ADC Reviews

Looking at the Development Trend of ADC from World ADC

world adc

In recent years, the ADC field has seen frequent blockbuster transactions and layouts, showing a pattern of contention among a hundred schools of thought. Only this year, Mersana announced a $1.46 billion authorization cooperation with GSK to jointly develop an immune synthesis ADC project targeting HER2 neo-epitopes; Kelun Pharmaceuticals announced that its holding company, Kelun Botai, and Merck & Co. reached a $1.4 billion deal. Licensing agreement to license an ADC drug to Merck; Daiichi Sankyo clearly stated that it will invest US$13.6 billion in ADC and double antibody technology in the next five years…

From 2017 to 2021, the down payment of ADC drug transactions has increased by 2.5 times, and the total transaction value has increased by 3.84 times.

The 13th World ADC San Diego 2022 (2022 World Antibody Drug Conjugation Conference, hereinafter referred to as World ADC Conference). As the largest international academic conference in the field of ADC, this World ADC conference was held in San Diego, USA from September 6th to 9th. More than 600 experts and scholars in the field of ADC from all over the world participated in this conference. Highlights and latest trends from the World ADC Conference:

Hotspot: Payload-linker technology platform is diversified

Historically, the payload-linker technology platforms available for ADC product development have been limited. In this World ADC conference, many companies have demonstrated their self-developed Payload-linker technology platform.

For example, Cellectar Biosciences shared radiotherapy compound conjugation technology; Bolt Biotherapeutics shared immunostimulatory antibody conjugation technology; Avidity Biosciences shared oligonucleotide antibody conjugation technology, etc. The mechanism of action of these payloads is very different from that of traditional ADC toxins. In addition, foreign companies have systematically studied the relationship between the structure and function of the ADC linker.

According to the sharing of the leading ADC company Seagen, by changing the length, structure or coupling point of the linker, the endocytosis of the ADC can be increased, thereby enhancing the cell killing power of the ADC, increasing the release of the intracellular payload, and achieving the purpose of enhancing drug efficacy. .

At this World ADC conference, a UK ADC company presented its ADC pipeline project based on the HER2 target. As we all know, the competition for HER2 targets is quite fierce, and related ADC products have already been approved for marketing. The toxin of this company is also very old, but because they chose a relatively new linker, the clinical data revealed surprising efficacy.

It is precisely based on the research and development and breakthrough of Payload technology that the ADC leader Daiichi Sankyo has now become a leader in the ADC field. Its self-developed DXd platform not only enabled Enhurtu, but also allowed ADCs targeting Trop-2, HER3, B7H3 and other targets to show impressive results in early clinical trials. This also pointed out the direction and increased motivation for many ADC companies to study the new generation of Payload-linker.

At this World ADC conference, Tubulis, an emerging ADC company, delivered a keynote speech related to Payload. Its differentiated technology platform is highly flexible, enabling the correct match between targets, linkers, payloads, and combining selective antibodies with payloads during the ADC design process. By optimizing its technology platform, it can also reduce toxicity and expand the therapeutic window to develop safe and effective ADCs. Most importantly, the flexibility of this technology platform heralds the development of ADC “custom” designs.

Customized R&D has been mentioned by many companies, or will it become the next competitive high ground for ADC?

While the research and development of Payload-linker is diversified, it is not difficult to see that the industry’s view of developing ADCs is changing. There are three parts that make up the ADC: antibody, linker, and toxin. Any improvement in any part may make a differentiated ADC product. Therefore, in the future, the research and development direction of ADC needs to specifically design ADC molecules according to the characteristics of the target and indication, which is the so-called “customized” research and development.

The two keynote speeches on the first day of the conference both emphasized a concept of ADC development, which is to design ADCs according to indications and targets, and select appropriate technologies such as antibodies, different linkers, toxins with different mechanisms of action, and DAR values.

In addition, because ADCs are currently mainly used for tumor treatment, there are great differences between tumors in terms of pathology, and biological targets are also very different, so different targets, even different types of the same target Tumor ADC drugs all require the design of different characteristics.

For example, T-DM1 has a good effect on advanced breast cancer with high HER2 expression, but it is not ideal for other tumors with high HER2 expression but high heterogeneity (such as gastric cancer). For another example, Enhurtu is the most successful ADC drug at present, and it has a good effect on a variety of tumors (such as breast cancer, gastric cancer, NSCLC). The success of Enhurtu comes from DXd technology. DS-1062, which targets 2, also uses DXd technology. Since Trop-2 is highly expressed in normal tissues, in order to reduce the damage to normal tissues, its DAR value needs to be reduced to 4.

So far, most of the research and development of ADC is to combine a payload-linker technology and antibody to make ADC, and then try it in the clinic to screen out effective indication pipelines for different tumor indications. It is not an ideal approach to develop ADCs with different targets indiscriminately with one payload-linker technology to treat different tumor indications.

The future direction is to specifically design ADC molecules according to the characteristics of targets and indications, that is to say, modular development will be carried out in the direction of more detailed ADC technology.

Customized R&D can differentiate ADCs, but why did the industry only pay attention this year?

Since Payload-linker technology plays a crucial role in the development of the ADC field, why did the industry not emphasize the concept of customized R&D in the past?

To carry out the customized research and development of ADC, it is necessary to have different antibodies and different Payload-linker technology platforms to choose from. At present, there are not many mature Payload-linker technologies and they are all protected by patents, which limits the use rights of enterprises. For an enterprise to independently innovate a Payload technology platform, it requires the enterprise to have rich experience and deep understanding of multiple interdisciplinary disciplines such as chemistry, biology, pharmacology, and biological analysis, and then it can be completed based on a lot of manpower and material resources. This is not cost-effective in a short period of time for many companies that are pursuing short-term and fast-paced products.

In addition, demonstrating a new technology platform is expensive, time-consuming, and faces the risk of not necessarily being successful, so people tend to use the same technology for all ADC projects. So many companies will make all the antibodies into ADCs after they get the technology, and then screen and eliminate them in the clinic.”

With the gradual maturity of ADC technology, the industry has a deeper understanding of the structure and function of each module in the ADC, which also improves the success rate of ADC transformation and innovation. On the other hand, the patents of some second-generation ADC payloads, such as SMCC-DM1 and VC-MMAE, have expired or are about to expire, and many companies have gradually begun to use the second-generation payload technology.

The high barriers of Payload technology restrict some companies from being able to freely conduct differentiated layouts, and at the same time screen out some ADC new drug R&D companies with real comprehensive strength to a certain extent.

Trends: Double antibodies, combination drugs, non-tumor applications…

In addition to the frequent appearance of Payload-linker as a hot word in this World ADC conference, some new trends and hot spots also appeared in this conference, such as: ADC combination drug mechanism and method, ADC application in non-tumor field, dual Specific antibody ADCs or even tertiary antibodies or small molecule ADCs, using immune checkpoints as targets for ADC development…

ADC targets are usually selected to be highly expressed in tumors and low expressed in normal tissues. At this conference, a company actually proposed that targets that are highly expressed in normal tissues can also be used as ADC targets. But its premise is that you have to pair it with a different Payload-linker technology. So this goes back to the customized development of ADCs, which can broaden the selection of targets, so that ADCs can be used in more cancer types and benefit more patients.

In the face of new trends, everyone can’t help thinking: ADC itself still has many problems to be solved, and the molecular design is also more complicated. In addition to antibodies, ADC also involves cytotoxins, linkers, coupling methods and DAR values; different targets, cells ADCs composed of toxins and linkers have different characteristics and activities. Are new technologies or new trends emerging at this conference just for the sake of “technology for technology” and do not have actual clinical needs and value?

Take the development of bispecific antibody ADCs as an example: the tumor itself is a highly heterogeneous disease, and the same tumor has different subtypes. Even in the same tumor of the same patient, there are differences between each tumor cell. big difference. Therefore, in the development of all tumor drugs, the response rate of targeted drugs is relatively low.

How to solve the problem of heterogeneity between different tumors or between different cells of the same tumor? Making bispecific antibody ADC drugs is a good solution. Bispecific ADC antibodies can simultaneously target two different targets, theoretically with better response rates and better efficacy. On the other hand, this is also an effective way to combat the “involution” of ADC targets.

Faced with the topic of ADC “involution”, many articles currently compare ADC and PD-1 to show that the ADC field is very involute, it is very difficult to achieve differentiation, and it seems to have reached the end of development. ADC products seem to be very introverted from the perspective of the target, but unlike pure antibody drugs, ADC does not play a therapeutic role by killing tumor cells by affecting the intrinsic function of the target. The target is just a transit point, and it is the toxin that actually performs the therapeutic effect.

From a macro perspective, there are more than 100 approved traditional chemotherapy drugs, and each tumor type has several chemotherapy drugs distributed in different lines of treatment. At present, 70% of tumor treatments rely on traditional chemotherapy drugs. As a precision targeted chemotherapy drug, ADC is likely to replace a large part of traditional chemotherapy drugs. As you can imagine, this will undoubtedly require many new ADC products.

From the analysis of the existing ADC products, the therapeutic window of the existing ADC drugs is still relatively narrow, and it is far from the safety that people expect from the “magic warhead”, so there is a lot of room for improvement.

From a technical point of view, all aspects of ADC can be improved and improved, including the specific binding of antibodies, the diversity of toxin action mechanisms, and the specific cleavage release of linkers. In addition, the application of ADC in non-tumor diseases is also a blue ocean field to be explored.