ADC: An Innovative Drug
for Cancer Therapy
I. Concept and composition
of ADC drugs
ADC drugs, namely antibody-conjugated drugs, are new anticancer drugs bridged by antibodies, cytotoxic drugs and conjugates. Antibodies play a key targeting role in this process, which can specifically identify and guide drugs to the lesion site accurately. Conjugates can generally break under the specific PH environment of the lesion site, thus releasing cytotoxins with powerful therapeutic effects. These cytotoxins can induce apoptosis of tumor cells and achieve precise attack on tumors.
Currently, ADC drugs have been widely used in the field of cancer therapy. Its unique structural design enables the drug to recognize the special protein on the surface of cancer cells through the antibody part after entering the body, and then to deliver the chemotherapeutic drug to the tumor site directionally. This precise delivery method, while effectively killing cancer cells, can avoid the damage of drugs to normal cells to the greatest extent. Therefore, ADC drugs have significant advantages such as strong targeting and less side effects.
However, it should be emphasized that before using ADC anticancer drugs, patients must strictly follow the medical supervision of medication, and must not blindly self-medication, so as not to delay the condition and affect the therapeutic effect.
Application
of
ADC drugs in breast cancer
(I) Success rate
of ADC therapy for breast cancer
At present, the main ADC drugs for breast cancer are Enmetrazumab, Viticitumumab, Trastuzumab-Drutecan and so on. These drugs can accurately identify and kill breast cancer cells, while inhibiting the proliferation of tumor cells, and are mostly used in the adjuvant treatment of metastatic breast cancer. Although the curative effect of ADC treatment is good, the cost is high and the pertinence is strong. It also needs to be supplemented by other anti-tumor treatments such as surgery and radiotherapy. Regular review is also needed after treatment in order to detect recurrence or metastasis in time and deal with them in time.
(2) What
are the ADC drugs for breast cancer?
1. Vedisitotal monoclonal antibody for injection: It has both antibody targeting and small molecule drug killing, can accurately identify and kill tumor cells, and has achieved good curative effect in gastric cancer, breast cancer and other tumors.
2. Enmetrizumab for injection: It is an anticancer drug, which can inhibit the proliferation of HER2-positive tumor cells. It is commonly used in the adjuvant treatment of metastatic breast cancer, metastatic gastric cancer and breast cancer.
3. Gosatuzumab for injection: It is an ADC drug targeting Trop-2, which can be used to treat unresectable locally advanced or metastatic triple-negative breast cancer that has received at least two systemic therapies.
4. De trastuzumab for injection: It has been officially approved by the National Medical Products Administration of China for the treatment of unresectable or metastatic HER2-positive adult breast cancer patients.
3. Application
of ADC drugs in other tumors
(1) Positive
effect of multiple solid tumors Studies in
Nature Medicine have shown that detrastuzumab has made significant progress as a new generation of antibody-conjugated drugs in the treatment of gastric and breast cancer. In the treatment of breast cancer, the DESTINY-BREAST03 study is a phase 3 head-to-head trial comparing DESTINY-BREAST03 with EMTRAZUMAB in the second-line treatment of HER2-positive advanced breast cancer. The results showed that the median progression-free survival of the detrastuzumab group was longer than that of the enmetrestuzumab group, reaching 29.0 months, compared with 7.2 months in the control group. At the same time, the 36-month progression-free survival rates were 45.7% and 12.4%, respectively, that is, nearly 50% of patients did not progress after 3 years of treatment with detrastuzumab. In addition, the median overall survival in the detrastuzumab group was 52.6 months, about 10 months longer than 42.7 months in the control group, and the risk of death was reduced by about 27%.
In the treatment of gastric cancer, the exploratory study of DESTINY-Gastric01 showed that the use of detrastuzumab in gastric cancer patients with low HER2 expression also had an active effect. The researchers found that patients with positive HER2 (IHC3) had a higher objective response rate than patients with low HER2 expression (IHC2/ISH), 58.2% versus 28.6%. Meanwhile, amplification of other key driver genes in ctDNA was associated with a low objective response rate, which was 58.3% in 12 patients with HER2 gain-of-function mutations.
(2) Application
in hematological malignancies
1. Description of
structure and mechanism of action
The ADC drug is composed of a monoclonal antibody, a linker and a cytotoxin, and is an immunoconjugate formed by connecting the monoclonal antibody and the cytotoxic drug through a specific linker. The core mechanism of its anti-tumor effect is that after the drug enters the body through intravenous administration, the antibody specifically binds to the target antigen on the tumor cells, the ADC drug is endocytosed or internalized to form primary endosomes, then matures into secondary endosomes, and finally fuses with lysosomes, and the cytotoxic payload is released through the chemical or enzymatic environment in lysosomes. Targeting deoxyribonucleic acid (DNA) or microtubules results in apoptosis or cell death. In addition, the antibody component can bind to immune effector cells to induce anti-tumor immunity, including complement-dependent cytotoxicity, antibody-dependent cytotoxicity and antibody-dependent phagocytosis; the antibody component of ADC drugs can also specifically bind to the surface antigens of tumor cells to inhibit the downstream signal transduction of antigen receptors, thereby inhibiting tumor growth.
2. Introduction
of approved indications
At present, a number of ADC drugs have been approved for hematological tumors. Webtuximab was approved for marketing in China in May 2020 for adult patients with CD30-positive lymphoma, including relapsed or refractory classical Hodgkin lymphoma, relapsed or refractory systemic anaplastic large cell lymphoma, primary cutaneous anaplastic large cell lymphoma or mycosis fungoides with previous systemic treatment. Ogaituzumab was approved for adult patients with relapsed or refractory precursor B-cell acute lymphoblastic leukemia in China in December 2021. Verpotuzumab was approved in China in January 2023, combined with rituximab, cyclophosphamide, doxorubicin and prednisone for previously untreated adult patients with diffuse large B-cell lymphoma, and combined with bendamustine and rituximab for adult patients with relapsed or refractory diffuse large B-cell lymphoma who are not suitable for hematopoietic stem cell transplantation.
4. The principle
of ADC drug therapy for tumors The mechanism
of action of ADC drugs is illustrated
by the example of Enmetrestuzumab. Enmetrestuzumab
is a typical ADC drug, which consists of HER2-targeted trastuzumab combined with the cytotoxic drug Imetacin (DM1). Its action mechanism mainly includes the following aspects:
1. Directed transport of DM1 to HER2-positive cells: The antibody part can specifically recognize and bind to HER2 protein on the surface of HER2-positive tumor cells, thus guiding the precise transport of cytotoxic drug DM1 to HER2-positive cells.
2. Inhibition of HER2 signaling pathway mediated by trastuzumab: After trastuzumab binds to HER2, it can inhibit the conduction of HER2 signaling pathway, thereby inhibiting the growth and proliferation of tumor cells.
3. Inhibit the shedding of HER2 extracellular domain from the cell membrane: This helps to maintain the stability of HER2 protein on the surface of tumor cells, thereby improving the binding efficiency of ADC drugs to tumor cells.
4. Antibody-mediated ADCC effect: The Fab fragment of antibody binds to the epitope of virus-infected cells or tumor cells, and its Fc fragment binds to the FcR on the surface of killer cells (NK cells, macrophages, neutrophil, etc.) To mediate the direct killing of target cells by killer cells. In Kadcyla’s primary mechanism of action, the antibody efficiently binds to HER2 on the cell surface and guides drug internalization, resulting in the intracellular release of DM1 molecules.
V. Summary and Prospect
As a new type of cancer therapy,
ADC drugs have shown great innovation and potential. It combines the targeting of antibodies with the killing power of cytotoxic drugs, bringing new hope for cancer treatment. In the treatment of cancer, ADC drugs have achieved remarkable results. It has not only shown positive effects in the treatment of solid tumors such as breast cancer and gastric cancer, but also played an important role in the treatment of hematological malignancies.
However, ADC drugs still face some challenges in their development. First, the issue of the level of technology is an important challenge. ADC preparation requires the use of a variety of different biochemical techniques and complex purification processes. This requires R & D manufacturers to have high-level technical teams and mature production lines. In addition, drug resistance is a challenge for future ADC development. To achieve a successful ADC product, a number of parameters must be optimized, including ADC stability, pharmacokinetics, retention of immunoreactivity, and effective delivery of the active form to the disease site.
Despite the challenges, the future of ADC drugs is still worth looking forward to. With the continuous progress of biotechnology and medical technology, the development and application of ADC drugs will continue to deepen. In the future, ADC drugs are expected to further expand their application fields and become a new starting point for the biopharmaceutical industry. For example, in the field of cancer treatment, ADC drugs are expected to be combined with other treatments, such as immunotherapy and targeted therapy, to provide more personalized treatment options for patients. At the same time, with the continuous progress of technology, the efficacy and safety of ADC drugs will continue to improve.
In conclusion, ADC drugs play an important role in the treatment of cancer. Although there are still some challenges, with the continuous progress of technology and the deepening of research, the future of ADC drugs will be broader.
