Antibody drugs are one of the fastest growing biopharmaceuticals, which bring huge benefits to the innovative drug market, with anti-tumor antibody drugs predominating. Since rituximab, the first antibody drug for cancer treatment, was approved by the US FDA in 1979, 17 antibody drugs have been approved for cancer treatment, but the gemtuzumab has withdrawn from the market. According to statistics from 2013, there are about 350 antibody drugs currently in clinical research, most of which are in the early evaluation stage. Therapeutic antibodies in Phase III clinical studies include 28 monoclonal antibodies and a mixture of monoclonal antibodies mainly used for cancer, inflammation or immune diseases, Alzheimer's disease and infectious diseases, 10 of which are cancer therapeutic antibodies.There are also many antibody drugs in preclinical studies, and their research trends are mainly focused on the following aspects, including: the discovery and confirmation of new antibody targets, new strategies to reduce antibody immunogenicity, conjugates of antibodies and drugs, and research on bispecific antibodies as well as other novel antibody drugs.
- 1.Discover new antibody target molecules
At present, the target molecules of antibody drugs are mainly divided into three categories: 1. Clinically validated target molecules, the efficacy of which has been confirmed, for example: CD20, HER2, EpCAM and CTLA-4; 2. Experimentally verified target molecules, the efficacy of this type of target molecule has been confirmed in cells and animals, such as IGF-1R, CD19, CD80, CXCR4 and ICAM-1; 3. New functional target molecules, newly discovered target molecules with certain efficacy, such as RAAG12, CD151, TSN-1, etc. To date, only a few target molecules for anti-tumor antibody drugs have been approved for marketing, and currently only nine. Many tumor-associated biomarker molecules have been reported, and thus so many target molecules for antibody therapy can be excavated. Even if the same target molecule has been developed, different molecular epitopes exist, and antibody drugs against different epitopes can be developed. For example, 5. Anti-CD20 antibody drugs have been marketed, and the 5 are now in clinical research.
In addition, many tumor cell transmembrane receptors and extracellular matrix-related genes can be spliced by differential splicing, which can generate new editing sequences and form new differential receptors and substrates as new antibody target molecules. The differentially spliced gene variants have been reported to be: FGFR variants, EGFR variants, EpCAM variants, L1CAM variants, Claudin18 and CD44 variants, and splicing of versican VN, fibronectin F and prion protein T Variants, etc. In recent years, many tumor-associated antibody target molecules have been studied, including EpCAM, PSMA and folate-binding proteins, as well as gangliosides, αVβ3, TRAILR2, FAP and toughlin. Recently, glypican proteoglycan has also been reported as a new target molecule for the treatment of liver cancer antibodies.
- Reduce antibody immunogenicity
Many antibody drugs are murine antibodies, which produce human anti-mouse antibody (HAMA) responses in clinical treatment. Therefore, for long-term treatment, an antibody drug that requires repeated administration is likely to produce a HAMA reaction, which requires humanization to reduce its immunogenicity. Humanized antibodies include chimeric antibodies, modified antibodies, and the like, which have biological properties such as reduced HAMA response and prolonged half-life in blood. In contrast to murine antibodies, the functional effector portion of the humanized antibody drug can be engineered as needed, and the humanized constant region of the antibody prevents the production of anti-isotype antibodies during treatment. The modified antibody further reduces the proportion of the murine fraction in the antibody compared to the chimeric antibody, and significantly reduces the HAMA response. In addition, the study of fully human antibodies has also received great attention and is one of the important development directions of antibody drug research. Fully human antibodies can be obtained by phage display technology, antibody library screening technology and transgenic animal technology. The anti-tumor antibody drugs produced by this technology have obvious inhibitory effects on cancer growth.
The immunogenicity of antibody drugs is one of its major toxic side effects, but there is no reliable prediction method for the frequency and timing of immunogenicity and antibody aggregation. If these problems are solved, new antibody detection techniques need to be developed. The results of studying the immunogenicity of human-derived antibodies, humanized antibodies and murine antibodies in humans indicate that: 1. More than 20% of mouse-derived antibodies induce tolerable immunogenicity, or negligible. These mouse antibodies do not need to be humanized; 2. Humanized antibodies can reduce immunogenicity, but their clinical therapeutic effects are also significantly reduced; 3. The immunogenicity of antibodies from different sources is not completely consistent with the law. A small number of humanized antibodies and fully human antibodies also produce significant immune responses; 4. Not only do we need to evaluate the utility of fully human and humanized antibodies item by item, but we also need to consider cost-effectiveness, while considering biochemical characteristics and targeted treatment indications. To date, there is no good way to completely eliminate the risk of antibodies binding to host cells. But classical research suggests that monomeric immunoglobulins are inherently tolerable if we are able to create methods to prevent antibody aggregation or immune complex formation.
To be continued in Section Two…