[Transfer] After the DS-8201 era, how to design the fourth-generation ADC?

Source: Same freehand/Gu Jinming

Speaking of the pharmaceutical industry, ten years of Hedong, ten years of Hexi.

In 2000, the first -generation ADC drug MYLOTARG developed by Pfizer was approved by the FDA, but it was eventually delisted in 2010 due to poison and sideline.

Ten years ago, Seattle Genetics (now renamed Seagen) and IMMUNOGEN 2nd-generation ADC drug AdCetris and T-DM1 (KADCYLA) successively launched a new era of ADC treatment. At that time, the two Biotech was undoubtedly a leading company in the ADC field, attracting many Big Pharma to cooperate with them.

At that time, in the field of ADC, the first and third companies were still unknown companies. Today, with its stunning clinical data of the DS-8201, the industry has made the industry be convinced, becoming a well-deserved third-generation ADC hegemon.

Ten years later, can we see the approval of the fourth -generation ADC drug? To answer this question, we may wish to predict what the four generations of ADC grows and what treatment effects need to be achieved.

ADC is essentially a targeted chemotherapy, the purpose is to expand the therapeutic index (TI). Judging from the previous ADC TI, the treatment window has shown a significant increasing trend, from less than 2 times the first generation to 12 times that of the third generation today. The treatment window should reach more than 20 times.

If the larger treatment window is to benefit more patients (higher orr), then how to make patients benefit for a longer time is the higher goal of drug development and eventually turn cancer into a controllable type. Chronic diseases.

However, at present, almost all drugs (chemotherapy, targeted and immune drugs), with the extension of the patient's use time, cancer will be resistant to drugs, causing the drug to stop the effect of cancer cells. Drug resistance of cancer cells is one of the main causes of cancer treatment. This may cause cancer to quickly recur on/disease, and eventually cause patients to die.

Take DS-8201 treatment that cannot be removed or metastasis HER2 low expression (HER2-LOW) patients with breast cancer as an example. Among HR+and the general population, the MPFS of the treatment group is 10.1 and 9.9 months, and the TPC control group is 5.4 respectively. Month and 5.1 months; MOS is 23.9 and 23.4 months, and the TPC control group is 17.5 months and 16.8 months, respectively. Although the DS-8201 has been greatly improved, it is far from chronic diseases that turn cancer into controllable chronic diseases. Therefore, how to further extend MPFS and MOS is the key to the success of the four generations of ADC.

ADC drug resistance mechanism and response strategy

If you want to design a larger TI, longer MPFS and the four -generation ADC of MOS, you may start from the ADC's drug -resistant mechanism. Studies have shown that there are at least 8 different drug resistance mechanisms in ADC [1].

1. Target antigen change

Tumor is a highly heterogeneous tissue, which has the instability of genes and phenotypes. At the same time, the expression of various proteases in the tumor micro -environment will cut the tumor surface antigen, which makes the target antigen and ADC combine with ADC The table is missing.

In addition, the binding tables of some target antigens and ADCs are also combined with ligands or other proteins. If this type of protein expression is elevated, a competitive binding target antigen will be formed with ADC.

Cancer cells can also directly reduce the expression of target antigen through genetic levels or even turn off the target antigen.

Using the third -generation ADC of the BYSTANDER KILLING, or two different tables that target the same antigen, or the two dual -resistant ADCs of the two different antigens on the same cell, can to a certain extent to a certain extent Solving this drug resistance.

2. Change the inner swallowing pathway

At present, the ADCs are almost dependent on the cell surface antigen to guide ADC to swallow the cells, and then reaches the ADC degradation to release toxin killing cells through the Endosome.

Studies have shown that cancer cells can change the expression of the ADC through the expression of the internal swallowing protein (such as the small nest protein Caveolae) to make it impossible to reach the lymphatic body and produce drug resistance. Mechanism, Pyxis Oncology is currently developing an ADC of an ADC of an ADC of an ADC of ONCOFETAL FIBRONECTIN EXTRADOMAIN-B (EDB).

3. Change of the lyon

Many of the LINKER of the ADC use PH sensitive hydrolyzed mode in the acidic (pH4.8) environment of the inescapynes and release toxins, while some cancer cells can raise the pH of the lymphatic body to make the toxins unreasonable. If you can find a hydrolyzed linker in the environment of the intracellular body (pH6.5) environment, you can avoid this resistance.

4. Expossed pump expression and increase in activity

A considerable number of tumors express ATP binding box protein (ABC), which is a type of ATP driver pump that can discharge small molecular drugs from the cells, thereby inhibiting the cell toxic effect of the drug. Many ADC Payload, including MMAE, is a substrate for ABC, so the high expression of ABC can also cause such ADC to resist. There are two main solutions: the toxins that choose non -ABC substrates are used as Payload or the ADC is used with the corresponding ABC inhibitor.

5. Cell cycle changes

Because the existing Payload mechanisms are mostly based on cell cycle regulation, cancer cells can escape from the killing of Payload by regulating the cycle of cells. For such drug -resistant problems, choosing Payload (such as PBD) that can kill the static state cells can be solved.

6. DNA damage repair (DDR) pathway changes

For Payload that produces the killing effect through DNA damage, cancer cells can generate drug resistance through DNA damage to repair the pathway. For such drug -resistant mechanisms, you can choose to use the corresponding inhibitors with DNA damage repair pathways. For example, Topotecan combined with ATR inhibitors in small cell lung cancer (SCLC) has achieved good curative effects.

7. The apoptosis pathway changes

Payload toxins want to kill cells in the end, and the apoptosis pathway of cancer cells sometimes cannot play a role because of normal cells, such as highly expressing anti-apoptic protein BCL-2 and BCL-XL, which causes cause ADC is resistant to drugs. The industry has a trial of choosing BCL-XL inhibitors as ADC Payload or using BCL-XL inhibitors with ADC.

8. The downstream signal pathway changes

Pi3k/AKT, as an important signal pathway node protein for cancer cells, has mutations in a considerable number of cancer patients, which has an important impact on the cycle cycle and apoptosis, which leads to cancer cells. The inhibitors and ADC are used to show certain efficacy.

Fourth -generation ADC molecular design

1. antibody

In the second and third-generation ADCs, the antibody part has not changed much. For example, both T-DM1 and DS-8201 use Herceptin, so the fourth-generation ADC antibody part still has a lot of room for improvement.

If it is a monoclonal ADC that determines the target, first evaluate the difference in expression of the target in tumor tissue and normal tissue, screen the appropriate antibody affinity and internal swallow efficiency to achieve the antibody can effectively combine cancer cells and swallow internal swallowing, but expression for expression The normal cells of this target are weak and less inside. This screening strategy can draw on the method of Teneobio to screen the CD3 antibody. Under the premise of activating T cells, minimize cytokine release to obtain the largest safety window.

In addition, the monoclonal antibody can be made into Conditional Antibody, which is activated only in the micro -environment of the tumor to improve the treatment window. Cytomx, Bioalta, Adagene and other companies are already trying in this area.

If it is a dual -resistant ADC, the problem is much more complicated. From the perspective of the current market research and development situation, it can be divided into two categories: one is two different binding tables (EPITOPE) targeting the same antigen to enhance affinity and inside, representing drugs such as the recycled yuan CMET/ CMET dual-resistant ADC (RegN5093-M114) and Zymeworks HER2/HER2 dual anti-ADC (ZW49); the other is two different antigens on the same cancer cells to enhance the targeted specificity and internal swallow of the cancer tissue. Representative drugs such as EGFR/MUC1 dual ADC (M1231) of Merck/SUTRO.

The first type of dual -resistant ADC, while enhancing the affinity of cancer cells and swallowing inwardly, may also enhance the affinity and inside of normal cells. Therefore, there is a question of whether the treatment window can increase ADC (MEDI4276) has stopped clinical due to toxicity.

The latter type of dual -resistant ADC needs to be cautious in terms of target selection. It is just that the cancer cells express that two antigen cannot be used as a basis for dual ADC.

Taking EGFR/MUC1 as an example, although EGFR is highly expressed in a variety of tumors, because it is also highly expressed in epithelial cells, EGFR-ADC cannot provide sufficient treatment windows. MUC1 can be identified by antibodies in tumors, so MUC1-ADC can provide larger treatment windows.

If you only consider EGFR/MUC1 to express this aspect, then MUC1-ADC obviously has a more obvious security advantage than EGFR/MUC1 dual-resistant ADC. Double -resistant ADC must provide a larger treatment window than monoclonal ADC to develop. To screen the dual -resistant ADC with larger treatment windows, you need to screen the affinity of 2 antibodies through the appropriate in vitro experiments, and choose the appropriate dual -resistant Format (1: 1, 2: 1, 2: 2), and finally pass the body through the body's internal body The efficacy and toxic experiments determine its treatment window.

2. Payload

Throughout the Payload of different R & D stages, it can be divided into 4 categories. Among them, microtubucta inhibitors represented by MMAE and DM1 are classic Payload, which is the second -generation ADC, which is still widely used; TOPO heterogeneous enzyme inhibitors represented by Wheeline -alkali derivatives are the third -generation ADC of the third -generation ADC Star Payload; DNA damage agent represented by PBD is also a classic ADC Payload. It has been improved for more than 20 years. In addition to the LonCastuximab Tesirine-lpyl (CD19-PBD), which has been approved for listing in 2021, it has been approved. The ADC is currently in the clinical stage; other niche ADC Payload has gradually entered everyone's attention recently, such as the RNA POL II inhibitors developed by German company Heidelberg Pharma, the RNA POL II inhibitors (α-amanitin) and American companies. Payload Immunology, developed by MERSANA.

More and more studies have shown that due to the huge differences in different tumors, no Payload can be effective for all cancer species. Therefore, the screening of Payload is also one of the elements of the fourth -generation ADC design after the target and antibodies are determined.

For example, the first three Communist Party did not stop at DXD, which has achieved huge success, but developed PBD as another Payload. In addition, the dual Payload ADC is also exploring from the concept of the laboratory to the industrial industry [2], but due to its high research and development costs and high -tech difficulties, most companies are discouraged.

Another idea of ​​developing the fourth -generation ADC Payload is to make Payload into a prior medicine, that is, it is activated to release the killing effect by activation only in the cancer cells, thereby further enhancing the specificity of the drug and the treatment window. The DPBD developed by Korean company Legochembio is a representative of this area. At present, this company has 2 ADCs in the clinical stage, and its clinical treatment results are worth looking forward to.

At present, the industry has two directions for the development of Payload: one is low toxins in high DAR values, and the other is that the low DAR value and high toxin.

3. Linker

LINKER can be divided into Cleavable (cut) and non-service (non-cut) according to its mechanism. The current consensus in the industry is aimed at the physical tumor Cleavable Linker to better provide bystander killing effects. The bystander killing mechanism is also a huge magic weapon for DS-8201 to achieve great success.

Cleavable Linker can be divided into 3 categories according to its chemical structure or shear mechanism. One type is linker dependent on acid hydrolysis; the second category is to depend on the sulfur linker for restore cutting and cut; Enzyme degradation linker. Existing data show that enzyme degradation LINKER can provide additional specific specificity to increase the treatment window if choosing high -expression enzymes of tumor cells.

The ideal LINKER played a balanced role in the entire ADC molecule. It balances the stability of Payload's hydrophobicity, enhanced the LINKER-PAYLOAD and the entire ADC molecule. LINKER-PAYLOAD is difficult to enter the cells even if it falls off from the antibody to the toxicity Essence Therefore, designing LINKER must be comprehensively considered with Payload.

4. Conjugation

ADC's coupling method has been from the earliest random random coupling to cysteine ​​semi -fixed -point coupling to the current fixed -point coupling. The technology is becoming increasingly mature, and the uniformity of ADC products is continuously improved. The average product obtained by fixed -point coupons can reduce the toxicity and instability of impurities, so it is expected to become the standard for the fourth -generation ADC.

The more mature fixed -point coupling can be divided into four categories: engineering cysteine ​​(Thiomab) couplet, non -natural amino acid (NNAA) puppet couplet, N297 glycogen coupling and antibody light chain (or heavy chain) C -end connection Short peptide occasion.

Among them, non -natural amino acid puppets have the highest technical difficulty, and are currently used in AMBRX and Sutro. The engineering cysteine ​​plywood is challenged to CMC because it is necessary to introduce non -pairing cysteine ​​to cause antibodies. N297 Glycogen Puppets are currently the most accepted way to be accepted by the industry. The representative company of this technology Synaffix has transferred its N297 glycoconnect to many ADC companies. It is worth mentioning that the first and third uses cysteine ​​patella in DS-8201, but its recently disclosed patent shows that it has developed its own N297 sugar-based fixed-point coupling technology for the next generation of ADCs' by the ADC of the next-generation ADC Development.

- Summarize-

The fourth -generation ADC needs to have greater treatment windows and (part) to solve the problem of drug resistance of the 3 -generation ADC. It is necessary to start with various aspects such as antibodies, Payload, LINKER, couplet, and use. The transformation of a certain part may not be iterated. For example, although the XMT-2056, which has just been bought by GSK, cannot be called the fourth-generation ADC, the clinical data shows that the XMT-2056+DS-8201 has a superposition effect. It is yet to be verified to further extend the survival time of patients. The third-generation ADC DS-8201 gives a revolutionary breakthrough in the field of cancer therapy, especially for HER2 low expression/HER2 mutations. It is expected that the fourth -generation ADC with more new technologies will bring better and lasting treatment effects to patients with cancer patients.

references:

1.NOVEL ADCS and Strategies to Overcom Resistance to Anti-Her2 Adcs. Cancers (Basel). 2021; 14 (1): 154.

2.Antibody-Drug Conjugates with Dual Payloads for Combating Breast Tumor Heterogeneity and Drug Resistance. Nature Communications. 2021; 12: 3528888

Disclaimer: This article is the content of Yaozhi.com, and the copyright of the pictures and text belongs to the original author. The purpose of reprinting is to pass more information, which does not represent the viewpoint of this platform. If the content, copyright and other issues are involved in the work, please leave a message on this platform, and we will delete it as soon as possible.

- END -