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Disease Prediction and Drug Development
Published in Arvind Kumar Bansal, Javed Iqbal Khan, S. Kaisar Alam, Introduction to Computational Health Informatics, 2019
Arvind Kumar Bansal, Javed Iqbal Khan, S. Kaisar Alam
Antibodies are Y-shaped multidomain proteins generated by the immune system to protect the cell-surface proteins within the host-cells from binding to the invading pathogens' antigens. Multiple disulfide-bonds (S–S bonds) provide stability to its structure. The forked part of the antibody has two parallel strands, and the outer strand binds to antigens; the inner strand is required for stability of the structure. Antibodies circulate through the blood and bind to the antigens thus neutralizing their effect. Antibodies have two types of regions: 1) constant region and 2) variable region. Antigen-binding region is at the tip of the light chain arm (outer arm) of the antibody as illustrated in Figure 10.17. These areas are called complementary determining region (CDR) because the antigen-binding site is complementary to the antigens. The remainder of the region is called the framework region (FR). The hinge region is flexible to support an angular change to the structure when seeking and binding the antigens.
Immunoglobulins
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
As if all of this diversity were not enough, another very important mechanism generating variation in V regions exists: somatic mutation. At some time after rearrangement is complete, the heavy and light chain V genes may accumulate point mutations in any CDR or framework region. One gene may collect up to 10 or more nucleotide changes, some fraction of which result in an amino acid substitution. These changes may alter antibody affinity, or may even alter specificity.
The Evolution of MAbs from Research Reagents to Mainstream Commercial Therapeutics
Published in Maurizio Zanetti, J. Donald Capra, The Antibodies, 1999
The CDR grafting or humanization technique, originally described by Winter and colleagues (Jones et al., 1986; Verhoeyen et al., 1988), further reduced the percentage of murine sequences present in the variable regions of murine antibodies. The original concept of simply transplanting the three light-chain and three heavy-chain CDRs from a mouse antibody onto a human variable region acceptor framework rarely achieves the retention of murine antibody affinity without further modification to the framework region. The reintroduction of murine residues, to allow the CDRs to adopt the appropriate configuration, usually numbers anywhere from 0 to 18, with the average being around 7–8 residues. Therefore, the idea of utilizing a totally human framework has been compromised by the need to reintroduce potentially immunogenic murine residues to retain the configuration of the CDRs needed for antigen binding (Queen et al., 1989). The immunogenicity of each humanized antibody, therefore, needs to be evaluated for its own inherent immunogenicity and will vary depending on the number and types of changes made and may not always be predictable. In cases where too many changes are needed to the human framework to maintain CDR conformation, the approach has often been to select a different murine antibody with CDRs that require fewer changes to the human acceptor framework to maintain antigen binding affinity. Design and expression of humanized antibodies has become much less variable, due in part to the availability of more information on antibody structure, a larger antibody sequence database, and more refined algorithms used by antibody modelers to predict the effect of various amino acid residues on antibody conformation (Padlan, 1994). Variable regions of humanized antibodies can now be made totally synthetically in a short timeframe once the sequence has been “designed.” Nevertheless, there is still no way to predict the immunogenicity of humanized antibodies to date, and surprises have occurred when some antibodies have been administered to humans (Saleh et al, 1992).
An engineered T-cell engager with selectivity for high mesothelin-expressing cells and activity in the presence of soluble mesothelin
Published in OncoImmunology, 2023
Daniel Snell, Tea Gunde, Stefan Warmuth, Bithi Chatterjee, Matthias Brock, Christian Hess, Maria Johansson, Alexandre Simonin, Fabio Mario Spiga, Christopher Weinert, Niels Kirk, Nicole Bassler, Lucia Campos Carrascosa, Naomi Flückiger, Robin Heiz, Sandro Wagen, Noreen Giezendanner, Alessandra Alberti, Yasemin Yaman, Dana Mahler, Dania Diem, Peter Lichtlen, David Urech
Complementarity-determining regions (CDRs) from rabbit antibodies targeting human MSLN, CD3 epsilon, and serum albumin were grafted onto a stability-promoting human variable domain acceptor scaffold in which framework region 4 (FR4) of the kappa-type light chain was replaced by a lambda-type FR4 (see Egan et al.,18 resulting in λcapped antibody Fvs and single-chain Fvs. The three target-specific variable domains were assembled into the trispecific, trivalent single-chain (sc) MATCH3 antibody format (NM28-1872) or into the trispecific, tetravalent MATCH4 antibody format (NM28-2746). See Table 1 for a guide to the MATCH molecules used in this study. The polypeptide chains were expressed in CHO cells and clarified from the cell supernatant by standard capture and polishing processes. NM21-1480 and its mouse analog (NM21-1601) were produced as described previously.19
Improved pharmacokinetics of HIV-neutralizing VRC01-class antibodies achieved by reduction of net positive charge on variable domain
Published in mAbs, 2023
Young D. Kwon, Amarendra Pegu, Eun Sung Yang, Baoshan Zhang, Michael F. Bender, Mangaiarkarasi Asokan, Qingbo Liu, Krisha McKee, Bob C. Lin, Tracy Liu, Mark K. Louder, Reda Rawi, Mateo Reveiz, Andrew J. Schaub, Chen-Hsiang Shen, Nicole A. Doria-Rose, Paolo Lusso, John R. Mascola, Peter D. Kwong
Previously, we reported that insertion of antibody VRC03 framework region 3 (03FR3) loop to VRC01-class antibodies improved potency, reduced polyreactivity, and improved PK.32 However, the mechanistic basis for the reduced polyreactivity and improved PK was unclear. In this study, we investigated the basis for reduced polyreactivity and increased half-lives of VRC01-class antibodies and found that four aspartates introduced by 03FR3 loop insertion were responsible for reduced polyreactivity. Based on this finding, we hypothesized that reducing net positive charge of the variable domain, in general, could serve as a means to improve antibody half-life and sought to improve the half-lives of VRC01-class antibodies, VRC07-523LS and N6LS, which are among the best-in-class, in terms of neutralization potency and breadth. We generated a panel of antibody variants with select Arg or Lys mutated to Asp, Gln, Glu, or Ser, and assessed polyreactivity, neutralizing potency, affinity to heparin, and in vivo half-lives in human FcRn transgenic mice. Our findings reveal reduction in net positive charge of an antibody variable domain as a means to improve its serum PK, while maintaining function: high potency and breadth of HIV−1 neutralization.
Rabbits transgenic for human IgG genes recapitulating rabbit B-cell biology to generate human antibodies of high specificity and affinity
Published in mAbs, 2020
Francesca Ros, Sonja Offner, Stefan Klostermann, Irmgard Thorey, Helmut Niersbach, Sebastian Breuer, Grit Zarnt, Stefan Lorenz, Juergen Puels, Basile Siewe, Nicole Schueler, Tajana Dragicevic, Dominique Ostler, Imke Hansen-Wester, Valeria Lifke, Brigitte Kaluza, Klaus Kaluza, Wim van Schooten, Roland Buelow, Alain C Tissot, Josef Platzer
We further looked at the impact of GC on mutation rate on both the CDR and FR (Framework Region) regions as illustrated in Figure 11(a,b). The DNA mutation rate in percentage compared to the reference best matching human germline was calculated for all CDRs and FRs of the BMP9 human binders (Figure 11(a)). The mutation rate was significantly higher in the CDR than the FR regions. In CDR2, the mutation rate is clearly increased for sequences having undergone 3 GC events, demonstrating the contribution of this mechanism to sequence diversity in addition to somatic hypermutation. In reverse, GC does not increase the mutation rate in the FR regions. To confirm the result, a quite comparable distribution was observed when a similar analysis was performed (on protein level) on 1700 human antigen-specific binders from 10 different immunization campaign (ca. 30 transgenic rabbits) (Figure 11(b)).