Physiological Antibodies

Before discussing the pharmacokinetic characteristics of therapeutic mAbs, the present section will focus on the catabolism of physiological antibodies. This process is also highly relevant for therapeutic mAbs. 

Antibodies have been generated which produce immunoassays that discriminate between GH-V and GH-N. These assay systems have shown that the secretion of GH-V becomes elevated at about three weeks of pregnancy and increases to approximately 15 ng/mL near term (8). The physiological role of GH-V is uncertain. Genetic deficiency of GH-V does not adversely affect pregnancy or fetal development (9). GH-V is a potent growth-stimulator but possesses considerably less lactogenic activity than GH-N (10). There are no clinical appHcations (ca 1993) for GH-V. 

Radiotracers have also been used extensively for the quantitative rnicrodeterrnination of blood semm levels of hormones (qv), proteins, neurotransmitters, and other physiologically important compounds. Radioimmunoassay, which involves the competition of a known quantity of radiolabeled tracer, usually I or H, with the unknown quantity of semm component for binding to a specific antibody that has been raised against the component to be deterrnined, is used in the rnicro deterrnination of physiologically active materials in biological samples (see Immunoassay). 

The chimeric human/murine (basiliximab and dacluzi-mab) or murine (inolimomab) monoclonal antibodies are specifically directed against a part (CD25) of the interleukin-2 (IL-2) receptor. Binding of one of these antibodies to CD25 thereby displaces physiological IL-2 and prevents proliferation of activated T-lymphocytes. 

K. Sikora, Monoclonal antibodies and drug targeting in cancer, in Targeting of Drugs. Anatomical and Physiological Considerations (G. Gregoriadis and G. Poste, eds.), Plenum Press, New York, 1987, p. 69. 

A domino RCM of an ene-yne was also used by Granja and coworkers [250] for their synthesis of the B-bishomo-steroid analogue 6/3-70. Reaction of the substrate 6/3-69 with the ruthenium catalyst 6/3-13 led to 6/3-70 in 48% yield as a 6.5 l-mix-ture of the two C-10-epimers (Scheme 6/3.20). The aim of this study was to prepare haptenes for the production of catalytic monoclonal antibodies that could be used to study the mechanism of the physiologically important transformation of previtamin D3 into vitamin D3 [251]. 

Square-650-pH having a pKa in the physiological pH range (pKa = 7.1 for free dye and the pKa 6.1 when labeled to an antibody) was recently introduced by SETA BioMedicals [119]. This dye is commercially available as a free carboxylic acid and a mono-NHS ester. Square-650-pH has spectral properties similar to those of the CypHer dyes but is fluorescent in both the protonated and deproto-nated forms. This dye displays reasonable molar absorptivities (135,000 and 48,000 M-1cm-1) and quantum yields (16% and 9%) for the protonated and deprotonated forms, an extremely large Stokes shift of more than 100 nm for the deprotonated form, and enables excitation and emission ratiometric measurement... 

In passively immunized neonatal rats, Tyv-specific antibodies exclude larvae from the epithelium (Appleton et al., 1988), where large numbers of excluded larvae become entrapped in mucus (Carlisle et al., 1991a). Similarly, when immune adult rats are challenged with larvae, many luminal parasites are observed entrapped in mucus (Lee and Ogilvie, 1982 Bell et al, 1984). Larvae are neither injured nor killed by mucus entrapment, which is reversible and is not a requirement for expulsion (Carlisle et al., 1990). Rather, mucus appears to participate in expulsion by temporarily confining larvae to the lumen, thus facilitating their elimination from the intestine by normal physiological processes. 

Another potential source of iron, at least for hepatocytes, is receptor-independent uptake of iron from transferrin. This appears to involve an iron uptake pathway from transferrin which is neither suppressed in hepatocytes by antibodies to TfR (Trinder et at, 1988), nor by transfection of HuH-7 hepatoma cells with transferrin receptor anti-sense cDNA (Trinder etat, 1996). The same pathway may also be utilized for iron uptake from isolated transferrin N-lobe, which is not recognized by the receptor (Thorstensen et at, 1995). The possible role of TfR2 in this process remains to be established, as does the physiological importance of this pathway in intact liver. Human melanoma cells (Richardson and Baker, 1994) and Chinese hamster cells lacking transferrin receptors but transfected with melanotransferrin (Kennard et at, 1995) use another pathway for transferrin iron uptake, independent of the transferrin receptor, but utilizing iron transfer from transferrin or simple iron chelates to membrane-anchored melanotransferrin, and from there onwards into the cellular interior. 

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