Antibody targeting of tumours holds great potential for diagnosis and therapy but has been limited by poor uptake efficiency. we have developed a mathematical compartmental model to analyse antibody distribution between body compartments after intravenous injection. This suggested two fundamental requirements to improve uptake: very high antibody affinity and a large injected dose. This was tested in 6 patients with primary colorectal tumours using a high affinity (10(10)M-1) technetium labelled anti-CEA monoclonal antibody (BW431/26). Each patient was scanned after 1 mg of antibody and again after a higher dose (1mg labelled;12-30mg cold antibody). Tumour uptake ratios following the higher dose were significantly increased. Fitting the model parameters to patient data including plasma clearance, uptake ratios from SPECT and planar scans and tumour CEA levels, showed that measured:available tumour antigen ratios were around 10:1. Therefore in an attempt to increase antigen accessibility, 3 patients with recurrent colorectal cancer (8 tumour Bites), were given a 24 hour course of dexamethasone (to increase tumour blood flow) between 2 high dose (20mg) scans. This resulted in an average increase in uptake ratio of 60%. In addition, lesions not seen prior to steroid administration were visualised. The results of this pilot study indicate that high doses of high affinity antibody and increased antigen access can improve antibody targeting of colorectal cancer.

To determine the relative importance of factors influencing tumour uptake of antibodies, we used a mathematical model to simulate intravenous injection of substances of varying molecular sizes and tumour-binding affinities at several dose levels. The FACSIMILE program was used to simulate the time course of tumour uptake of the tumour-binding substance by calculating the instantaneous tumour content (TC) and tumour:background uptake ratios (UR). Relative total doses to tumour and normal tissue were calculated by integration of TC/time curves. The model was used to make theoretical predictions on the effects of altering different parameters. The size of the injected dose in relation to the number of tumour receptors was crucial:if too low, uptake could not be improved by manipulating other variables, and if too high, the UR for large binding molecules was reduced. Using the standard scanning dose of labelled antibody, absolute numbers of labelled molecules binding to tumour could be increased by injection of a large excess of unlabelled molecules. Given an adequate dose, peak tumour content increased with increasing affinity up to receptor saturation. The peak uptake ratio rose progressively with affinity for a small ligand, but reached a relatively low plateau for antibody due to constant high background levels. At low doses such as those currently administered for diagnostic scanning with antibody, no effect of increasing affinity was predicted.

A mathematical model has been developed to optimize tumor targeting with labeled antibodies. The model is compartmental and nonlinear, incorporating saturable binding. Published parameter values have been used in the model, and the resulting stiff differential equations have been solved using FACSIMILE, a computer package that can simulate very stiff differential systems. Results show that successful tumor targeting depends on an optimal combination of antibody dose, affinity, and molecular size. The model has allowed an assessment to be made of the complicated and interrelated dynamic relationships that these factors have on tumor targeting. It has also offered an explanation for previously unsatisfactory results from tumor targeting with labeled antibodies. The structural identifiability of the model parameters is also analyzed and it is shown that, with the prior knowledge of some parameters which is likely in practice, the remaining model parameters are uniquely identifiable.

A mathematical model has been developed to determine the best approach to improving tumor targeting with antibody. The amount of antibody in the tumor (tumor content) and the tumor:normal tissue antibody concentration ratio (uptake ratio) were calculated over 12 days from injection, using the computer program FACSIMILE to solve the stiff nonlinear differential equations describing the system. Results indicate that success requires an optimal combination of dose, size, and binding affinity of antibody. Increasing the dose to 100 times that presently used for scanning increased both the percentage of injected antibody in the tumor and the uptake ratio by up to 2 orders of magnitude to maximal values determined by affinity. This result could be achieved by coinjecting unlabeled antibody. Increasing affinity from Keq = 10(9) to 10(13)M-1 increased the uptake ratio from 5 to 100 for whole antibody and to 550 for a small ligand, at the calculated optimal dose, but had no effect at the current scanning dose. With decreasing molecular size at average affinity, the same maximum tumor content and uptake ratio were achieved but progressively earlier. At high affinity there was a substantial advantage for a small ligand compared with whole antibody in terms of uptake ratio (550 versus 100) and tumor:normal tissue integral dose ratio (330 versus 60). The uptake of a small ligand was not increased by binding to plasma protein but with increasing time the tumor content was higher than without protein binding.

Conference Abstract| January 01 1988 Limitations of Antibodies for Immunoscintigraphy of Tumours GD Thomas; GD Thomas 1Department of Immunology, Medical School, Birmingham University, B15 2TJ, UK and Department of Mathematics, Brandon University, Manitoba, Canada Search for other works by this author on: This Site PubMed Google Scholar AR Bradwell; AR Bradwell 1Department of Immunology, Medical School, Birmingham University, B15 2TJ, UK and Department of Mathematics, Brandon University, Manitoba, Canada Search for other works by this author on: This Site PubMed Google Scholar PW Dykes; PW Dykes 1Department of Immunology, Medical School, Birmingham University, B15 2TJ, UK and Department of Mathematics, Brandon University, Manitoba, Canada Search for other works by this author on: This Site PubMed Google Scholar JG Williams; JG Williams 1Department of Immunology, Medical School, Birmingham University, B15 2TJ, UK and Department of Mathematics, Brandon University, Manitoba, Canada Search for other works by this author on: This Site PubMed Google Scholar J Ellis J Ellis 1Department of Immunology, Medical School, Birmingham University, B15 2TJ, UK and Department of Mathematics, Brandon University, Manitoba, Canada Search for other works by this author on: This Site PubMed Google Scholar Clin Sci (Lond) (1988) 74 (s18): 59P. https://doi.org/10.1042/cs074059Pb Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Citation GD Thomas, AR Bradwell, PW Dykes, JG Williams, J Ellis; Limitations of Antibodies for Immunoscintigraphy of Tumours. Clin Sci (Lond) 1 January 1988; 74 (s18): 59P. doi: https://doi.org/10.1042/cs074059Pb Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu nav search search input Search input auto suggest search filter All ContentAll JournalsClinical Science Search Advanced Search This content is only available as a PDF. © 1988 The Biochemical Society and the Medical Research Society1988 Article PDF first page preview Close Modal You do not currently have access to this content.