Ricin A-Chain and Ricin A-Chain Immunotoxins Rapidly Damage Human Endothelial Cells: Implications for Vascular Leak Syndrome

Soler-Rodriguez, A.M.; Ghetie, Maria Ana; Oppenheimer‐Marks, Nancy; Uhr, Jonathan W.; Vitetta, Ellen S.

doi:10.1006/excr.1993.1142

Cited by 100 publications

(34 citation statements)

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“…Immunogenicity, vascular leak syndrome, and nonspecific hepatotoxicity are among major concerns of immunotoxins constructed with plant and bacterial toxins (68,69). Because the native sequence of Rap lacks the amino acid sequence motif that is responsible for binding to endothelial cells (70), vascular leak syndrome may be less of a concern for Rapcontaining immunotoxins.…”

Section: Drug and Toxin Antibody Conjugatesmentioning

confidence: 99%

CD74: A New Candidate Target for the Immunotherapy of B-Cell Neoplasms

Stein

Mattes

Cardillo

et al. 2007

Clinical Cancer Research

197

164

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CD74 is an integral membrane protein that functions as a MHC class II chaperone. Moreover, it has recently been shown to have a role as an accessory-signaling molecule and has been implicated in malignant B-cell proliferation and survival.These biological functions combined with expression of CD74 on malignant B cells and limited expression on normal tissues implicate CD74 as a potential therapeutic target. The anti-CD74 monoclonal antibody LL1 has been humanized (hLL1milatuzumab or IMMU-115) and can provide the basis for novel therapeutic approaches to B-cell malignancies, particularly because this antibody shows rapid internalization into CD74 + malignant cells. This article reviews the preclinical evaluations of LL1, its humanized form, and isotope, drug, and toxin conjugates. These studies show that unconjugated hLL1and conjugates of hLL1constructs with radioisotopes, doxorubicin, and frog RNase have high antitumor activity innon^Hodgkin's lymphoma and multiple myeloma invitro andin tumor xenograft models. Singledose studies of hLL1 in monkeys showed no adverse effects but did decrease circulating B and T lymphocytes and natural killer cells. When evaluated in combination with rituximab, either equivalent or improved efficacy, compared with either antibody alone, was observed. CD74 is a new candidate target for the immunotherapy of neoplasms expressing this antigen, which can be exploited using either a naked antibody or conjugated to isotopes, drugs, or toxins. CD74 (invariant chain, Ii) is a type II transmembraneglycoprotein that associates with the MHC class II a and h chains and directs the transport of the ahIi (invariant chain) complexes to endosomes and lysosomes (1 -4). In addition, CD74 is involved in signaling pathway functioning as a survival receptor (5). These biological functions, combined with expression of CD74 on malignant B cells and limited expression on normal tissues, implicate CD74 as a potential therapeutic target. The anti-CD74 monoclonal antibody (mAb) LL1 has been humanized (hLL1 milatuzumab or IMMU-115) and can provide the basis for novel therapeutic approaches to B-cell malignancies. This article reviews the preclinical evaluations of LL1, its humanized form, and isotope, drug, and toxin conjugates. The evidence suggests that hLL1 is a promising candidate antibody for the therapy of CD74-expressing malignancies, such as non -Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Due to its rapid internalization property, hLL1 also shows considerable promise as a drug, isotope, or toxin immunoconjugate. CD74 Molecule: Structure, Function, and ExpressionCD74 has 30 NH 2 -terminal, intracytoplasmic amino acid residues, a 26-amino acid hydrophobic transmembrane region, and a 160-amino acid extracytoplasmic domain containing two N-linked carbohydrate chains (1, 6). Once synthesized, CD74, DRa, and DRh begin to associate within the endoplasmic reticulum. This is believed to occur by sequential addition of DRa/h heterodimers to a trimeric core of CD74 molecules until a nine-subunit...

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Section: Drug and Toxin Antibody Conjugatesmentioning

confidence: 99%

CD74: A New Candidate Target for the Immunotherapy of B-Cell Neoplasms

Stein

Mattes

Cardillo

et al. 2007

Clinical Cancer Research

197

164

View full text Add to dashboard Cite

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“…The dose was limited by vascular leak syndrome (VLS), which in several cases was fatal. Studies of human endothelial cells have indicated that dgA damages these cells directly, whereas the truncated bacterial toxin Pseudomonas exotoxin (PE) does not unless it is connected to a ligand that binds specifically to endothelial cells (Kuan et al, 1995;Soler-Rodriguez et al, 1993). As has been observed in rat models (Rozemuller et al, 1996;Siegall et al, 1997), it is possible that PE could cause VLS, but its incidence might be minimized by a smaller recombinant toxin which would more quickly exit from the vasculature.…”

mentioning

confidence: 99%

Complete regression of human B-cell lymphoma xenografts in mice treated with recombinant anti-CD22 immunotoxin RFB4(dsFv)-PE38 at doses tolerated by cynomolgus monkeys

et al. 1999

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“…Clinical trials have exploited the toxicity of RTA in RTA-antibody constructs to kill leukemia and lymphoma cells (e.g., RTA conjugated to anti-CD22) (2)(3)(4)(5). Side effects limit the utility of RTA immunotoxins (6,7). Targeted inhibitors against ribosome-inactivating proteins (RIPs) could improve immunotoxin cancer therapies by rescuing normal cells following toxin treatment.…”

mentioning

confidence: 99%

Transition state analogues in structures of ricin and saporin ribosome-inactivating proteins

Sturm

Almo

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Ricin A-chain (RTA) and saporin-L1 (SAP) catalyze adenosine depurination of 28S rRNA to inhibit protein synthesis and cause cell death. We present the crystal structures of RTA and SAP in complex with transition state analogue inhibitors. These tight-binding inhibitors mimic the sarcin-ricin recognition loop of 28S rRNA and the dissociative ribocation transition state established for RTA catalysis. RTA and SAP share unique purine-binding geometry with quadruple -stacking interactions between adjacent adenine and guanine bases and 2 conserved tyrosines. An arginine at one end of the -stack provides cationic polarization and enhanced leaving group ability to the susceptible adenine. Common features of these ribosome-inactivating proteins include adenine leaving group activation, a remarkable lack of ribocation stabilization, and conserved glutamates as general bases for activation of the H2O nucleophile. Catalytic forces originate primarily from leaving group activation evident in both RTA and SAP in complex with transition state analogues.is the catalytic subunit of ricin, a Centers for Disease Control and Prevention category B bioterrorism agent derived from Ricinus communis seeds. RTA catalyzes the depurination of an invariant adenosine residue, A 4234, within the GA 4234 GA tetraloop motif of the highly conserved sarcin-ricin loop of eukaryotic 28S rRNA (1). Clinical trials have exploited the toxicity of RTA in RTA-antibody constructs to kill leukemia and lymphoma cells (e.g., RTA conjugated to anti-CD22) (2-5). Side effects limit the utility of RTA immunotoxins (6, 7). Targeted inhibitors against ribosome-inactivating proteins (RIPs) could improve immunotoxin cancer therapies by rescuing normal cells following toxin treatment.Saporin-L1 (SAP), a homologue of RTA from Saponaria officinalis (soapwort) leaves, exhibits N-glycohydrolase activities on 80S ribosomes, poly(A) RNA, and other cellular . SAP releases multiple adenines from ribosomes, whereas RTA shows exquisite specificity.Truncated oligonucleotide constructs of the ribosomal sarcinricin loop are RTA and SAP substrates (13-16). In addition to hairpin stem-loop structures, RTA hydrolyzes adenine from cyclic GAGA loops that possess a 5Ј-to 3Ј-covalently closed synthetic linker (17, 18) (Fig. 1).Transition state analysis of RTA-mediated depurinations established that hydrolysis of adenine involves a ribocation intermediate, followed by attack of an activated water. Adenine activation is a major driving force for RTA catalysis (19,20). Efficient catalysis by RTA requires the invariant Glu-177 and Arg-180 residues (21-25). RTA and other RIPs have evolved to become near-perfect catalysts for mammalian ribosomes (21,(26)(27)(28). Here, we use transition state analogues to establish the catalytic site features contributing to this remarkable catalytic activity.RTA transition state structures have guided the design and synthesis of potent RIP inhibitors (17, 29). Inhibitors for RTA and SAP include 1Ј-aza-sugars with a nonhydrolyzable 9-deazaadenine to mimic the...

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Ricin A-Chain and Ricin A-Chain Immunotoxins Rapidly Damage Human Endothelial Cells: Implications for Vascular Leak Syndrome

Cited by 100 publications

References 0 publications

CD74: A New Candidate Target for the Immunotherapy of B-Cell Neoplasms

CD74: A New Candidate Target for the Immunotherapy of B-Cell Neoplasms

Complete regression of human B-cell lymphoma xenografts in mice treated with recombinant anti-CD22 immunotoxin RFB4(dsFv)-PE38 at doses tolerated by cynomolgus monkeys

Transition state analogues in structures of ricin and saporin ribosome-inactivating proteins

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