Antibody-drug Conjugates

Antibody-drug conjugates or ADCs are an important class of highly potent biopharmaceutical drugs designed as a targeted therapy for the treatment of people with cancer. Unlike chemotherapy, ADCs are intended to target and kill only the cancer cells and spare healthy cells. ADCs are complex molecules composed of an antibody linked to a biologically active cytotoxic (anticancer) payload or drug. Antibody-drug conjugates are examples of bioconjugates and immunoconjugates. By combining the unique targeting capabilities of monoclonal antibodies with the cancer-killing ability of cytotoxic drugs, antibody-drug conjugates allow sensitive discrimination between healthy and diseased tissue. This means that, in contrast to traditional chemotherapeutic agents, antibody-drug conjugates target and attack the cancer cell so that healthy cells are less severely affected.

1350456-56-2
Fmoc-Val-Cit-PAB-MMAE
1350456-56-2
1361644-26-9
INNO-206
1361644-26-9
1401963-15-2
Mc-MMAD
1401963-15-2
1401963-17-4
Vc-MMAD
1401963-17-4
1411977-95-1
1411977-95-1
1491152-26-1
mDPR-Val-Cit-PAB-MMAE
1491152-26-1
151038-96-9
Aldoxorubicin
151038-96-9
B0084-463303
VcMMAE
646502-53-6
863971-24-8
Mc-MMAE
863971-24-8

Background


Antibody-drug conjugates (ADCs) are an important class of highly potent biopharmaceutical drugs designed as a targeted therapy for the treatment of people with cancer. Unlike chemotherapy, ADCs are intended to target and kill only the cancer cells and spare healthy cells.

Structure and Development of ADCs

ADCs perfectly conjugate cytotoxic drugs with monoclonal antibodies through chemical bonds, and can accurately transport cytotoxic drugs to tumor cells by using specific recognition of antibodies to tumor cells. At the same time, the drug concentration in normal tissues and organs was decreased, and the antitumor effect of high efficiency and low toxicity was achieved. ADCs perfectly demonstrated the advantages of high activity and high selectivity of cytotoxic drugs, while avoiding the defects of cytotoxic drugs with systemic toxicity and poor anti-tumor effect of antibodies. ADCs consist of three parts, monoclonal antibody, coupling chain and cytotoxic drugs. The properties of each component have a significant impact on the efficacy of IDC drugs. When the drug enters the body, it faces a complex environment, including the circulatory system and the subcellular structure of tumor tissue. Therefore, the selection of each component must take into account a number of factors. The development of ADC mainly depends on the optimization of these three parts. With the development of the humanized target antibody, the increase of cytotoxic activity, the stability of the new type joint and the enhancement of the cracking efficiency, the development of ADCs has also entered the golden period.

Basic Mechanism of ADCs

ADCs covalently couple cytotoxic drugs to McAbs with a chemical coupling chain and carry cytotoxic drugs specifically onto the surface of cancer cells expressing cancer-specific antigens. Then the antigen-antibody complex enters the tumor cells by endocytosis. ADCs need to be stable in the blood circulation. After entering cancer cells, the coupling chain of ADCs in lysosomal low pH environment or in the role of enzymes, reductive substances is the release of cytotoxic drugs and play an anti-tumor activity.

Factors influencing the Optimization of ADCs

The selection of targets and antibodies is the first step in the design of ADC drugs. In general, antibodies are required to bind specifically to antigens that are specifically expressed or overexpressed in target cells but not expressed in normal cells. At present, ADCs used in clinical trials include three subtypes of IgG G1 G2 and IgG G 4, among which IgG G 1 type is the most widely used. The coupling chain is a bridge between antibodies and cytotoxic drugs. The ideal coupling chain should be stabilized in the extracorporeal or blood circulation to prevent systemic toxicity caused by the early release of cytotoxic drugs, and to rapidly release effective cytotoxic drugs into cancer cells to kill cancer cells. The coupling of cytotoxic drugs to antibodies is usually accomplished by modifying cysteine residues or lysine residues that are close to solvent on antibodies, but the coupling with natural amino acid residues often results in different drug antibody ratios. The lower Dar may lead to the decrease of conjugate activity and the higher Dar may have a negative effect on pharmacokinetics.

Cytotoxic drugs are the key sites in ADCs to play an anti-tumor role, which requires that the cytotoxic drugs must have high activity (picomolar level) to meet the anti-tumor requirements. Cytotoxic drugs should have the ability to couple with antibodies and remain stable and fully dissolved in antibody solution. At present, most of the ADCs studied in clinic choose auristatins, maytansinoids and their derivatives as "warhead" drugs.

Reference:

Zhu Mingyue, Guo Jing, Hao Chenzhou, Zhao Dongmei. Progress in the study of Antibody Drug Coupling [J]. Chinese Journal of Pharmacochemistry: 2706: 490-497.