that it will invest $13.6 billion in ADC and bispecific antibody technologies over the next five years...

According to statistics from Qide Medicine, between 2017 and 2021, the upfront payments for ADC drug deals increased by 2.5 times, while the total transaction value grew by 3.84 times. Dongya Qianhai Securities projects that China’s ADC market size will reach approximately RMB 7.4 billion in 2024 and around RMB 29.2 billion by 2030, representing a compound annual growth rate (CAGR) of 25.8%.

VCBeat has been continuously monitoring the ADC sector and following up onThe 13th World ADC San Diego 2022 (the 2022 World Antibody-Drug Conjugate Conference, hereinafter referred to as the World ADC Conference).As the largest international academic conference in the field of ADCs, this year’s World ADC Conference was held in San Diego, USA, from September 6 to 9,More than 600 experts and scholars in the field of antibody-drug conjugates (ADCs) from around the world participated in this conference.

To gain immediate insights into the latest research findings and development trends in the ADC field, VCBeat New Medicine interviewed two ADC experts attending the conference, namelyDr. Haihong Zhong, Senior Vice President of Baikai Biomedical; Dr. Jiang Bao, Executive Vice President of Baikai Biomedical.Dr. Zhong and Dr. Bao have previously engaged in new drug development at major pharmaceutical companies such as AstraZeneca, Pfizer, and Amgen. With over a decade of R&D experience specifically in the field of antibody-drug conjugates (ADCs), they have witnessed the fluctuating trajectory of ADCs, from their initial surge in popularity to a period of downturn, and finally to their current resurgence.

Let’s take a direct look at the key insights and latest trends from this year’s World ADC Conference:

For a long time, the payload-linker technology platforms available for ADC product development have been very limited. According to Dr. Zhong Haihong and Dr. Bao Jiang,At the World ADC Conference, multiple companies showcased their independently developed payload-linker technology platforms.

For example, Cellectar Biosciences shared its radioisotope-conjugate technology; Bolt Biotherapeutics presented its immune-stimulating antibody conjugate technology; and Avidity Biosciences discussed its oligonucleotide-antibody conjugate technology. The mechanisms of action of these payloads differ significantly from those of traditional ADC toxins. Additionally, foreign companies have conducted systematic research on the structure-function relationship of ADC linkers.

“During the conference,We have found that many companies have achieved a highly “refined” level of research in linker technology..” Dr. Zhong told VBInsight.

According toADC Leader SeagenSharing that by modifying the linker length, structure, or conjugation site, the internalization of ADCs can be enhanced, thereby boosting their cytotoxicity and increasing intracellular payload release, ultimately achieving improved therapeutic efficacy.

Dr. Bao added:“At this conference, many companies have begun to systematically study the impact of linkers on ADC development. Some companies have even managed to produce “new blooms” from “old trees.”

At the World ADC Conference, a UK-based ADC company presented its HER2-targeted ADC pipeline. As is well known, competition in the HER2 space is intense, with several related ADC products already approved and marketed. Although the company employs a relatively conventional cytotoxic payload, its selection of a novel linker has yielded clinical data that reveal surprisingly promising efficacy.

ADC Leader: Daiichi SankyoIt is precisely based on the research, development, and breakthroughs in payload technology that it has become a leader in the ADC field. Its independently developed DXd platform has not only enabled the success of Enhertu but also allowed ADCs targeting Trop-2, HER3, B7-H3, and other targets to demonstrate impressive results in early-stage clinical trials. This has also provided direction and momentum for numerous ADC companies in their research on next-generation payload-linker technologies.

At this World ADC Conference,Tubulis, an Emerging ADC Companydelivered a keynote speech on payload-related topics. Its differentiated technology platform offers high flexibility, enabling precise matching among the target, linker, and payload, thereby integrating selective antibodies with payloads during ADC design. By optimizing its technology platform, it can also reduce toxicity and broaden the therapeutic window, thus facilitating the development of safe and effective ADCs. Most importantly,The flexibility of this technology platform heralds the possibility of “customized” design and development of ADCs.

As payload-linkers diversify, it is evident that the industry’s perspective on ADC development is shifting.The Three Components of ADCs: Antibody, Linker, and Toxin. Improvements in any one of these components can lead to differentiated ADC products. Therefore, future ADC R&D should focus on the specific design of ADC molecules based on the characteristics of targets and indications, a approach known as “customized” development.

Dr. Zhong introduced,“Both keynote speeches on the first day of the conference emphasized a guiding principle in ADC development: ADCs should be designed based on the indication and target, with appropriate selection of technologies such as the antibody, linker, toxin with distinct mechanisms of action, and drug-to-antibody ratio (DAR).”

Furthermore, since antibody-drug conjugates (ADCs) are currently primarily used in oncology, and given the substantial histological heterogeneity among tumors as well as the significant biological differences between drug targets, ADC therapies must be tailored with distinct design characteristics for different targets—and even for different tumor types sharing the same target.

For instance, T-DM1 demonstrates significant efficacy in advanced breast cancer with high HER2 expression, but yields suboptimal outcomes in other tumors characterized by high HER2 expression coupled with marked heterogeneity, such as gastric cancer. Another example is Enhertu, currently the most successful antibody-drug conjugate (ADC), which exhibits robust efficacy across multiple tumor types, including breast cancer, gastric cancer, and non-small cell lung cancer (NSCLC). The success of Enhertu stems from its DXd technology, featuring a drug-to-antibody ratio (DAR) of 8. In contrast, DS-1062, an ADC targeting Trop-2, also utilizes the DXd technology; however, due to the relatively high expression of Trop-2 in normal tissues, its DAR is reduced to 4 to minimize off-target toxicity to healthy tissues.

“To date, most ADC development has involved conjugating a payload-linker technology with an antibody to create an ADC, which is then evaluated in clinical trials to identify effective indications across various tumor types.”“It is not an ideal approach to indiscriminately apply a single payload-linker technology to develop antibody-drug conjugates (ADCs) targeting different antigens for the treatment of various tumor indications.”Dr. Bao told VCBeat New Medicine.

Dr. Zhong summarized,“The future direction is to design ADC molecules specifically based on the characteristics of targets and indications, meaning that development will move toward more granular, modular approaches in ADC technology.”

Dr. Zhong introduced that Baikai has long applied the same philosophy to its product development. For instance, during the development of BIO-106 (a Trop-2 ADC), Baikai noted that although Trop-2 is overexpressed in multiple tumor types, it is also highly expressed in normal tissues such as skin and mucosa. Therefore, in molecular design, Baikai Biopharmaceuticals specifically adopted a third-generation maytansinoid technology platform featuring a non-cleavable linker and a high drug-to-antibody ratio (DAR) to minimize on-target toxicity to normal tissues, rather than selecting an alternative payload-linker with a bystander effect.

Currently, the world’s first and only approved Trop-2-targeted antibody-drug conjugate (ADC) is Trodelvy (IMMU-132). Trodelvy has been approved for the treatment of triple-negative breast cancer and metastatic urothelial carcinoma; however, it demonstrates limited clinical efficacy in certain other malignancies, such as gastrointestinal tumors. In translational human preclinical studies, Hangzhou Baikai Biomedical Co., Ltd. discovered that BIO-106, owing to its use of a toxin with a distinct mechanism of action, exhibits significant efficacy against some tumors that are insensitive to Trodelvy, thereby enabling differentiated clinical development.

Given that payload-linker technology plays a crucial role in the development of the antibody-drug conjugate (ADC) field, why has the industry not emphasized the concept of customized R&D in the past?

Facing this issue, Dr. Zhong remarked, “Customized R&D is easier said than done, posing significant challenges in practice.”

To undertake customized research and development of antibody-drug conjugates (ADCs), it is essential to have access to diverse antibodies and various payload-linker technology platforms. Currently, there are few mature payload-linker technologies available, and most are protected by patents, which restricts corporate access. Developing an independent payload technology platform requires a company to possess extensive experience and profound expertise across multiple interdisciplinary fields, including chemistry, biology, pharmacology, and bioanalysis, along with substantial human and material resources. For many companies currently prioritizing rapid, low-cost outcomes, such an endeavor lacks cost-effectiveness in the short term.

Furthermore, validating a new technology platform is costly, time-consuming, and carries the risk of failure; consequently, developers often apply the same technology across all ADC projects.“Securing a patent for Payload-linker technology is no small feat. Consequently, many companies, upon acquiring the technology, convert all their antibodies into antibody-drug conjugates (ADCs) and then screen and eliminate candidates through clinical trials.”

As ADC technology matures, the industry has gained a deeper understanding of the structural functions of each module within ADCs, thereby increasing the success rate of ADC modification and innovation.On the other hand, patents for some second-generation ADC payloads, such as SMCC-DM1 and VC-MMAE, have expired or are about to expire, and many companies are gradually beginning to adopt second-generation payload technologies.

The high barriers associated with payload technology have not only restricted some companies from freely pursuing differentiated strategies, but also, to a certain extent, filtered for ADC novel drug R&D enterprises that truly possess comprehensive capabilities.Dr. Bao pointed out,“This is highly advantageous for companies with genuine technical development capabilities. It is also a key reason why Chinese ADC companies have been able to develop a portfolio of ADC products and successfully expand into overseas markets.”

In addition to “Payload-linker” frequently appearing as a buzzword at the World ADC Conference,The conference also highlighted several emerging trends and hotspots, such as: mechanisms and strategies for ADC combination therapy, applications of ADCs in non-oncology fields, bispecific antibody-drug conjugates (ADCs), and even trispecific antibody or small-molecule ADCs, as well as the development of ADCs targeting immune checkpoints.

“ADC targets are typically selected based on their high expression in tumors and low expression in normal tissues. At this conference, however, one company proposed that targets highly expressed in normal tissues could also serve as ADC targets, provided they are paired with a distinct payload-linker technology. This underscores the importance of customized ADC development, which can broaden the range of selectable targets, enable ADC applications across more cancer types, and ultimately benefit more patients,” introduced Dr. Zhong.

In the face of emerging trends, it is inevitable to reflect on the fact that antibody-drug conjugates (ADCs) still present numerous unresolved challenges. Their molecular design is highly complex, involving not only antibodies but also cytotoxic payloads, linkers, conjugation methods, and drug-to-antibody ratios (DAR). ADCs composed of different targets, cytotoxins, and linkers exhibit distinct characteristics and biological activities.Are the new technologies or emerging trends showcased at this conference merely “technology for technology’s sake,” lacking genuine clinical needs and value?

Taking the development of bispecific antibody-drug conjugates (ADCs) as an example: Cancer is a highly heterogeneous disease. Even within the same tumor type, there are different subtypes, and significant variations exist among individual tumor cells, even within the same tumor in a single patient. Consequently, targeted therapies generally exhibit relatively low response rates in oncology drug development.

How can the heterogeneity between different tumors or among different cells within the same tumor be addressed? Developing bispecific antibody-drug conjugates (ADCs) is an excellent solution.Bispecific ADC antibodies can simultaneously target two distinct antigens, theoretically offering higher response rates and superior efficacy. Furthermore, this approach serves as an effective strategy to counter the intense competition surrounding ADC targets.

Regarding the topic of “involution” in the ADC field, many current articles compare ADCs with PD-1 inhibitors to illustrate that the ADC sector is highly saturated, making differentiation extremely difficult and seemingly reaching the end of its development trajectory. Dr. Bao expressed a different perspective, stating, “‘Involution’ is merely a superficial observation. From the standpoint of targets alone, ADC products may appear highly saturated,”"However, unlike pure antibody drugs, ADCs do not exert their therapeutic effect by killing tumor cells through modulating the intrinsic function of the target. The target merely serves as a docking site; it is the toxin that truly delivers the therapeutic effect."

From a broader perspective，More than 100 conventional chemotherapy drugs have been approved, with several agents allocated across different lines of therapy for each tumor type. Currently, 70% of cancer treatments rely on conventional chemotherapy. As precision targeted chemotherapeutics, antibody-drug conjugates (ADCs) are highly likely to replace a substantial portion of these traditional agents. It is conceivable that this shift will necessitate the development of many new ADC products.

Based on an analysis of existing ADC products,The therapeutic window of current antibody-drug conjugate (ADC) drugs remains relatively narrow, falling far short of the safety profile expected of an ideal “magic bullet,” thus leaving substantial room for improvement.

From a technical perspective,All aspects of antibody-drug conjugates (ADCs) can be improved and enhanced, including the specific binding of antibodies, the diversity of toxin mechanisms of action, and the specific cleavage and release by linkers. Additionally, the application of ADCs in non-oncological diseases represents a blue-ocean market yet to be fully explored.

Therefore, Dr. Zhong and Dr. Bao concurred that antibody-drug conjugates (ADCs) are only just entering their takeoff phase, with ample room for expansion across many areas. With this clear vision, both doctors left the large pharmaceutical companies where they had worked for years, forsaking lucrative benefits to join Hangzhou Baikai Biomedical Co., Ltd., and embark on their entrepreneurial journey in the ADC sector.

Baikai Biopharma is a biotech company focused on ADC R&D, having successfully developed multiple payload-linker technology platforms. Its lead candidate, BIO-106, is currently undergoing Phase I clinical trials in the United States.

Finally, both industry “veterans” agreed that “if researchers are genuinely committed to the philosophy of developing novel drugs, antibody–drug conjugates (ADCs) represent a new drug development field least prone to hyper-competition and offering unlimited potential. Because ADCs are neither simple antibodies nor small molecules alone; after obtaining these two components, they must be assembled through complex systems engineering. This provides us veterans, who have been engaged in new drug development for many years, with a broader arena to tackle challenges and create more differentiated ADC products.”