Comparison of the pharmacokinetics, biodistribution and dosimetry of monoclonal antibodies OC125, OV-TL 3, and 139H2 as IgG and F(ab')2 fragments in experimental ovarian cancer

Abstract

Monoclonal antibody (MAb) 139H2 was previously shown to localise specifically into ovarian cancer xenografts in nude mice. MAb 139H2 was compared with MAbs OC125 and OV-TL 3, all reactive with ovarian carcinomas, for the binding characteristics as IgG and F(ab')2 fragments with the use of the OVCAR-3 cell line grown in vitro and as s.c. xenografts. Immunoperoxidase staining of OVCAR-3 tissue sections with MAbs OC125 and 139H2 was heterogeneous, whereas MAb OV-TL 3 showed homogeneity. No differences in binding were observed between IgG and F(ab')2. The avidity expressed as apparent affinity constants of MAbs OC125, OV-TL 3 and 139H2 for OVAR-3 cells were 1 x 10(9) M-1, 1 x 10(9) M-1, and 1 x 10(8) M-1, while the number of antigenic determinants were 5 x 10(6), 1 x 10(6) and 7 x 10(6), respectively. In OVCAR-3 bearing nude mice the blood half-lives of the MAbs as IgG and F(ab')2 were approximately 50 h and 6 h, respectively. Maximum tumour uptake for the whole MAbs OC125, OV-TL 3, 139H2 and a control MAb 2C7 was 8.5%, 17.7%, 11.1% and 2.5% of the injected dose g-1, reached at 72 h after injection. For the respective F(ab')2 fragments, the maximum values were 5.2%, 10.0%, 5.5% and 1.9% of the injected dose g-1, reached between 6 h and 15 h. Tumour to non-tumour ratios were more favourable for the F(ab')2 fragments as compared to those for MAbs as IgG. Biodistribution in mice bearing a control tumour confirmed the specificity of tumour localisation of MAbs OC125, OV-TL 3 and 139H2. After injection of a tracer dose of 10 microCi of radiolabelled MAbs OC125, OV-TL 3 and 139H2 as IgG, tumours received 38 cGy, and 9 cGy. In our OVCAR-3 model, a ranking in efficiency in tumour localisation would indicate MAb OV-TL 3 as most favourable MAb, but cross-reactivity with subpopulations of human white blood cells might hamper its clinical use. Dosimetric data indicate a 4-fold higher radiation absorbed dose to tumours for IgG compared with F(ab')2 fragments.

A Comparison of thein Vitroandin VivoActivities of IgG and F(ab′)2 Fragments of a Mixture of Three Monoclonal Anti-Her-2 Antibodies

“…The results indicated that the half-life of the IgG is 5-fold longer than that of its corresponding F(abЈ) 2 fragment. This correlates with the reported half-life values of 120 -200 h for IgG and 12-57 h for F(abЈ) 2 fragments (27)(28)(29).…”

Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu

“…The tumour-bone marrow estimate of 12:1 and tumour-kidney value of 2.6:1 would permit the delivery of approximately 4000 cGy to tumour at a marrow dose of 250 cGy. This represents a significant improvement over results in preclinical models observed with other antibody-based molecules, including scFv (Adams et al, unpublished results), (scFv')2 , Fab (Yorke et al, 1991), F(ab')2 (Stein et al, 1991(Stein et al, , 1994 and IgG (Stein et al, 1991;Molthoff et al, 1991Molthoff et al, , 1992. While the predicted tumour-blood AUCs for Flex minibodies are similar to those reported here for the C6.5 diabody, the smaller diabody structure may confer an advantage when penetration of large solid tumours is required.…”

Pharmacokinetics of Monoclonal Antibodies

“…The mAbs that have a target in the tissue compartment are expected to potentially have a greater volume of distribution. For endogenous and exogenous antibodies, the tissue:blood concentration ratio is in the range of 0.1–0.5 (i.e., mAb concentrations are substantially lower in the tissue interstitial fluid than in plasma) . For brain tissue, the ratio is even in the range of 0.01 or lower, but may be higher in cases of compromised blood‐brain barrier .…”

“…For brain tissue, the ratio is even in the range of 0.01 or lower, but may be higher in cases of compromised blood‐brain barrier . In cases where the mAb binds with high affinity to extravascular sites with high binding capacity tissue:blood concentration ratios may be much higher . It is worth noting that, in cases in which the binding capacity of the target is limited, a nonlinear distribution could occur where the volume at steady‐state decreases with increasing plasma mAb concentrations …”