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Breast Imaging with Radiolabeled Antibodies
Published in Raymond Taillefer, Iraj Khalkhali, Alan D. Waxman, Hans J. Biersack, Radionuclide Imaging of the Breast, 2021
Lamk M. Lamki, Bruce J. Barron
One area that will contribute significantly to the potential future clinical role of Mabs in breast cancer management is the developments in the technical aspect of bioengineering of Mabs. Better fragments of old antibodies, such as B72.3, are already in the making. Antibodies to more specific antigens and epitopes for breast cancer for diagnosis and therapy will be developed [55,111,105,120,126-128], Human or humanized antibody fragments are in clinical trials. Improvement in radiolabeling techniques for both diagnosis and therapy are being explored.
The Immunogenicity of Foreign Monoclonal Antibodies in Human Disease Applications: Problems and Current Approaches
Published in Ronald H. Goldfarb, Theresa L. Whiteside, Tumor Immunology and Cancer Therapy, 2020
The second approach which is currently pursued toward the generation of “humanized” murine monoclonal antibodies is the insertion of the CDRs of the murine antibody in a human monoclonal antibody molecule (Figure 3). This work has been pioneered by Winter and colleagues (54). Since it involves the transplant of selected smaller regions of the murine antibody molecule, CDR-grafting is theoretically a superior approach to chimerization, yielding an antibody molecule with fewer murine sequences. However, grafting CDR regions defined by sequence variability is often not sufficient to maintain antigen-binding affinity of the humanized antibody. Certain residues of the original murine framework make key contacts with the CDRs that help maintain their conformation. Alteration of these critical contacts by replacement with human frameworks may distort the shape of the CDRs, resulting in reduction or abrogation of antibody affinity. Therefore, to preserve specificity and affinity of a murine antibody, its CDRs, as well as their interaction with one another and with the rest of the variable domains should not be altered. For practical purposes, this represents the need of having to maintain sufficient murine sequences for optimal antibody specificity and affinity while minimizing the overall murine content to decrease the immunogenicity of the humanized antibody. Several laboratories are actively pursuing various methods of humanization of murine antibodies with potential clinical applications. I will summarize here the most recent progress in this field.
Recombinant Antibodies
Published in Siegfried Matzku, Rolf A. Stahel, Antibodies in Diagnosis and Therapy, 2019
Melvyn Little, Sergey M. Kipriyanov
In the alternative approach, murine CDRs are grafted onto a given human V region. If the humanized antibody has reduced or no binding affinity, new constructs are made that incorporate one to three additional mouse residues near the CDRs, and so on iteratively until binding is restored. While minimizing the amount of murine sequence required for binding, the full biological activity of the original antibody may not be recovered. This approach was used for the humanization of rat anti-CAMPATH-1 mAb recognizing the human cell-surface glycoprotein CDw52 (Riechmann et al., 1988) and a murine mAb against the human respiratory syncytial virus (RSV; Tempest et al., 1991).
A perspective toward mass spectrometry-based de novo sequencing of endogenous antibodies
Published in mAbs, 2022
Sebastiaan C. de Graaf, Max Hoek, Sem Tamara, Albert J. R. Heck
Due to the structural complexity and immense sequence diversity of antibodies, the development of therapeutic antibodies has always been a very challenging and labor-intense task, especially when compared to small-molecule drug development. For example, the discovery of trastuzumab was achieved by using mice immunized with antigen-expressing cells. Following the generation and selection of hybridomas that showed specific activity,37 the sequence of the selected antibody was determined after cloning and expression. A humanized antibody could be produced only thereafter by adapting and modifying the sequence accordingly.38 The same approach was used in the development of other mAbs.39–42 Apart from being expensive and laborious, these early strategies required knowledge and availability of purified antigens and animal models that can produce specific antibodies in response to these antigens.43
Targeting platelet inhibition receptors for novel therapies: PECAM-1 and G6b-B
Published in Platelets, 2021
Eva M Soriano Jerez, Jonathan M Gibbins, Craig E Hughes
Another approach would be to use a monoclonal antibody that activates PECAM-1 or G6b-B to prevent platelet aggregation. Specifically, a Fab or Fab2 fragment of a humanized antibody would most likely be required to avoid impaired interactions with the immune system. This approach has been applied successfully with Abciximab, the first anti-integrin αIIbβ3 antigen-binding fragment approved to inhibit platelet aggregation in cardiovascular disease [84]. The numbers of antibodies approved as therapeutic agents rise every year, with their success likely due to their high specificity, affinity and stability [85]. Nevertheless, a key disadvantage of antibody therapy is that they are not suitable for oral therapy. Nanobodies could be an alternative that may be suitable for oral therapy due to their proteolytic resistance thereby retaining their activity as they pass through the gastrointestinal tract. An example of this is V565, an anti-TNFα oral nanobody currently in phase II of clinical trials [86]. However, the first nanobody approved by the FDA in 2019, Cablivi™ is an intravenous therapy [87], although this may reflect the nature of the target disorder, thrombotic thrombocytopenic purpura, and that it is used in combination with plasma exchange and immunosuppressive therapy [87]. A single nanobody may not cause clustering, however it would be possible to fuse them, for example, to generate a bispecific nanobody, binding both PECAM-1 and G6b-B. The incorporation of the G6b-B nanobody would allow selective activation of PECAM-1 on platelets over other cell types expressing PECAM-1.
Vaccine development against methamphetamine drug addiction
Published in Expert Review of Vaccines, 2020
Md Kamal Hossain, Majid Hassanzadeganroudsari, Kulmira Nurgali, Vasso Apostolopoulos
There are number of technologies for the development of mAbs for therapeutic application such as chimeric mAbs which is 70% human, Phage display for humanized mAb, transgenic mouse for human mAb, and Single B cells for human mAb [43]. The later technologies are getting increased attention due to the ease of production of highly specific, sensitive, and less immunogenic mAbs and number of approved mAb are increasing from these newer technologies and could be explored for anti-METH mAb. Although chimeric mAbs are 70% human, still it is too immunogenic and required further modification for humanization. On the other hand a humanized antibody demonstrated lower immunogenicity, efficiently activate the human effector functions to take place; and the serum half-life of the humanized mAb is significantly higher than mouse/chimeric mAbs [44,45]. Every type of mAbs development technologies have their own challenges and the common one is the requirement of sophisticated technology.