Intratumour factors influencing the access of antibody to tumour cells

Cobb, L. M.

doi:10.1007/bf00205231

Cited by 45 publications

(14 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…B-B4-DM1 toxicity in humans can therefore be examined only in a doseescalation phase 1 clinical trial. Several mAbs directed against epithelial antigens have been used in vivo to target malignancies of epithelial origin, and uptake of these antibodies by the tumors was higher than that by normal epithelia, [53][54][55] indicating that target cell accessibility 56 may vary in normal versus neoplastic tissues. In a clonogenic assay, a B-B4 immunotoxin was not effective in killing the CD138 ϩ HepG2 hepatocyte cell line or normal endothelial cells, but was potent against the MM cell line RPMI8226.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic activity of the maytansinoid immunoconjugate B-B4–DM1 against CD138+ multiple myeloma cells

Tassone

Goldmacher

Neri

et al. 2004

Blood

114

View full text Add to dashboard Cite

IntroductionFollowing the discovery of monoclonal antibody (mAb) technology, 1 numerous attempts have been made to use mAbs targeted to cancer-associated antigens for the treatment of human cancer. Of many mAbs tested, several were found to be therapeutically active, either as naked antibodies or as immunoconjugates of radionuclides. [2][3][4] Conjugates of antibodies with cytotoxic agents have also been explored as anticancer agents 2,3 as a means of improving the selectivity of cytotoxic drugs by targeting them to antigens preferentially expressed on the surface of malignant cells. Gemtuzumab ozogamicin (Mylotarg), a conjugate of anti-CD33 humanized monoclonal antibody with a highly cytotoxic DNA-damaging agent calicheamicin, has recently been approved by the FDA as the first drug of this type for clinical treatment of myeloid leukemia. [5][6][7] Immunoconjugates of the highly potent cytotoxic drug maytansine derivative DM1 (N 2Ј -deacetyl-N 2Ј -(3-mercapto-1-oxopropyl)-maytansine) are also being evaluated as antigen-targeted anticancer agents. 8 Maytansine 9 is a natural product originally derived from the Ethiopian shrub Maytenus serrata. This drug inhibits tubulin polymerization, 9-11 resulting in mitotic block and cell death. The cytotoxicity of maytansine is 200-to 1000-fold higher than that of anticancer drugs in clinical use that affect tubulin polymerization, such as Vinca alkaloids or taxol. However, clinical trials of maytansine indicated that it lacked a therapeutic window, due to high systemic toxicity. DM1 is 3-to 10-fold more cytotoxic than maytansine, and can be converted into a prodrug by linking it via disulfide bond to a mAb directed against a tumorassociated antigen. Such a conjugate (tumor-activated prodrug or TAP) is not cytotoxic in the blood compartment, since it is activated only upon binding to target cells, with subsequent release of the drug. 12 Several mAb-DM1 conjugates have been developed, 13 and, to date, huC242-DM1 and huN901-DM1 have been evaluated in clinical trials. These conjugates were well tolerated, did not induce any detectable immune response, and had a long circulation time. [14][15][16] The murine IgG1 mAb B-B4 binds to a linear epitope between residues 90 to 95 of the core protein on human syndecan-1 (CD138), a member of the family of transmembrane heparan sulfate proteoglycans. 17,18 This antigen was originally described as a membrane proteoglycan present on cells of epithelial origin, and was subsequently found on hematopoietic cells. 19 In the normal human hematopoietic compartment, CD138 expression is restricted to plasma cells 17,20 ; in particular, CD34 ϩ stem and progenitor cells do not express CD138. 17 In malignant hematopoiesis, CD138 is highly expressed on the majority of multiple myeloma (MM) cells, many Hodgkin lymphomas with classic Reed-Sternberg cells, 17,20 From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA; the VA Boston Healthcare System, Harvard Medical School, Boston, MA; the University of "Magna Graecia," Ca...

show abstract

Section: Discussionmentioning

confidence: 99%

Cytotoxic activity of the maytansinoid immunoconjugate B-B4–DM1 against CD138+ multiple myeloma cells

Tassone

Goldmacher

Neri

et al. 2004

Blood

114

View full text Add to dashboard Cite

show abstract

“…E48 F(ab')2 fragments however did show specific localisation in tumour tissue, and although the percentage ID/g was almost one third of the percentage ID/g of E48 F(ab')2 in HNX-HN bearing mice and the SLI of F(ab')2 in VX-A431 bearing mice was less than half the SLI of F(ab')2 in HNX-HN bearing mice, tumours could still well be visualised at day 1. These differences in percentage ID/g and specificity of localisation between the HNX-HN and VX-A431 xenograft lines might be due to such variables as vascularisation, blood vessel morphology and permeability, tumour microcirculation, necrosis, composition of extracellular matrix and intratumoural hydrostatic pressure, parameters likely to be of considerable influence on the efficacy of non-surgical modalities (Sands et al, 1988;Cobb, 1989;Kallinowski et al, 1989;Jain & Wie, 1977;Sweet et al, 1979;Hori et al, 1986).…”

Section: Methodsmentioning

confidence: 99%

Superior localisation and imaging of radiolabelled monoclonal antibody E48 F(ab')2 fragment in xenografts of human squamous cell carcinoma of the head and neck and of the vulva as compared to monoclonal antibody E48 IgG

Gerretsen

Quak²,

Suh³

et al. 1991

Br J Cancer

View full text Add to dashboard Cite

Monoclonal antibody (MAb) E48 and its F(ab')2 fragment, radiolabelled with 131I, were tested for tumour localisation and imaging in nude mice bearing a squamous cell carcinoma xenograft line derived from a head and neck carcinoma (HNX-HN) or from a vulva carcinoma (VX-A431). MAb IgG or F(ab')2 fragments were injected in parallel and at day 1, 2, 3 and 6 or 7, mice were either scanned with a gamma camera or dissected for determination of isotope biodistribution. In HNX-HN bearing mice, E48 IgG as well as F(ab')2 showed highly specific localisation in tumour tissue. The mean tumour uptake (n = 4) expressed as the percentage of the injected dose per gram of tumour tissue (percentage ID/g) of IgG was 11.9% at day 1 and increased to 14.6% at day 6 whereas percentage ID/g of F(ab')2 was 7.2% at day 1 and decreased during subsequent days. Tumour to blood ratios (T/B) at day 1 were 1.2 for IgG and 13.6 for F(ab')2 and reached a maximum at day 6 with values of 6.4 and 54.2 respectively. In VX-A431 bearing mice, only E48 F(ab')2 showed preferential localisation in tumour tissue. At day 1, Percentage ID/g of IgG was 3.7 and T/B was 0.3, while percentage ID/g of F(ab')2 was 2.4 and T/B was 3.2. Percentage ID/g decreased after day 1 while T/B increased. In these experiments no preferential localisation of either isotype matched 125I-labelled control IgG or F(ab')2 was observed. In F(ab')2 injected HNX-HN bearing mice as well as VX-A431 bearing mice, tumours could be visualised at day 1 and 2 without any appreciable background activity. With MAb IgG this was also possible in HNX-HN bearing mice (but not in VX-A431 bearing mice) but only at day 3 and 6. These findings suggest that the superior tumour to non-tumour ratios render the E48 F(ab')2 fragment more qualified for specific targeting of radioisotopes to tumour xenografts in this experimental setting. Images Figure 1 Figure 2 Figure 6 Figure 7 Figure 8

show abstract

“…Highly elevated IFP might lead to a pressure difference between the microvascular and interstitial space that is close to 0 mmHg and hence to inadequate uptake and heterogeneous distribution of monoclonal antibodies and other macromolecular therapeutic agents (Jain and Baxter, 1988;Cobb, 1989). Many human tumours show a maximum antibody uptake per gram of tissue of only around 0.005% of the injected dose per gram of body weight (Bradwell et al, 1985).…”

mentioning

confidence: 99%

Proton relaxation times and interstitial fluid pressure in human melanoma xenografts

Lyng

Tufto²,

Skretting³

et al. 1997

Br J Cancer

View full text Add to dashboard Cite

Summary The interstitial fluid pressure (IFP) and the proton spin-lattice and spin-spin relaxation times (T, and T2) of some experimental tumours have been shown to be related to tumour water content. These observations have led to the hypothesis that magnetic resonance imaging (MRI) might be a clinically useful non-invasive method for assessment of tumour IFP. The purpose of the work reported here was to examine the general validity of this hypothesis. R-1 8 human melanoma xenografts grown intradermally in Balb/c nu/nu mice were used as the tumour model system. Median T, and T2 were determined by spin-echo MRI using a 1 .5-T clinical whole-body tomograph. IFP was measured using the wick-in-needle technique. No correlation was found between tumour IFP and fractional tumour water content. Moreover, there was no correlation between median T, or T2 and IFP, suggesting that proton T, and T2 values determined by MRI cannot be used clinically to assess tumour IFP and thereby to predict the uptake of macromolecular therapeutic agents.Keywords: melanoma xenografts; interstitial fluid pressure; magnetic resonance imaging; relaxation times; tumour water content Most tumours show an elevated interstitial fluid pressure (IFP) compared with normal tissues (Jain, 1987). Highly elevated IFP might lead to a pressure difference between the microvascular and interstitial space that is close to 0 mmHg and hence to inadequate uptake and heterogeneous distribution of monoclonal antibodies and other macromolecular therapeutic agents (Jain and Baxter, 1988;Cobb, 1989). Many human tumours show a maximum antibody uptake per gram of tissue of only around 0.005% of the injected dose per gram of body weight (Bradwell et al, 1985). Antibodies are preferentially distributed in regions close to blood vessels, and there are many regions without or with negligible antibody uptake (Jones et al 1986;Sands et al, 1988).Measurements of IFP in human tumours using the wickin-needle technique have shown that the IFP can differ substantially among individual tumours of the same histological type (Boucher et al, 1991;Less et al, 1992). Patients with tumours showing an IFP close to normal tissue values, i.e. tumours with a significant pressure difference between the microvascular and interstitial space are more likely to benefit from treatment modalities involving macromolecular therapeutic agents than patients with highly elevated tumour IFP (Jain and Baxter, 1988). The wickin-needle technique is invasive and can be used to measure IFP only in superficial tumours. A non-invasive method for measurement of IFP would therefore be useful for predicting the uptake of macromolecules in tumours and hence therapeutic response.Studies of experimental tumours have suggested that the IFP is related to tumour water content in some tumour lines (Lee et al, 1992;Leunig et al, 1994). The proton spin-lattice and spin-spin relaxation times (T1 and T2) of tumour tissue are, to a large extent, (Braunschweiger et al, 1986;Belfi et al, 1991). These observations have le...

show abstract

Intratumour factors influencing the access of antibody to tumour cells

Cited by 45 publications

References 41 publications

Cytotoxic activity of the maytansinoid immunoconjugate B-B4–DM1 against CD138+ multiple myeloma cells

Cytotoxic activity of the maytansinoid immunoconjugate B-B4–DM1 against CD138+ multiple myeloma cells

Superior localisation and imaging of radiolabelled monoclonal antibody E48 F(ab')2 fragment in xenografts of human squamous cell carcinoma of the head and neck and of the vulva as compared to monoclonal antibody E48 IgG

Proton relaxation times and interstitial fluid pressure in human melanoma xenografts

Contact Info

Product

Resources

About