Many biopharmaceuticals are immunogenic in animals. Generally speaking, drugs that show strong immunogenicity to animals are also immunogenic to humans. Therefore, immunogenicity tests are required to evaluate the safety of drugs during the development of biological drugs. . For patients, immunogenicity easily affects the safety and effectiveness of drugs, and even causes new fatal diseases to patients because of the crossover of anti-drug antibody ADA and endogenous protein. For R&D companies, the immunogenicity test design is reasonable and the prediction methods are better, which can avoid R&D risks and losses caused by discovering problems until the clinical stage.
The immunogenicity of biopharmaceuticals is one of the special toxicities of biopharmaceuticals. Biopharmaceuticals stimulate the activation, proliferation, and differentiation of immune cells in the body, and finally produce specific immune response of immune effect substance antibodies and sensitized lymphocytes. For example, antibody drugs can produce antibodies against antibody drugs in animals after single or multiple administrations, triggering human anti-mouse antibody responses or human anti-human antibody responses, which can reduce the effectiveness of drugs or produce a series of adverse consequences, such as Local reactions at the injection site or mild and fatal systemic reactions.
In order to avoid the risk of enhanced elimination of drugs caused by immunogenicity as much as possible, when developing biologic drugs, various computer, in vitro and preclinical tools should be used to conduct immunogenicity tests on candidate drugs in the early development stage to predict their effects on humans. The immunogenicity is strong or weak. Medicilon Bioanalysis Department provides bioanalysis services in full compliance with FDA/CFDA GLP to support the screening and development of small molecule drugs, macromolecule drugs, biotechnology drugs, vaccines and biomarkers, as well as preclinical and clinical research .
Immunogenicity is related to factors such as the size of biomolecules, biochemical structure, host, and mode of administration. It is also related to individual differences in patients. Confounding factors such as the patient suffering from other diseases and combined use of other drugs will also affect the drug Human immunogenicity.
1. Molecular size of biological drugs
The molecular size of biopharmaceuticals is an important factor for the strength of immunogenicity. Protein peptides with relative molecules greater than 10,000 are often immunogenic, but the relative molecular mass of polymer substances such as gelatin can be greater than 100,000 because of its linear amino acid structure. It is easily degraded into low-molecular-weight substances in the body, showing weak immunogenicity. Protein peptides with a relative molecular mass of 5000 to 10000 are also immunogenic, but the immune response caused is relatively weak. The immunogenicity of compounds with relative molecular masses between 1000 and 5000 is unpredictable.
2. The chemical structure of biopharmaceuticals
The production of immunogenicity is related to the chemical structure of biopharmaceuticals. Biopharmaceuticals with complex structures cause strong immunogenicity, and vice versa. The structural complexity depends on the type and quantity of amino acids and monosaccharides. Any protein that contains a lot of aromatic amino acids, especially tyrosine, has strong immunogenicity. Polymeric protein molecules are more immunogenic than monomeric soluble protein molecules.
3. Host and mode of administration
Host factors also greatly affect the immunogenicity of biological drugs. Under normal immune function conditions, only heterologous or allogeneic immunogenic drugs can induce the host’s normal immune response. Therefore, the source of biological drugs and host species The farther the relationship is, the stronger the immunogenicity it causes. Due to the genetic differences of the host, there are also differences in the immune response to the same biological drug among different individuals of the same animal.
The administration of therapeutic proteins to patients can trigger an immune response, leading to the formation of anti-drug antibodies (ADA), which in turn changes the elimination rate of protein therapeutics. All protein therapeutics have potential immunogenicity, and their immunogenic potential is related to factors such as the part of the non-human sequence in the protein molecule, the route of administration, and the dose and duration of treatment. Generally speaking, the impact on the immune response is inversely proportional to the degree of humanization of antibodies, but fully human antibodies and their derivatives may still have high immunogenicity. Compared with intramuscular injection and intravenous injection, subcutaneous injection of protein drugs is more likely to cause immunogenicity.
The dosage of monoclonal antibodies (mAb) may be inversely proportional to immunogenicity. Studies have shown that low-dose mAbs often cause greater immune responses, and the probability of immunogenicity generally increases with the extension of treatment time.
4. Influence of adjuvant
Some adjuvants are added to biological drugs, such as microorganisms and their products, polynucleotides, Freund’s adjuvant, inorganic substances, etc. The combination of these adjuvants with drugs can also enhance or weaken the ability of drugs to produce immunogenicity. .
The evaluation of immunogenicity has become a key factor to clarify the clinical safety and effectiveness of biopharmaceuticals. The challenge for immunogenicity evaluation is to optimize immunological detection methods and improve the predictability of animal and in vitro models. Therefore, in the research and development of biopharmaceuticals, the immunogenicity test of candidate drugs and the optimization of immunogenicity detection methods are very important to the development and application of biopharmaceuticals.