Direct-targeting monoclonal antibodies (mAbs) approved for usage in oncology mainly belong to the immunoglobulin (Ig) G class currently. In fact, non-IgG therapeutic antibodies come of age with major progress in different kinds of human diseases, such as cancers and chronic inflammation. IgG mAb is no longer the only player in the therapeutic fields owing to antibody engineering technique, which is further driving the development of novel antibody formats. Besides, genetically modified cell-based therapies that harness the power of the immune system, together with non-IgG therapeutic antibodies, have improved cures in intractable human diseases. As an acknowledged antibody service provider, Creative Biolabs now offers various non-IgG therapeutic antibody engineering services to help our customers obtain ideal results and promote their research and projects successfully.
Non-IgG Isotype Selection
IgA is of great importance in mucosal immunity and, in contrast to IgG, it has only two isotypes, IgA1 and IgA2. Much of the recent interests in using IgA as a therapeutic isotype have focused on its potential to recruit the anti-tumor properties of neutrophils, which express the predominant receptor of IgA (FcαRI, CD89).
Besides IgA, the anti-tumor potential of IgE has recently been identified, leading to an indication that IgE may be an alternative Ig class for IgG mAb therapeutics. Diverse models were utilized to illustrate that control of tumor growth was mediated in an IgE- and Fc epsilon receptor (FcεRI)-dependent manner, with an additional role for CD8+ T cells. Further evidence proves that tumors can induce effective IgE responses. This kind of response can limit tumor growth, highlighting that the FcεRI-IgE axis is worth considering in the setting of mAb therapy.
As for IgM, this isotype provides 10-12 binding units to their immune system target, exhibiting far greater binding power to a cell surface target as opposed to 2 binding units of IgG antibody. More importantly, IgM antibodies also display many biological advantages in disease treatment, such as much more effective complement-dependent cytotoxicity (CDC), and higher affinity to difficult targets (e.g. carbohydrates and highly glycosylated proteins).
Fig. 1 The 5 major classes of immunoglobulin. (Yuan, 2021)
Non-IgG Therapeutic Antibodies Engineering
As mentioned before, antibody engineering is a highly valuable approach to improving intractable human disease cures. Creative Biolabs provides optional non-IgG antibody engineering strategies for your projects.
Chimeric antibodies greatly improve the immunogenicity and limitations of non-parental antibodies applications. Chimeric technologies to engineered non-IgG antibodies are necessary. Taking IgA for instance, IgA Fc receptor, FcαRI, effectively triggers cytotoxicity. It was reported that a chimeric secretory IgA (SIgA) was developed to prevent the avian influenza H5N1 by cloning the variable regions' genes of a mouse mAb against H5N1 and further fusion with human IgA constant regions. Additionally, using the heavy chain (VH) and light chain (VL) sequences from a mouse anti-HLA class II hybridoma, scientists successfully produced a series of chimeric human/mouse antibodies including human IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Results showed that IgG1 and both IgA isotypes were equally effective in killing freshly isolated human chronic lymphocytic leukemia cells.
Fig.2 Killing of lymphoma cells by chimeric antibodies. (Dechant, 2002)
For those mAbs produced from non-human systems, antibody humanization is important for decreasing the immunogenicity and improving the performance. Creative Biolabs now offers a newly developed set of humanized IgM, IgG and IgA that can be used for therapeutic research areas based on our innovative technology platform.
Glycosylation of the Fc region of an antibody has a profound impact on the safety and clinical efficacy of therapeutic antibodies. Through modern recombination techniques, the genes of a set of specific glycosyltransferases and/or glycosidases can be systematically knocked out or knocked in to produce glycol-engineered non-IgG antibodies with more humanized and homogeneous glycosylation, better pharmacokinetics and enhanced pharmacological efficacy.
Bi-specific antibodies have many advantages with great potential for clinical application over traditional antibodies, such as two distinct binding specificities, improving immune responses and activating T-lymphocytes. The most important application of bi-specific is disease immunotherapy. For instance, therapeutic non-IgG antibodies have been modified to be bi-specific antibodies by joining the non-IgG antibody with an additional transporter antibody to promote the brain-blood barrier (BBB) delivery, so as to increase the targeting of neurological diseases treatment.
Half-life extension technology is suitable for therapeutic antibodies that have a relatively short half-life. Despite presenting many advantages, the main limitation of these non-IgG antibodies is a much shorter half-life compared with IgG isotype (~21 days). The half-life indirectly affects the therapeutic efficacy of the non-IgG antibodies by influencing the elimination in vivo. Approaches, such as glycoengineering and protein fusions, are available to extend the half-life of non-IgG therapeutic antibodies.
Antibody isotype switching is a biological process occurring in humoral immune response, in which the constant region of the antibody heavy chain is replaced by a different chain, while the variable region remains unchanged. Antibody class switching does not affect antigen-binding specificity, retains antigen affinity and allows interaction with different effector molecules. Aided by antibody engineering techniques, we provide isotype switching services among the IgG, IgA, IgE, and IgM isotypes.
Fig.3 Mechanism of class-switch recombination that allows isotype switching in activated B cells.
Antibodies and antibody-based drugs are currently the fastest-growing class of therapeutics. Similar to IgG, non-IgG antibodies (mainly IgA, IgM, and IgE) could also be conjugated with payload through the well-chosen linker to achieve better clinical efficacy.
Our breakthroughs in manufacturing and protein engineering have enabled the optimization of therapeutic IgA, IgM, and IgE. Creative Biolabs offers a range of therapeutic non-IgG antibody products and engineering services for our clients. If you are interested in our services, please contact us for more information.
- Yuan, H., Silberstein, S.D. Monoclonal Antibody Biology. In: Maassen van den Brink, A., Martelletti, P. (eds) Monoclonal Antibodies in Headache. 2021, pp 25-42.
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