Antibody-Photosensitizer Conjugation (APC)

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Antibody-photosensitizer conjugate (APC) refers to the combination of photosensitizer and monoclonal antibody and it can be used for photoimmunotherapy which is a new method of tumor targeted phototherapy. APC combines the tumor specificity of monoclonal antibodies with the phototoxicity of light absorbers, which can selectively transport photosensitizers to tumor sites, increase the concentration of photosensitizers at tumor sites and induce the rapid death of tumor cells.

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Introduction

APC is mainly composed of two parts, photosensitizer and monoclonal antibody. A certain amount of photosensitizer is given to the body. After the photosensitizer is enriched in the tumor, the photosensitizer is activated by the visible light of a specific wavelength, and the singlet oxygen produced kills the tumor cells, so as to achieve the purpose of treatment. Monoclonal antibodies are the most potential transport molecules to selectively transport photosensitizers to tumor sites. It has the characteristics of specific binding with the corresponding antigen, so it has a high degree of directional specificity. Therefore, APC has the characteristics of strong targeting and small side effects of photoimmunotherapy, so as to achieve highly targeted tumor therapy and minimal normal tissue damage.

APC Preparation Method

Preparation method is one of the key factors affecting the properties of APC. Generally, monoclonal antibodies and anticancer drugs are crosslinked by chemical methods. The selective photosensitizer should contain a functional group, which can be directly or indirectly connected to the amino, mercapto or carboxyl group of the antibody. The main preparation methods of APC include direct crosslinking method and indirect crosslinking method. The specific preparation method is shown in the table 1.

  • Direct crosslinking method
Specific methodsPreparation principleCharacteristic
Carbodiimide method1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) forms an amide bond between the carboxyl group of photosensitizer and the amino group of monoclonal antibody to obtain APCAPC selectively kills a component of mixed cells and can be used in bone marrow transplantation
Active ester methodThe carboxyl group of photosensitizer reacts with N-hydroxysulfosuccinimide sodium (NHS) or tetrafluorophenol (TFP) to produce active ester, and then reacts with antibody amino group to prepare APCThe antibody activity of APC obtained by esterification is well preserved, but its aqueous solution is unstable and prone to precipitation, which will reduce the drug activity
Amino acid ligationAmino acid as a small molecule crosslinker connects photosensitizer and monoclonal antibodyAPC has good binding with the whole target cell and cell surface
  • Indirect crosslinking method
Specific methodsPreparation principleCharacteristic
Polyethanol methodBenzoporphyrin derivative monoacid (BPD) is attached to the modified polyvinyl alcohol (PVA) skeleton, and BPD-PVA is crosslinked with the amino group of antibodyAPC has good biocompatibility and superior controlled release performance
Polyglutamic acid (PGA) methodChlorin e6-monoethylenediamine monoamide (CMC) is crosslinked with monoclonal antibody to obtain APCAfter transporting drugs, APC is hydrolyzed by proteolytic enzymes in vivo to produce harmless amino acids
Poly-L-lysine methodNHS and dicyclohexyl carbodiimide (DCC) react the carboxyl group of photosensitizer with the amino group of poly-L-lysine to form an amide bond, and then react with N-succinimidyl-3-(2-pyridyldithiol)propionate (SPDP) to form a conjugate. Monoclonal antibody reacts with SPDP, sulfhydryl group is introduced into the molecule, and then reacts with the above conjugate to produce APCAPC is easy to reach effective concentration at the application site, and has affinity for some cancer cells
Dextran methodDextran is carboxymethylated with chloroacetic acid, and then reacted with hydrazine hydrate. The introduced hydrazide group forms hydrazone bond with CMA carboxyl group, and then combines with monoclonal antibody to form APCThe antibody loading site of APC is far away from the binding site of antibody and antigen, so as to reduce the loss of possible immune response

Application

  • Cancer treatment

Photoimmunotherapy using APC has been used in the treatment of head and neck tumors, esophageal cancer, basal cell carcinoma and other tumors. For example, one kind of APC drug is a combination of photoactivated dye and interleukin receptor α chain (CD25) specific monoclonal antibody. The APC targets regulatory T cells in tumor lesions. Through the characteristics of light activation, The APC can strengthen the immune killing effect of the focus. In other words, this therapy can avoid the cells in normal tissues, and only reduce the immunosuppressive effect in the tumor microenvironment, so as to enhance the killing ability of T cells in specific parts to cancer cells.

  • Cancer diagnosis

APC can be used in the diagnosis of cancer. For example, when APC is injected into the body, the fluorescence at the tumor site can be observed with a small dose, and the fluorescence intensity is significantly higher than that of fluorescein without monoclonal antibody.

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