Anti-CD6-blocked ricin: An anti-pan T-cell immunotoxin

Collinson, Albert R.; Lambert, John M.; Liu, Yimao; O’Dea, Conor; Shah, Sudhir; Rasmussen, Robert A.; Goldmacher, Victor S.

doi:10.1016/0192-0561(94)90117-1

Cited by 13 publications

(4 citation statements)

References 23 publications

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“…Minimal toxicity by free blocked ricin (1 nM) was observed. These results are consistent with the levels of killing we have recently reported, which showed that anti-CD6-bR-induced killing of T cells occurred in a dose-dependent manner [6]. However, as demonstrated in Table 1, experiment 2, when cells were incubated with anti-CD6-bR for 2 h to as long as 24 h, washed and then assayed for plating efficiency, a SF of only about 0.2 was observed despite that fact that cells had been treated with anti-CD6-bR at 0.5 nM, which saturates a Colonies from the limiting-dilution cultures described in Table 1, experiment 1, were expanded and both indirect and direct immunofluorescence was performed as described in Materials and methods on those colonies having enough viable cells for cytometric analysis b No.…”

Section: Kinetics and Degree Oft Cell Killing By Anti-cd6-brsupporting

confidence: 95%

“…Recombinant intefleukin-2 (IL-2) was obtained from Biogen, Inc. (Cambridge, Mass.). Blocked ricin and anti-CD6-bR were made following established methods [20,21] as described elsewhere [6]. The activity of the CD19-specific control IT, anti-B4-bR, has been documented previously [20].…”

Section: Methodsmentioning

confidence: 99%

“…The cellular specificity of anti-CD6-bR-induced toxicity was previously demonstrated using lymphoblastoid cell lines and it was found that any non-specific killing of CD6-cell lines by the IT required treatment with at least 100 × greater concentration of the IT than was necessary to achieve killing of CD6 + cell lines [6]. To examine the cellular specificity of anti-CD6-bR using normal cells, nylon-wool-non-adherent cells were treated with anti-CD6-bR for 24 h, washed, and then incubated with either irradiated allogeneic cells (JY lymphoblastoid cells) in a one-way MLC to generate MHC-restricted effectors, or with rlL-2 (200 U/ml) to generate LAK activity from LAK cell precursors.…”

Section: Differential Effect Of Anti-cd6-br On Mhc-restricted Ctl Actmentioning

confidence: 95%

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Blocked ricin-conjugated T cell immunotoxins: Effect of anti-CD6-blocked ricin on normal T cell function

Rasmussen

Counts

Lambert

et al. 1992

Cancer Immunol Immunother

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The biological properties of an immunotoxin composed of an anti-CD6 monoclonal antibody conjugated to whole ricin, which had been modified so that the galactose-binding sites of the B chain were blocked ("blocked ricin"), were examined. Treatment of peripheral blood lymphocytes with anti-CD6-blocked ricin for a 24-h period prevented T cell proliferation induced by phytohemagglutinin in a dose-dependent manner with concentrations causing 50% inhibition (IC50) ranging from 5 pM to 30 pM. In contrast, treatment with either blocked ricin alone or with a control immunotoxin prepared with a B-cell-lineage-restricted monoclonal antibody gave IC50 values of approximately 2 nM. Although shortening the duration of the anti-CD6-blocked ricin treatment to as little as 3 h had little significant effect on the observed inhibition, T cell viability experiments demonstrated that the magnitude of immunotoxin-induced killing after a given time period is significantly higher when the target cells become activated. Thus, from the initial concentration of cells treated with anti-CD6-blocked ricin placed in culture, 40%-45% viable cells remained after 2 days yet only 3%-9% remained if phorbol ester and Ca2+ ionophore were added; activation of T cells after mock treatment using blocked ricin plus nonconjugated anti-CD6 demonstrated that this effect was not the result of activation alone. The toxicity of anti-CD6-blocked ricin was also measured by inhibition of PHA-induced clonogenic growth of normal T cells. Continuous treatment of the cells using anti-CD6-blocked ricin at 0.1 nM resulted in a surviving fraction of about 3.5 x 10(-3); when immunotoxin treatment was for 24 h or less, the surviving fraction was only about 10(-1). As an indication of the unique specificity of anti-CD6-blocked ricin, immunotoxin pretreatment of potential responder cells prevented the generation of allogeneic cytolytic T lymphocytes in mixed lymphocyte cultures yet had little effect on the generation of interleukin-2-induced lymphokine-activated killer cell activity. We conclude that anti-CD6-blocked ricin demonstrates a cellular specificity and potency that make it a highly promising anti-T cell reagent.

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Section: Kinetics and Degree Oft Cell Killing By Anti-cd6-brsupporting

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Section: Differential Effect Of Anti-cd6-br On Mhc-restricted Ctl Actmentioning

confidence: 95%

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Blocked ricin-conjugated T cell immunotoxins: Effect of anti-CD6-blocked ricin on normal T cell function

Rasmussen

Counts

Lambert

et al. 1992

Cancer Immunol Immunother

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“…Another advantage of this approach is that these constructs are more homogeneous (only one linkage per ricin molecule) and more specific. Clinical trials of “blocked ricin” conjugates gave interesting early results, both in leukemias and in the therapy of small-cell lung cancer [47,48], nevertheless the studies on patients with chronic lymphocytic leukemia with minimal residual disease were suspended in 2003 [49] due to very limited activity of anti-B4 blocked ricin. The same results were obtained in untreated acute lymphoblastic leukemia [50].…”

Section: Immunotoxinsmentioning

confidence: 99%

Immunotoxins and Anticancer Drug Conjugate Assemblies: The Role of the Linkage between Components

Dosio

Brusa

Cattel

2011

Toxins

138

123

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Immunotoxins and antibody-drug conjugates are protein-based drugs combining a target-specific binding domain with a cytotoxic domain. Such compounds are potentially therapeutic against diseases including cancer, and several clinical trials have shown encouraging results. Although the targeted elimination of malignant cells is an elegant concept, there are numerous practical challenges that limit conjugates’ therapeutic use, including inefficient cellular uptake, low cytotoxicity, and off-target effects. During the preparation of immunoconjugates by chemical synthesis, the choice of the hinge component joining the two building blocks is of paramount importance: the conjugate must remain stable in vivo but must afford efficient release of the toxic moiety when the target is reached. Vast efforts have been made, and the present article reviews strategies employed in developing immunoconjugates, focusing on the evolution of chemical linkers.

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