Lars Lindgren

Extracorporeal immunoadsorption therapy on rats. In vivo depletion of specific antibodies

A technique for extracorporeal immunoadsorption of circulating specific antibodies from the plasma of rats is described. Catheterization of rats was performed using the carotid and the jugular blood vessels. The rats were treated non‐anaesthetized. Blood was pumped continuously through a hollow‐fibre plasma filter at a rate of 1.5 ml/min and plasma was separated and passed through an adsorbent column at a flow of 0.2 ml/min. The treated plasma was mixed with the blood cells before being returned to the rat. The column contained the antigen covalently linked to agarose beads. About three plasma volumes were treated during a period of 3 h and 30 min, which resulted in an antibody depletion of about 90–95%. The antibody levels returned to pre‐adsorption levels after 4–5 days, or in some cases even exceeded the titres before treatment.

Improving radioimmonotargeting of tumors. Variation in the amount of L6 MAb administered, combined with an immunoadsorption system (ECIA).

Extracorporeal immunoadsorption (ECIA) is a new method for the selective removal of circulating radiolabeled monoclonal antibodies (MAb) from plasma to increase the uptake in tumor versus normal tissues (T/N-ratio). To ascertain whether the amount of MAb affects T/N ratios immediately and 24 h after ECIA, we used a rat model with two tumor sites--one intramuscular (im) and one below the subrenal capsule (SR). Extracorporeal immunoadsorption was done with an avidin-agarose column after injection of 125I-labeled biotinylated L6 MAb. The animals received 10, 50 or 250 micrograms of L6 only (controls), or followed by ECIA. The efficacy of the procedure in removing plasma activity was 80-95%. For both tumor sites, the highest T/N-ratios were obtained with 10 micrograms L6. All T/N-ratios significantly improved for SR tumors by a factor ranging from 3.2 (lung) to 12.6 (bone marrow). The T/N-ratios were still elevated 24 h after ECIA. Injection of larger amounts of MAb, probably causing a higher degree of tumor saturation, will not necessarily improve the T/N ratio after ECIA.

Blood Pharmacokinetics of Various Monoclonal Antibodies Labeled with a New Trifunctional Chelating Reagent for Simultaneous Conjugation with 1,4,7,10-Tetraazacyclododecane-N,N′,N″,N‴-Tetraacetic Acid and Biotin before Radiolabeling

Purpose: Knowledge of the blood pharmacokinetics of monoclonal antibodies is crucial in deciding the optimal time for starting the administration of a “clearing agent” or using a “clearing device.” The primary purpose was to investigate whether the pharmacokinetics of various antibodies labeled with the same chelator and 111In differed significantly after i.v. injection in immunocompetent rats. A new trifunctional chelator called “1033” containing a biotin and a radiometal chelation moiety is introduced, making it possible to use only one conjugation procedure for the antibody. Experimental Design: Sixty-five non–tumor-bearing rats were included and divided into four groups (I-IV). The blood pharmacokinetics was investigated for rituximab, BR96, and trastuzumab labeled with 1033 and 111In (I-III). The whole-body activity and activity uptake in muscle, liver, and kidney, which might explain differences in the early pharmacokinetics in blood, were also measured. hMN14 labeled with another chelator [1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA)], but with the same radionuclide (111In-biotin-DOTA-hMN14), was studied (IV). The blood pharmacokinetics from another 15 tumor-bearing rats was compared with those of non–tumor-bearing rats (III) by injection of 111In-1033-BR96. Results: No statistical difference was detected between the groups regarding the blood pharmacokinetics of rituximab, BR96, or trastuzumab. The pharmacokinetics and biodistribution of 111In-biotin-DOTA-hMN14 exhibited a clear difference compared with others. There were no significant differences in the blood pharmacokinetics of 111In-1033-BR96 between tumor-bearing rats and non–tumor-bearing rats. Conclusions: Different antibodies labeled with the trifunctional chelator 1033 and 111In did not exhibit different blood pharmacokinetics, which means that the pharmacokinetics could be predicted irrespective of the IgG1 antibody chosen. A small tumor burden did not change the pharmacokinetics of the radioimmunoconjugates.

A general extracorporeal immunoadsorption method to increase tumor-to-tissue ratio

The idea of applying extracorporeal immunoadsorption (ECIA) in radioimmunodiagnosis and radioimmuno‐therapy has been proposed previously. The authors here report on the development of new concept using a general method for ECIA based on biotinylated MoAb adsorbed on an avidin column.

Electric roads: The importance of sharing the infrastructure among different vehicle types

Electric Road Systems (ERS) are analysed here as a feasible solution for the electrification of heavy traffic, where the predominant approach for passenger cars based only on batteries and a network of fast-charging stations combined with slower overnight charging becomes unrealistic due to the large amount of batteries required. Nonetheless, this study shows that in most cases, building such ERS so that they can be used by both types of vehicles results in added value to society.