Linker Technology: Antibody-Mediated Delivery Systems

Rodwell, John D.; McKearn, Thomas J.

doi:10.1038/nbt1085-889

Cited by 13 publications

(10 citation statements)

References 15 publications

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“…Site-specifically conjugated tumor-targeting antibodies have been shown to exhibit a greater uptake at the cancerous site and less non-specific uptake in off-target tissues compared to heterogeneous immunoconjugates [4], [5]. A similar tendency has been observed for stoichiometry: antibodies with a high number of conjugated entities were cleared faster from the blood, counteracting the high tumor accumulation [6].…”

Section: Introductionmentioning

confidence: 76%

DOTA-Functionalized Polylysine: A High Number of DOTA Chelates Positively Influences the Biodistribution of Enzymatic Conjugated Anti-Tumor Antibody chCE7agl

et al. 2013

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Site-specific enzymatic reactions with microbial transglutaminase (mTGase) lead to a homogenous species of immunoconjugates with a defined ligand/antibody ratio. In the present study, we have investigated the influence of different numbers of 1,4,7,10-tetraazacyclododecane-N-N′-N′′-N′′′-tetraacetic acid (DOTA) chelats coupled to a decalysine backbone on the in vivo behavior of the chimeric monoclonal anti-L1CAM antibody chCE7agl. The enzymatic conjugation of (DOTA)1-decalysine, (DOTA)3-decalysine or (DOTA)5-decalysine to the antibody heavy chain (via Gln295/297) gave rise to immunoconjugates containing two, six or ten DOTA moieties respectively. Radiolabeling of the immunoconjugates with 177Lu yielded specific activities of approximately 70 MBq/mg, 400 MBq/mg and 700 MBq/mg with increasing numbers of DOTA chelates. Biodistribution experiments in SKOV3ip human ovarian cancer cell xenografts demonstrated a high and specific accumulation of radioactivity at the tumor site for all antibody derivatives with a maximal tumor accumulation of 43.6±4.3% ID/g at 24 h for chCE7agl-[(DOTA)-decalysine]2, 30.6±12.0% ID/g at 24 h for chCE7agl-[(DOTA)3-decalysine]2 and 49.9±3.1% ID/g at 48 h for chCE7agl-[(DOTA)5-decalysine)]2. The rapid elimination from the blood of chCE7agl-[(DOTA)-decalysine]2 (1.0±0.1% ID/g at 24 h) is associated with a high liver accumulation (23.2±4.6% ID/g at 24 h). This behavior changed depending on the numbers of DOTA moieties coupled to the decalysine peptide with a slower blood clearance (5.1±1.0 (DOTA)3 versus 11.7±1.4% ID/g (DOTA)5, p<0.005 at 24 h) and lower radioactivity levels in the liver (21.4±3.4 (DOTA)3 versus 5.8±0.7 (DOTA)5, p<0.005 at 24 h). We conclude that the site-specific and stoichiometric uniform conjugation of the highly DOTA-substituted decalysine ((DOTA)5-decalysine) to an anti-tumor antibody leads to the formation of immunoconjugates with high specific activity and excellent in vivo behavior and is a valuable option for radioimmunotherapy and potentially antibody-drug conjugates (ADCs).

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Section: Introductionmentioning

confidence: 76%

DOTA-Functionalized Polylysine: A High Number of DOTA Chelates Positively Influences the Biodistribution of Enzymatic Conjugated Anti-Tumor Antibody chCE7agl

et al. 2013

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“…The optimal choice of the toxic agent might vary from application to application. In certain cases radioactive nuclides like 90Y and other high-energy beta emitters could be useful and in other cases cytostatics or toxins might be more beneficial (Rodwell, 1988;Quash and Rodwell, 1989). Cultured cells with large amounts of EGF receptors can be selectively killed by EGF-toxin conjugates (Herschman et al, 1982;Shimizu et al, 1984;Vollmar et al, 1987;Amano et al, 1988;Ozawa et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

“…One approach to circumvent this is the attempted use of antibody-mediated delivery systems, in which antibodies specifically carry toxic agents to the tumor cells (Rodwell, 1988;Quash and Rodwell, 1989). This is called "targeting" of toxic agents and the anti-tumor agent is specifically directed to the malignant cells in the hope of causing only small or nearly no side-effects to normal tissue.…”

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confidence: 99%

“…The conjugate should be internalized into the target cells and the carrier part with its toxic load, for example radioactive nuclides, should remain inside the cells for the time needed to inactivate cell proliferation (Vaughan et al, 1987;Wheldon et al, 1988;Capala et al, 1990). If the toxic agent is a cytostatic drug, it has to be cleaved off from the conjugate to be active in the cytoplasm or in the cell nucleus (Rodwell, 1988;Quash and Rodwell, 1989). EGF-dextran conjugates with different radiolabelled parts were constructed for the analysis of binding to the EGF-receptor, the internalization in the test cells, the time pattern of degradation and the comparison with properties of radiolabelled unconjugated EGF.…”

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confidence: 99%

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Binding of epidermal growth factor‐dextran conjugates to cultured glioma cells

Andersson¹,

Holmberg²,

Carlsson³

et al. 1991

Intl Journal of Cancer

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Some gliomas, melanomas and squamous carcinomas have large numbers of EGF receptors which could, in these cases, be used for targeting with toxic agents. We investigated whether EGF could be conjugated to dextran, which is a suitable carrier for toxic agents, without losing its ability to bind to the receptor. Dextran of 20 kDa molecular weight was activated with I-cyano-4-dimethylamino pyridinium tetrafluoroborate (CDAP) yielding highly active pyridinium-isourea derivatives. EGF was coupled to the activated dextran through the amino terminus and glycine was added to block residual activity. The EGF-dextran conjugate was, after purification on Sephadex G25 and Sephacryl 200 columns, tested for its receptor binding properties on human malignant glioma, U343MGaC12:6, cells. The conjugate inhibited binding of 125I-EGF in a competitive assay, showing that the binding was receptor-specific. Dextran conjugated with glycine, without EGF, had no inhibitory effect. The conjugate was radio-labelled either on the EGF part with 125I or on the dextran part with 3H-glycine, and the internalization patterns were compared to the internalization of 125I-EGF. The radioactivity of the conjugates remained cell-associated for more than 20 hr, regardless of whether the radioactivity was on the EGF or on the dextran part, while the radioactivity of unconjugated EGF rapidly disappeared from the cells. Most of the cell-associated radioactivity was, at all analysed time intervals, located intracellularly. Thus, it seems promising to use dextran, conjugated with EGF, as a carrier of, for example, toxic radioactive nuclides.

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“…Such modifications can lead to dramatic losses in pharmacological activity of the drug [21,23] and decreases in the antigen-binding capacity of the antibody [1,10]. As targeting the drug to a tumour via one of the antigen-binding sites of the bispecific antibody allows concentration of free pharmacologically active drug at the tumour site, this mode of transport could overcome the antigenic heterogeneity of tumour cells [2,13].…”

Section: Introductionmentioning

confidence: 99%

Suppression of well-established tumour xenografts by a hybrid-hybrid monoclonal antibody and vinblastine

Smith

Gore

Brandon

et al. 1990

Cancer Immunol Immunother

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The hybrid-hybrid monoclonal antibody 28-19-8 has specificity for the tumour-associated antigen carcinoembryonic antigen and the vinca alkaloids. This bifunctional antibody has been used to target unmodified vinblastine sulphate to well-established MAWI human tumour xenografts implanted in nude mice. The highly significant suppression of tumour growth achieved throughout treatment has also been sustained for over 2 months after the withdrawal of treatment. Histological examination of excised tumours from treated animals has shown profound changes in their morphology when compared with tumours from control animals. Cells in tumours that had started to grow again after withdrawal of therapy were shown still to express carcinoembryonic antigen, the target antigen recognised by the bispecific antibody.

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Linker Technology: Antibody-Mediated Delivery Systems

Cited by 13 publications

References 15 publications

DOTA-Functionalized Polylysine: A High Number of DOTA Chelates Positively Influences the Biodistribution of Enzymatic Conjugated Anti-Tumor Antibody chCE7agl

DOTA-Functionalized Polylysine: A High Number of DOTA Chelates Positively Influences the Biodistribution of Enzymatic Conjugated Anti-Tumor Antibody chCE7agl

Binding of epidermal growth factor‐dextran conjugates to cultured glioma cells

Suppression of well-established tumour xenografts by a hybrid-hybrid monoclonal antibody and vinblastine

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