Antibodies cytotoxic complexes

IVpe 2, cytotoxic reaction. Drug-antibody (IgG) complexes adhere to the surface of blood cells, where either circulating drug molecules or complexes al-Lullmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of iicense. 

Humanized anti-CD33 antibody linked to calicheamicin, a potent toxin binding to the CD33 receptor results in internalization of the antibody-antigen complex calicheamicin is then released intracellularly and exerts cytotoxicity by causing DNA double-strand breaks, resulting in cell death... 

Perifascicular capillaries are closer to aggregates of antibody-secreting cells (B-lymphocytes) situated in perimysial connective tissue and therefore are most severely affected by antibody-dependent cytotoxic reactions. Immune-complex deposition occurs at a higher level in the vascular tree (i.e., at arteriolar level) and this may cause fluctuations in perfusion pressure. Perifascicular capillaries are most distal from the head of vascular pressure and therefore most likely to suffer from periodic anoxia. 

NHS-LC-biotin can be used to add a biotin tag to monoclonal antibodies directed at certain tumor antigens. The biotinylated monoclonals are allowed to bind to the tumor cell surfaces in vivo, and subsequent administration of an avidin or streptavidin conjugate can form the basis for inducing cytotoxic effects or creating traceable complexes for use in imaging techniques (Hnatowich et al., 1987). 

Figure 21.1 The basic design of an immunotoxin conjugate consists of an antibody-targeting component crosslinked to a toxin molecule. The complexation typically includes a disulfide bond between the antibody portion and the cytotoxic component of the conjugate to allow release of the toxin intracellularly. In this illustration, an intact A-B toxin protein provides the requisite disulfide, but the linkage also may be designed into the crosslinker itself.

A-chain immunotoxins, however, may not be quite as cytotoxic as conjugates formed from intact toxin molecules (Manske et al., 1989). In an alternative approach to A chain use, the intact toxin of two-subunit proteins is directly conjugated to a monoclonal without isolation of the A chain. Conjugation of an antibody with intact A-B chain toxins can be done without a cleavable linker, as long as the A chain can still separate from the B chain once it is internalized. Therefore, it is important to avoid intramolecular crosslinking during the conjugation process which can prevent release of the A-B complex. In addition, since the B chain... 

The method for the preparation of immunotoxins with SMPB is identical to that used for MBS (above). Since the thioether bonds formed with sulfhydryl-containing molecules are non-cleavable, A-chain isolates or single-chain toxin molecules can not be conjugated with antibodies with retention of cytotoxicity. Only intact A-B toxin molecules may be used with this crosslinker, since the A chain still is capable of being reductively released from the complex. 

Lymphocytes, the effector cells of the acquired immune system, include morphologically indistinguishable T and B cells, the former divided into CD4+ T helper cells and CD8+ cytotoxic T cells. Since the functions of those cell subsets differ so drastically, it became important to develop tools to distinguish them from each other. Efforts to identify cell subsets according to their expression of different surface antigens have been successful, including various Cluster of Determination (CD) markers (Table 23.1). In addition, cross-reactive monoclonal antibodies, and subsequently developed species-specific polyclonal and monoclonal antibodies towards the major histocompatibility complex (MHC) have been used to label cells in circulation and in tissue sections (Table 23.1). 

Types II and III Hypersensitivity. No simple animal models are currently available to assess Type II (antibody-mediated cytotoxicity) hypersensitivity reactions. IgE antibodies and immune complexes in the sera of exposed animals can be assayed using ELISA or RIA techniques that require the use of specific antibodies to the drug. 

Immunoglobulin M (IgM), a membrane protein on the surface of B lymphocytes, serves to bind free antigens to the B cells. By contrast, T cell receptors only bind antigens when they are presented by another cell as a complex with an MHC protein (see below). Interaction between MHC-bound antigens and T cell receptors is supported by co-recep-tors. This group includes CDS, a membrane protein that is typical in cytotoxic T cells. T helper cells use CD4 as a co-receptor instead (not shown). The abbreviation CD stands for cluster of differentiation. It is the term for a large group of proteins that are all located on the cell surface and can therefore be identified by antibodies. In addition to CD4 and CDS, there are many other co-receptors on immune cells (not shown). 

---