Antibody-drug conjugates (ADCs) are a novel anti-tumor drug that combines antibodies with targeted properties and strong cytotoxic drugs. ADC are composed of recombinant monoclonal antibodies (mAbs), ADC cytotoxins and ADC linkers between them. ADC has since then been gifted the powerful killing power of small molecule drugs and also the high targeting power of pure monoclonal antibodies, making it a research focus of tumor targeted therapy.

Since the first ADC drug was approved by the FDA in 2001, there have been 4 ADC drugs on the market till now. Their history of evolvement presents the following indications:

The rapid development of ADC drugs has also brought new problems to preclinical safety evaluation. ADC drugs have the characteristics of both small molecule cytotoxic drugs and macromolecular antibody drugs. Therefore, toxicology tests need to pay attention to the toxicity of both small molecule drugs and macromolecular antibodies. The structure and process of ADC drugs are complex, and the molecular type, the attachment site, the polymerization and the cleavage caused by the combination of antibodies and small molecules are all important factors affecting toxicity. The targeting of the ADC comes from the antibody part. The toxicity is mostly from the small molecule drug payload, although the antibody part can also be toxic (ADCC and CDC).

Things to be considered when Filing for Approval in China There are no specific guidelines for ADC. References are available in ICH S6, ICH S9 and related literature (Expert consensus on quality control and pre-clinical evaluation of ADCs, Chinese Pharmacy, July 2018, 32(7), 993-1005, for example ), and experiment design should accord with the principle of "case by case". There are more Investigational New Drug (IND) filings that need to be submitted in China than in the West, and changes in domestic regulatory environment should also be closely watched. The guiding principles for the preclinical safety assessment of ADC drugs are as follows:

The basic non-clinical safety evaluation package required for IND/BLA submission is as follows:

Safety pharmacology test: It can be combined with toxicology test, and hERG test is needed for new small molecule drugs.

Tissue crossover assay: ADC and naked mAbs need to be evaluated in humans and monkeys.

Toxicological test:
1) When there is only one species of related animal species, it is permitted to carry out a toxicological test in one species, but data support is required.

2) In the absence of related animal species, the transgenic animal model is superior to the ADC replacement molecule.

3) It is beneficial to perform a one-month toxicological test on unrelated species (such as rodents).

4) To test the toxicity of small molecules, it is necessary to carry out toxicological tests in two animal species.

5) Toxic tests are not required for mAb and Linker.

6) Perform immunogenicity tests in the toxicology test.

PK/TK research:
1) A separate PK test is required, but if the toxicological test design is very good and the scientific basis is sufficient, this part can be negotiated with the CED. The combination of PK and TK alone can be done in the toxicological test, which saves both time and funds.

2) Need to analyze free drug, conjugated drug, intact ADC and TAb.

3) Need to evaluate the distribution of ADC drugs, distribution, metabolism, excretion and material balance of small molecule drugs.

4) Plasma stability tests in humans and animals are required.

5) In order to detect the toxicity of small molecules, biotransformation, plasma protein binding, and drug metabolism enzyme tests should also be carried out.

Regardless the fact that there is no specific guiding principle for ADC, and there must be a reasonable scientific explanation behind the experimental design in the preclinical trials of antibody drug conjugate drugs. The experimental design is based on scientific and risk-based strategies, and the specific analysis methods are based on specific problems. It is also important to choose the right center for drug safety assessment. Communication with CDE is very important, the sooner the better. The CED recommendation is very important, and the IND should apply for pre-IND meeting before submission. In addition, the official meeting record should be included in the IND package. All will help the IND to declare success.

Because ADC can reduce the systemic toxicity of drugs, reduce the amount of cytotoxic drugs, increase the targeted distribution of drugs, and increase the safety of cytotoxic drugs, more and more are used to treat tumors. There are still safety concerns in ADC. Common toxic reactions include liver damage, myelosuppression, and peripheral neuropathy. At present, there is no safety evaluation guideline for ADC at home and abroad. At present, there is no ADC marketed in China, and the market prospect is broad.

Author's Bio: 

This article is provided by researchers from BOC Sciences, a company that keeps close watch on strategies to tackling major disease challenges such as cancer by offering of inhibitors, including checkpoint immune inhibitors such as Galectins Inhibitor, Antiparasitic Inhibitor, APC Inhibitor, Apelin Receptors Inhibitor, Apoptosis Inducer Inhibitor, Aquaporins Inhibitor, CD155 Inhibitor, GITR Inhibitor, CCR Inhibitor, etc.