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. 2009 Apr;1(1):32-50.

Modern Technologies for Creating Synthetic Antibodies for Clinical application

S M Deyev  1 , E N Lebedenko
Affiliations

Modern Technologies for Creating Synthetic Antibodies for Clinical application

S M Deyev et al. Acta Naturae. 2009 Apr.

Abstract

The modular structure and versatility of antibodies enables one to modify natural immunoglobulins in different ways for various clinical applications. Rational design and molecular engineering make it possible to directionally modify the molecular size, affinity, specificity, and immunogenicity and effector functions of an antibody, as well as to combine them with other functional agents. This review focuses on up-to-date methods of antibody engineering for diagnosing and treating various diseases, particularly on new technologies meant to refine the effector functions of therapeutic antibodies.

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Figures

Fig. 1.
Fig. 1.
Natural antibodies and their fragments. Fab and (Fab)2 are antigen-binding IgG fragments produced by papain and pepsin hydrolysis, respectively; Fc is the C-end part of IgG composed of CH2 and CH3 constant domains of heavy chains responsible for effector functions; Fv is the variable fragment composed of variable domains of light (VL) and heavy (VH) chains; scFv is the single-chain variable fragment composed of VL and VH (conjugated by the gene engineering method); VHH is the nanoantibody, variable domain of cartilaginous fish and Camelidae antibodies containing only heavy chains; -S-S- is the disulfide bond. The indicated linear dimensions of antibodies and their fragments were measured by force microscopy methods [2, 3]; hydrodynamic diameter dc was calculated by the Stokes-Einstein formula [4, 5].
Fig. 2.
Fig. 2.
Interaction Pattern of Unloaded antibodies and Target Cell. (1) antibodies can cause apoptosis or block the proliferation of target cells, binding with membrane antigens on their surface (membrane raft mechanism) . (2) antibody-dependent cellular cytotoxicity (ADCC). Killer cells carrying receptors of IgG FcyRI (CD16), FcyRII (CD32), FcyIII (CD64) constant domains (natural killers, killers activated by lymphokines, macrophages, and phagocytes) and receptors of IgE FcεRI and FcεRII (CD23) constant domains (acidocytes) on their surface attack the target cell, whose surface antigens were bound with antibodies. (3) Complement-dependent cytotoxicity (CDC). antibodies conjugated in pairs bind to protein C1q complex, causing a cascade of reactions of the complement system, which leads to membrane destruction. Some products of this reaction cascade involve immune cells or cause allergic shock.
Fig. 3.
Fig. 3.
Modification of mouse monoclonal antibodies (Mab) for clinical application. The following Mab fragments produced by gene engineering are considered: (1) single chain antibodies (scFv or mini-antibodies) of different specificity and composed of VL- and VH-domains bound by peptide linker; (2) bispecific mini-antibody; (3) dimeric mini-antibody; (4, 5) dimmer and trimer of mini-antibody bound by the barnase-barstar module; (6) conjugate of mini-antibody with bioactive agent produced by the gene engineering method; (13) human Mab with modified constant domains; (14) human Mab with modified carbohydrate component (15). Legends of antibodies and their fragments are as in Fig. 1; hypervariable sites of variable domains (CDR) are indicated with black color; mouse antibodies and fragments, with dark gray; human antibodies and fragments, with light grey; variable domains of different specificity (1-5) and modified constant domains (13) are indicated with hatching. White semicircle and black triangle denote barnase and barstar, respectively. A denotes the bioactive component (radioactive isotope, toxin, ferment, fluorescent protein, etc.).
Fig. 4.
Fig. 4.
Scheme of two-stage target-killing technologies. (1) Pretargeting using antibodies with the following target killing by the involved a agent. (2) Preliminary delivery of E ferment to the target. at the second stage, E ferment transforms the nonactive medicine precursor into an active form (aDEPT, antibody-directed enzyme pro-drug therapy).
Fig. 5.
Fig. 5.
Immunodibarnase as a perspective agent for treating malignant neoplasms . (1) Scheme of immunodibarnase structure. (2) Interaction of immunodibarnase with the cells expressing the HER2/neu cancer marker: surface binding at 4°C (a) and internalization at 37°C (B). (3) Cytotoxicity of immunodibarnase for the cells with hyperexpression of the HER2/neu cancer marker.
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