Immunotoxins for the Treatment of B-Cell Lymphomas

Ghetie, Maria Ana; Gheţie, Victor; Vitetta, Ellen S.

doi:10.1007/bf03401689

Cited by 18 publications

(8 citation statements)

References 43 publications

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“…CD19 and CD22 are expressed on greater than 90% and 60-80% of B lymphomas, respectively [149]. The rationale for using Combotox in this setting is to avoid the emergence of antigen-negative variants [109], in addition to the additive activity of the two immunotoxins to each other, as was detected in the preclinical studies [150].…”

Section: Rfb4-dga + Hd37-dga (Combotox)mentioning

confidence: 99%

Antibody-Based Immunotoxins for the Treatment of Cancer

Becker

Benhar

2012

Antibodies

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Antibody-based immunotoxins comprise an important group in targeted cancer therapeutics. These chimeric proteins are a form of biological guided missiles that combine a targeting moiety with a potent effector molecule. The targeting moiety is mostly a monoclonal antibody (MAb) or a recombinant antibody-based fragment that confers target specificity to the immunotoxin. The effector domain is a potent protein toxin of bacterial or plant origin, which, following binding to the target cells, undergoes internalization and causes cell death. Over time and following research progression, immunotoxins become better fitted to their purpose, losing immunogenic fragments and non-specific targeting moieties. Many immunotoxins have gone through clinical evaluation. Some of these have been shown to be active and work is progressing with them in the form of further clinical trials. Others, mostly developed in the previous century, failed to generate a response in patients, or even caused undesired side effects. This article reviews the antibody and protein-toxin based immunotoxins that were clinically evaluated up to the present day.

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Section: Rfb4-dga + Hd37-dga (Combotox)mentioning

confidence: 99%

Antibody-Based Immunotoxins for the Treatment of Cancer

Becker

Benhar

2012

Antibodies

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“…RFB4-dgRTA was prepared in our good laboratory practice (GLP) scale-up laboratory as described. 16 RFB4-dgRTA, has been evaluated in severe combined immunodeficient (SCID)/Daudi mice (reviewed in Ghetie et al 17 ) and in patients with B-cell lymphoma (reviewed in Sausville and Vitetta 18 and Engert et al 19 ).…”

Section: Preparation Of An Immunotoxin Using Good Laboratory Practicementioning

confidence: 99%

Homodimers but not monomers of Rituxan (chimeric anti-CD20) induce apoptosis in human B-lymphoma cells and synergize with a chemotherapeutic agent and an immunotoxin

Ghetie

Bright

Vitetta

2001

Blood

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170

126

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“…The emergence of clinically relevant, nonspecific toxicity has limited the therapeutic potential of numerous immunotoxins (40)(41)(42) and is a significant limitation to the clinical development of this class of molecules in general. Therefore, it is of paramount importance to design immunotoxins with minimal toxicity to normal tissues.…”

Section: Discussionmentioning

confidence: 99%

Single-Chain Antibody-Based Immunotoxins Targeting Her2/neu: Design Optimization and Impact of Affinity on Antitumor Efficacy and Off-Target Toxicity

Cao

Marks

Huang

et al. 2012

Molecular Cancer Therapeutics

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Recombinant immunotoxins, consisting of single-chain variable fragments (scFv) genetically fused to polypeptide toxins, represent potentially effective candidates for cancer therapeutics. We evaluated the affinity of various anti-Her2/neu scFv fused to recombinant gelonin (rGel) and its effect on antitumor efficacy and off-target toxicity. A series of rGel-based immunotoxins were created from the human anti-Her2/neu scFv C6.5 and various affinity mutants (designated ML3-9, MH3-B1, and B1D3) with affinities ranging from 10 À8 to 10 À11 mol/L. Against Her2/neu-overexpressing tumor cells, immunotoxins with increasing affinity displayed improved internalization and enhanced autophagic cytotoxicity. Targeting indices were highest for the highest affinity B1D3/rGel construct. However, the addition of free Her2/neu extracellular domain (ECD) significantly reduced the cytotoxicity of B1D3/rGel because of immune complex formation. In contrast, ECD addition had little impact on the lower affinity constructs in vitro. In vivo studies against established BT474 M1 xenografts showed growth suppression by all immunotoxins. Surprisingly, therapy with the B1D3-rGel induced significant liver toxicity because of immune complex formation with shed Her2/neu antigen in circulation. The MH3-B1/rGel construct with intermediate affinity showed effective tumor growth inhibition without inducing hepatotoxicity or complex formation. These findings show that while high-affinity constructs can be potent antitumor agents, they may also be associated with mistargeting through the facile formation of complexes with soluble antigen leading to significant off-target toxicity.

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Immunotoxins for the Treatment of B-Cell Lymphomas

Cited by 18 publications

References 43 publications

Antibody-Based Immunotoxins for the Treatment of Cancer

Antibody-Based Immunotoxins for the Treatment of Cancer

Homodimers but not monomers of Rituxan (chimeric anti-CD20) induce apoptosis in human B-lymphoma cells and synergize with a chemotherapeutic agent and an immunotoxin

Single-Chain Antibody-Based Immunotoxins Targeting Her2/neu: Design Optimization and Impact of Affinity on Antitumor Efficacy and Off-Target Toxicity

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