The Experts below are selected from a list of 1989 Experts worldwide ranked by ideXlab platform
K. C. Nicolaou - One of the best experts on this subject based on the ideXlab platform.
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a total synthesis trilogy Calicheamicin γ1i taxol and brevetoxin a
Chemical Record, 2012Co-Authors: K. C. Nicolaou, Christopher R H Hale, Christian NilewskiAbstract:Detailed behind-the-scenes accounts of the total syntheses of Calicheamicin γ1I, Taxol®, and brevetoxin A are discussed with particular emphasis placed on strategies and tactics employed in these campaigns. DOI 10.1002/tcr.201200005
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targeted therapy with a novel enediyene antibiotic Calicheamicin ϑi1 effectively suppresses growth and dissemination of liver metastases in a syngeneic model of murine neuroblastoma
Cancer Research, 1998Co-Authors: Holger N. Lode, Gerhard Gaedicke, K. C. Nicolaou, Ralph A Reisfeld, Rupert Handgretinger, Wolfgang WrasidloAbstract:The suppression of metastases in malignant diseases is one of the major goals in targeted chemotherapy. This was achieved with an antibody drug conjugate between a novel, rationally designed enediyene antibiotic Calicheamicin ϑI1 of exceptionally high cytotoxic potency and an antiganglioside GD2 monoclonal antibody 14G2a. Effective suppression of hepatic metastases was demonstrated in a novel syngeneic model of murine neuroblastoma that simulates the situation in patients in terms of antigen heterogeneity and presence of the target antigen on normal tissues. Here, we describe the first successful use of Calicheamicin ϑI1 for targeted chemotherapy in a clinically relevant syngeneic metastasis model.
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DNA–carbohydrate interactions. Design and synthesis of a head-to-tail dimer of the Calicheamicin oligosaccharide
Chemical Communications, 1996Co-Authors: K. C. Nicolaou, Keiichi Ajito, Hironori Komatsu, Brian M. Smith, P. Bertinato, Luigi Gomez‐palomaAbstract:The chemical synthesis of the head-to-tail dimmer 4 of the Calicheamicin oligosaccharide from building blocks 5, 6 and 12 is described.
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Synthetic Calicheamicin mimics with novel initiation mechanisms: DNA cleavage, cytotoxicity, and apoptosis
Chemistry & Biology, 1994Co-Authors: K. C. Nicolaou, Emmanuel N. Pitsinos, Emmanuel A. Theodorakis, H. Saimoto, Wolfgang WrasidloAbstract:Abstract Background : Calicheamicin γ 1 I is a bacterial product that is a prominent member of the enediyne class of antitumor antibiotics, and has been extensively studied. Calicheamicin γ 1 I binds to DNA, causing double-stranded breaks, and cells exposed to it eventually become apoptotic. It can now be made synthetically, and highly potent biological mimics have been designed. Such molecules have many potential clinical applications, but are complex to make. We therefore investigated whether simplified versions of these molecules are biologically active. Results : We designed and synthesized a number of simple Calicheamicin mimics and evaluated their biological activity. We also constructed mimics that are particularly suitable for conjugation to proteins, oligonucleotides, and other delivery systems. Several active mimics were found, and two in particular, which lack the trisulfide and oligosaccharide moieties of Calicheamicin, had potent DNA-cleaving and cytotoxic activities. They caused chiefly single-stranded cuts in DNA, however, unlike the natural molecule, which causes double-stranded DNA cuts. Although they were able to induce apoptosis, they were less potent than the natural compound in this assay. Conclusions : The simple enediyne mimics were less potent than Calicheamicin γ 1 I , presumably because they lack the oligosaccharide DNA-binding domain. Nevertheless, considering their relatively primitive structures, they have remarkable biological properties. They may be useful biological tools and are potential leads for the development of chemotherapeutic agents.We propose that the ability of the enediynes to induce apoptosis is related to their ability to make double-stranded cuts in DNA.
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der kampf um Calicheamicin γ 1i
Angewandte Chemie, 1993Co-Authors: K. C. NicolaouAbstract:Vor ziemlich genau einem Jahr war die erste Totalsynthese von Calicheamicin γI1 vollbracht. Dieser Beitrag schildert -aus sehr personlicher Sicht - in chronologischer Abfolge die Ereignisse, die zu diesem Triumph der Naturstoffsynthese fuhrten.
Philip R Hamann - One of the best experts on this subject based on the ideXlab platform.
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cmc 544 inotuzumab ozogamicin a cd22 targeted immunoconjugate of Calicheamicin
Hematology Meeting Reports (formerly Haematologica Reports), 2009Co-Authors: John Francis Dijoseph, Douglas C. Armellino, Kiran Khandke, Maureen M. Dougher, Deborah Evans, Philip R Hamann, Nitin DamleAbstract:CMC-544 (Inotuzumab ozogamicin) is a CD22-targeted immunoconjugate of Calicheamicin currently being evaluated in phase III clinical trials in patients with non- Hodgkin’s B-cell lymphoma. CMC-544 is the product of a collaboration between Wyeth and UCB-Celltech. CMC-544 has demonstrated significant clinical activity in both follicular and diffuse large B-cell lymphoma patients who had failed multiple therapies.1,2 CMC-544 (Figure 1) is a humanized IgG4 anti-CD22 antibody (G5/44) covalently linked to N-acetyl gamma Calicheamicin dimethyl hydrazide (CalichDMH) via an acid-labile 4-(4-acetylphenoxy)butanoic acid (AcBut) linker.3,4 CD22 is a Blymphoid lineage-specific differentiation antigen expressed on the surface of both normal and malignant B cells. CD22 is not expressed on hematopoietic progenitors of the B-lymphoid lineage. CD22 efficiently internalizes upon binding to an antibody making it an ideal candidate for targeted drug delivery. Targeting malignant B-cells through CD22 by the CD22 specific antibody G5/44 could, therefore, be an efficient way to deliver Calicheamicin to destroy malignant B-cells.
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determination of pharmacokinetic values of Calicheamicin antibody conjugates in mice by plasmon resonance analysis of small 5 μl blood samples
Cancer Chemotherapy and Pharmacology, 2008Co-Authors: Erwin Raymond Boghaert, Kiran Khandke, Maureen M. Dougher, John Francis Dijoseph, Philip R Hamann, Arthur Kunz, Latha Sridharan, Justin K Moran, Inder Chaudhary, Nitin DamleAbstract:Purpose The present study aims to establish a method that provides fast, precise and reproducible pharmacokinetic (PK) parameters of antibody-Calicheamicin conjugates. The method should discriminate between PK of the antibody moiety and PK of the conjugated Calicheamicin (CM).
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the oncofetal protein 5t4 is a suitable target for antibody guided anti cancer chemotherapy with Calicheamicin
International Journal of Oncology, 2008Co-Authors: Erwin Raymond Boghaert, Douglas C. Armellino, Kiran Khandke, Philip R Hamann, Arthur Kunz, Latha Sridharan, Matthew G Ryan, Kevin Alan Myers, Richard Harrop, Kimberly MarquetteAbstract:: The oncofetal protein, 5T4, is a tumor-associated protein displayed on the cell membrane of various carcinomas. This molecule is a promising target for anti-tumor vaccine development and for targeted therapy with staphylococcus exotoxin. The potential use of 5T4 as a target for antibody-guided chemotherapy has not been demonstrated. We report oncolytic efficacy and selectivity in vitro and in vivo with immuno-conjugates of Calicheamicin (CM) and the anti-5T4 antibody, H8. CM is a potent cytotoxic drug that causes double strand breaks in DNA. Conjugates of CM and H8 were constructed with acid-labile as well as acid-stabile linkers. In vitro, when applied to monolayers of 5T4(+) cells, CM-conjugates targeting 5T4 were consistently more toxic than either free drug or a non-binding control CM-conjugate. This difference was less pronounced on 5T4-deficient cells. In vivo, four 5T4-positive subcutaneous tumor models were treated with conjugates. Efficacy was demonstrated by reduction of tumor growth relative to controls treated with drug vehicle. To evidence selectivity, the efficacy of the anti-5T4 conjugates was compared to the efficacy of H8, a mixture of H8 and Calicheamicin, Calicheamicin alone or Calicheamicin conjugated to the anti-CD33 antibody, hP67.6. In addition, the efficacy and selectivity of an acid-labile conjugate of H8 was evaluated in an orthotopic model for 5T4(+) lung cancer. Increased survival following treatment was used as a parameter of efficacy. Calicheamicin conjugates of H8 were effective and selective in all the examined tumor models. Differences in efficacy between the acid-labile and acid-stabile conjugates depended on the investigated tumor model.
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cd20 specific antibody targeted chemotherapy of non hodgkin s b cell lymphoma using Calicheamicin conjugated rituximab
Cancer Immunology Immunotherapy, 2007Co-Authors: John Francis Dijoseph, Douglas C. Armellino, Maureen M. Dougher, Erwin Raymond Boghaert, Philip R Hamann, Arthur Kunz, Lyka B Kalyandrug, Nitin DamleAbstract:Tumor-targeted delivery of a potent cytotoxic agent, Calicheamicin, using its immunoconjugates is a clinically validated therapeutic strategy. Rituximab is a human CD20-specific chimeric antibody extensively used in B-NHL therapy. We investigated whether conjugation to Calicheamicin can improve the anti-tumor activity of rituximab against human B-cell lymphoma (BCL) xenografts in preclinical models. BCL cells were cultured with rituximab or its Calicheamicin conjugates and their in vitro growth was monitored. BCL cells were injected s.c. to establish localized xenografts in nude mice or i.v. to establish disseminated BCL in severe combined immunodeficient (scid) mice. I.p. treatment with rituximab or its Calicheamicin conjugates was initiated and its effect on s.c. BCL growth or survival of mice with disseminated BCL was monitored. Conjugation of Calicheamicin to rituximab vastly enhanced its growth inhibitory activity against BCL in vitro. Conjugation to Calicheamicin had no deleterious effect on the effector functional activity of rituximab. Calicheamicin conjugated to rituximab with an acid-labile linker exhibited greater anti-tumor activity against s.c. BCL xenografts and improved survival of mice with disseminated BCL over that of unconjugated rituximab. Anti-tumor activities of rituximab conjugated to Calicheamicin via an acid-stable linker were similar to that of unconjugated rituximab. Superior anti-tumor efficacy exhibited by a Calicheamicin immunoconjugate of rituximab with an acid-labile linker over that of rituximab demonstrates the therapeutic potential of CD20-specific antibody-targeted chemotherapy strategy in the treatment of B-NHL.
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tumoricidal effect of Calicheamicin immuno conjugates using a passive targeting strategy
International Journal of Oncology, 2006Co-Authors: Erwin Raymond Boghaert, Douglas C. Armellino, Kiran Khandke, Maureen M. Dougher, John Francis Dijoseph, Philip R Hamann, Arthur Kunz, Latha Sridharan, Ashwin Sridharan, Stanley JonesAbstract:: Calicheamicin is a potent chemotherapeutic with a low therapeutic index that requires targeting to tumor cells for its use in the clinic. To treat acute myeloid leukemia, Calicheamicin has been conjugated to an antibody that recognizes CD33 (gemtuzumab ozogamicin). The application range of this 'active' targeting strategy is limited since it depends on specific antigen expression by tumor cells. This limitation could be reduced by using an antigen-independent 'passive targeting' strategy for Calicheamicin. 'Passive targeting' relies on the dysfunctional vasculature of a neoplastic tumor that allows enhanced retention of macromolecules. We studied the efficacy of Calicheamicin conjugated to various carrier molecules: i.e. immunoglobulin, albumin or PEGylated Fc fragments. In nude mice, a conjugate of anti-CD33 and Calicheamicin accumulates in human tumor xenografts in the absence of detectable amounts of targeting antigen. Passive targeting provided sufficient accumulation of this conjugate to inhibit tumor growth of 10 different CD33-negative xenograft models. This efficacy depended on the use of an acid-labile linker between antibody and Calicheamicin. Substitution of immunoglobulin as a carrier with either albumin or PEGylated Fc reduced or eliminated the efficacy of the conjugate. The results showed that using 'non-specific' immunoglobulin for passive targeting of Calicheamicin might be an effective mode of cancer therapy.
Samuel J Danishefsky - One of the best experts on this subject based on the ideXlab platform.
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interaction of Calicheamicin γ1i and its related carbohydrates with dna protein complexes
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Claudia Sissi, Samuel J Danishefsky, Jayshree Aiyar, Serge H Boyer, Kris Depew, Donald M CrothersAbstract:We report studies of the contribution of DNA structure, holding the sequence constant, to the affinity of Calicheamicin γ1I and its aryltetrasaccharide moiety for DNA. We used polynucleotide chains as models of known protein-binding sequences [the catabolite activator protein (CAP) consensus sequence, AP-1 and cAMP response element (CRE) sites] in their free and protein-bound forms. The proteins were selected to provide examples in which the minor-groove binding site for the carbohydrate is (CAP) or is not (GCN4) covered by the protein. Additionally, peptides related to the GCN4 and CREB families, which have different bending effects on their DNA-binding sites, were used. We observe that proteins of the CREB class, which induce a tendency to bend toward the minor groove at the center of the site, inhibit drug-cleavage sites located at the center of the free AP-1 or CRE DNA sites. In the case of GCN4, which does not induce DNA bending, there is no effect on Calicheamicin cleavage of the CRE site, but we observe a GCN4-induced rearrangement of the cutting pattern in the AP-1 site. This effect may arise from either a subtle local conformational rearrangement not accompanied by bending or a localized reduction in DNA flexibility. Whereas GCN4 binding is not inhibited by the Calicheamicin aryltetrasaccharide, binding of CAP to its DNA target is significantly inhibited, and Calicheamicin cutting of DNA at the center of the CAP–DNA complex site is strongly reduced by protein binding. This result probably reflects steric inhibition of drug binding by the protein.
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Interaction of Calicheamicin γ1I and its related carbohydrates with DNA–protein complexes
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Claudia Sissi, Samuel J Danishefsky, Jayshree Aiyar, Serge H Boyer, Kris Depew, Donald M CrothersAbstract:We report studies of the contribution of DNA structure, holding the sequence constant, to the affinity of Calicheamicin γ1I and its aryltetrasaccharide moiety for DNA. We used polynucleotide chains as models of known protein-binding sequences [the catabolite activator protein (CAP) consensus sequence, AP-1 and cAMP response element (CRE) sites] in their free and protein-bound forms. The proteins were selected to provide examples in which the minor-groove binding site for the carbohydrate is (CAP) or is not (GCN4) covered by the protein. Additionally, peptides related to the GCN4 and CREB families, which have different bending effects on their DNA-binding sites, were used. We observe that proteins of the CREB class, which induce a tendency to bend toward the minor groove at the center of the site, inhibit drug-cleavage sites located at the center of the free AP-1 or CRE DNA sites. In the case of GCN4, which does not induce DNA bending, there is no effect on Calicheamicin cleavage of the CRE site, but we observe a GCN4-induced rearrangement of the cutting pattern in the AP-1 site. This effect may arise from either a subtle local conformational rearrangement not accompanied by bending or a localized reduction in DNA flexibility. Whereas GCN4 binding is not inhibited by the Calicheamicin aryltetrasaccharide, binding of CAP to its DNA target is significantly inhibited, and Calicheamicin cutting of DNA at the center of the CAP–DNA complex site is strongly reduced by protein binding. This result probably reflects steric inhibition of drug binding by the protein.
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Calicheamicin dna complexes warhead alignment and saccharide recognition of the minor groove
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: N Ikemoto, R A Kumar, T T Ling, G A Ellestad, Samuel J Danishefsky, Dinshaw J PatelAbstract:Abstract The solution structures of Calicheamicin gamma 1I, its cycloaromatized analog (Calicheamicin epsilon), and its aryl tetrasaccharide complexed to a common DNA hairpin duplex have been determined by NMR and distance-refined molecular dynamics computations. Sequence specificity is associated with carbohydrate-DNA recognition that places the aryl tetrasaccharide component of all three ligands in similar orientations in the minor groove at the d(T-C-C-T).d(A-G-G-A) segment. The complementary fit of the ligands and the DNA minor groove binding site creates numerous van der Waals contacts as well as hydrogen bonding interactions. Notable are the iodine and sulfur atoms of Calicheamicin that hydrogen bond with the exposed amino proton of the 5'- and 3'-guanines, respectively, of the d(A-G-G-A) segment. The sequence-specific carbohydrate binding orients the enediyne aglycone of Calicheamicin gamma 1I such that its C3 and C6 proradical centers are adjacent to the cleavage sites. While the enediyne aglycone of Calicheamicin gamma 1I is tilted relative to the helix axis and spans the minor groove, the cycloaromatized aglycone is aligned approximately parallel to the helix axis in the respective complexes. Specific localized conformational perturbations in the DNA have been identified from imino proton complexation shifts and changes in specific sugar pucker patterns on complex formation. The helical parameters for the carbohydrate binding site are comparable with corresponding values in B-DNA fibers while a widening of the groove is observed at the adjacent aglycone binding site.
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reductive desilanolation as a route to benzonitriles an application to a concise synthesis of the aromatic sector of Calicheamicin
Tetrahedron Letters, 1994Co-Authors: Steven H Olson, Samuel J DanishefskyAbstract:Abstract The TMS-cyanohydrins of quinones undergo reductive desilanolation in the presence of samarium iodide to form hydroxybenzonitriles. Benzoquinone 1 was converted to the hexasubstituted aromatic fragment of Calicheamicin 4 by this method.
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specific inhibition of formation of transcription complexes by a Calicheamicin oligosaccharide a paradigm for the development of transcriptional antagonists
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Steffan N Ho, Samuel J Danishefsky, Serge H Boyer, Stuart L Schreiber, Gerald R CrabtreeAbstract:Sequence-specific DNA ligands that antagonize DNA-protein interactions represent a potentially powerful means of modulating gene expression. Calicheamicin gamma 1I, a member of the DNA-cleaving enediyne class of anticancer antibiotics, binds to specific DNA sequences through an aryltetrasaccharide domain. To take advantage of this unique sequence-specific recognition capability, the methyl glycoside of the aryltetrasaccharide of Calicheamicin gamma 1I (CLM-MG) was used to investigate the ability of glycoconjugate DNA ligands to inhibit DNA-protein interactions. CLM-MG inhibits the formation of DNA-protein complexes at micromolar concentrations in a sequence-specific manner and rapidly dissociates preformed complexes. CLM-MG also inhibits transcription in vivo with similar sequence specificity. These results suggest a strategy for the development of a class of novel biological probes and therapeutic agents.
George A Ellestad - One of the best experts on this subject based on the ideXlab platform.
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structural and conformational features relevant to the anti tumor activity of Calicheamicin γ 1i
Chirality, 2011Co-Authors: George A EllestadAbstract:The structural and conformational features of the potent 10-membered enediyne-containing Calicheamicin γ 1I that account for its remarkable DNA site-specific binding and cleavage are reviewed. A variety of spectroscopic and biophysical techniques were used to gain insight into the binding and stereospecific DNA cleavage of this potent antitumor agent. These include gel-shift cleavage assays, atom transfer NMR experiments, drug-DNA conformational studies, circular dichroism, and capillary electrophoresis. Computational descriptions are described for the DNA binding and cleavage of Calicheamicin and its activated transient intermediates based on density functional and molecular mechanics calculations. In addition, the structure and clinical utility of Calicheamicin immunoconjugates for antibody-targeted chemotherapy is presented. Chirality, 2011. © 2011 Wiley-Liss, Inc.
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Calicheamicin γ1i and phenyl tert butyl nitrone pbn observation of a kinetic isotope effect by an esr study
Chemical Communications, 2010Co-Authors: Toyonobu Usuki, Mari Kawai, Koji Nakanishi, George A EllestadAbstract:ESR study of enediyne Calicheamicin γ1I with phenyl tert-butyl nitrone (PBN) gave a significant kinetic isotope effect (kH/kD = 1.8) for the formation of the phenyl radical PBN monoadducts.
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spin trapping of the p benzyne intermediates from ten membered enediyne Calicheamicin gamma1i
Organic Letters, 2006Co-Authors: Toyonobu Usuki, Koji Nakanishi, George A EllestadAbstract:In the presence of thiols, the ten-membered-ring enediyne Calicheamicin γ1I generates a p-benzyne biradical that initiates oxidative cleavage of double-stranded DNA. Application of spin-trapping ha...
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theoretical simulation of the electronic circular dichroism spectrum of Calicheamicin
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Egidio Giorgio, George A Ellestad, Weidong Ding, Keith Pitts, Girija Krishnamurthy, Katsunori Tanaka, Carlo Rosini, Nina BerovaAbstract:Abstract The aglycon, or so-called ‘warhead’ portion, of several potent 10-membered ring enediyne antitumor antibiotics contain dienonecarbamate and enediyne chromophores in an unusual bicyclic ring structure in which these two subunits are essentially orthogonal to each other. The circular dichroism (CD) spectra of the Calicheamicin, esperamicin, and shisijimicin A families, all of which contain this bicyclic ring system, exhibit a characteristic negative exciton coupled CD at about 310 and 270 nm. This signature CD feature suggested the absolute stereochemical relationship between these chromophores as originally assigned and which was later confirmed by stereospecific total synthesis. Because of the unique nature of this chromophoric interaction and the importance of using this CD spectral feature in the assignment of the absolute stereochemistry of other related enediynes, we report here simulations of the CD spectra of the Calicheamicin aglycon A, and of two other truncated models, B and C, by using density functional theory (DFT) and the DeVoe coupled oscillator approach. The DFT calculations provide a strong theoretical basis that the planar enediyne chromophore alone gives a negligible CD contribution, while that coming from the twisted dienonecarbamate is much more substantial. However, the shape and the largest part of the intensity of experimental CD spectrum can only be reproduced when the two unsaturated moieties are simultaneously present. Thus, the exciton coupling between the two chromophores provides the most important contribution to the experimental CD spectrum of Calicheamicin. This conclusion is in full agreement with the results from the DeVoe calculation.
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A re-examination of the circular dichroism of the Calicheamicin enediyne/dienone chromophoric interaction.
Organic Letters, 2004Co-Authors: Weidong Ding, George A Ellestad, Keith Pitts, Girija KrishnamurthyAbstract:A series of Calicheamicin derivatives have been made in an effort to delineate the origin of the strong circular dichroism (CD) of Calicheamicin reported previously. The CD spectrum of calicheamici...
Janis Upeslacis - One of the best experts on this subject based on the ideXlab platform.
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an anti muc1 antibody Calicheamicin conjugate for treatment of solid tumors choice of linker and overcoming drug resistance
Bioconjugate Chemistry, 2005Co-Authors: Philip R Hamann, Lois M Hinman, Ana T Menendez, Frederick E Durr, Delores Lindh, Carl Beyer, Lee M Greenberger, Rosalyn Wallace, Janis UpeslacisAbstract:The anti-MUC1 antibody, CTM01, has been chosen to target the potently cytotoxic Calicheamicin antitumor antibiotics to solid tumors of epithelial origin that express this antigen. Earlier Calicheamicin conjugates relied on the attachment of a hydrazide derivative to the oxidized carbohydrates that occur naturally on antibodies. This produced a “carbohydrate conjugate” capable of releasing active drug by hydrolysis in the lysosomes where the pH is low. Conjugates have now been made that are formed by reacting a Calicheamicin derivative containing an activated ester with the lysines of antibodies. This gives an “amide conjugate” that is stable to hydrolysis, leaving the disulfide that is present in all Calicheamicin conjugates as the only likely site of drug release from the conjugate. As previously shown for the carbohydrate conjugate, this amide conjugate of CTM01 produces complete regressions of xenograft tumors at doses of 300 μg/kg (Calicheamicin equivalents) given three times. This indicates that hydr...
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a Calicheamicin conjugate with a fully humanized anti muc1 antibody shows potent antitumor effects in breast and ovarian tumor xenografts
Bioconjugate Chemistry, 2005Co-Authors: Philip R Hamann, Lois M Hinman, Janis Upeslacis, Carl F Beyer, Delores Lindh, Dan Shochat, Andrew MountainAbstract:Murine CTM01 is an internalizing murine IgG1 monoclonal antibody that recognizes the MUC1 antigen expressed on many solid tumors of epithelial origin. Calicheamicin conjugates of this antibody have previously been shown to be potent, selective antitumor agents in preclinical models. A conjugate has now been made with a genetically engineered human version of this antibody, hCTM01. The hCTM01 is an IgG4 isotype, has an immunoaffinity approximately 30% higher than mCTM01 by competitive RIA, and is efficiently internalized into target cells. The hCTM01−NAc-gamma Calicheamicin DM amide conjugate, referred to as CMB-401, shows targeted killing of MUC1-expressing cells in vitro and produces pronounced dose-related antitumor effects over an 8-fold dose range against a MUC1-expressing, ovarian xenograft tumor, OvCar-3. The specificity of CMB-401 was confirmed by comparing its antitumor effects with those of an isotype-matched nonspecific conjugate against the MX-1 breast carcinoma. CMB-401, given either ip or iv,...
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an anti cd33 antibody Calicheamicin conjugate for treatment of acute myeloid leukemia choice of linker
Bioconjugate Chemistry, 2002Co-Authors: Philip R Hamann, Lois M Hinman, Janis Upeslacis, Carl F Beyer, Delores Lindh, David A Flowers, Irwin D. BernsteinAbstract:The anti-CD33 antibody, P67.6, has been chosen to target the potently cytotoxic Calicheamicin antitumor antibiotics to acute myeloid leukemia (AML) due to the presence of CD33 on >80% of patient samples and its lack of expression outside the myeloid cell lineages, especially its lack of expression on pluripotent stem cells. Previous Calicheamicin conjugates relied on the attachment of a hydrazide derivative to the oxidized carbohydrates that occur naturally on antibodies. This results in a “carbohydrate conjugate” capable of releasing active drug by hydrolysis of a hydrazone bond in the lysozomes where the pH is low. Conjugates have now been made that are formed by reacting a Calicheamicin derivative containing an activated ester with the lysines of antibodies. This results in an “amide conjugate” that is stable to hydrolysis, leaving the disulfide that is present in all Calicheamicin conjugates as the likely site of drug release from the conjugate. In this article, these two classes of Calicheamicin−anti...
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gemtuzumab ozogamicin a potent and selective anti cd33 antibody Calicheamicin conjugate for treatment of acute myeloid leukemia
Bioconjugate Chemistry, 2002Co-Authors: Philip R Hamann, Lois M Hinman, Janis Upeslacis, Irwin Hollander, Carl F Beyer, Delores Lindh, Ryan Holcomb, William Hallett, Hwei Ru Tsou, Dan ShochatAbstract:CD33 is expressed by acute myeloid leukemia (AML) cells in >80% of patients but not by normal hematopoietic stem cells, suggesting that elimination of CD33+ cells may be therapeutically beneficial. A conjugate of a Calicheamicin hydrazide derivative attached via hydrazone formation to the oxidized carbohydrates of the anti-CD33 murine antibody P67.6 had been chosen for use in AML prior to humanization of this antibody. However, the CDR-grafted humanized P67.6 could not be used to make the carbohydrate conjugate because of the unexpected sensitivity of this antibody to periodate oxidation. Exploration of a series of bifunctional linkers resulted in a new class of Calicheamicin conjugates, termed the hybrid conjugates, that allows for the attachment of the Calicheamicin to lysines but incorporates the site of hydrolytic release, a hydrazone, previously shown to be required for activity. The optimized conjugate chosen for clinical trials, gemtuzumab ozogamicin (“gem-ozo”, Mylotarg, formerly designated CMA-67...
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Preparation and Characterization of Monoclonal Antibody Conjugates of the Calicheamicins: A Novel and Potent Family of Antitumor Antibiotics
Cancer Research, 1993Co-Authors: Lois M Hinman, Philip R Hamann, Roslyn E. Wallace, Ana T Menendez, Frederick E Durr, Janis UpeslacisAbstract:Abstract The Calicheamicin family of antitumor antibiotics are capable of producing double-stranded DNA breaks at sub-picomolar concentrations. Their potency suggested that the Calicheamicins would be excellent candidates for targeted delivery and a hydrazide prepared from the most potent and abundant of the naturally occurring derivative, γ1i, was linked to oxidized sugars on CT-M-01, an internalizing anti-polyepithelial mucin antibody. The conjugates retained the immunoreactivity of the unmodified antibody and were specifically cytotoxic toward antigen positive tumor cells in vitro and in vivo. Hydrazide analogues of less potent Calicheamicin derivatives were also prepared and conjugated to CT-M-01. Comparison of the therapeutic efficacy of the conjugates against the MX-1 xenograft tumor implanted s.c. in nude mice showed that conjugates of derivatives missing the rhamnose, a sugar residue that is part of the DNA binding region of the drug, were not as promising as antitumor therapies. However, conjugates of two derivatives, α3i and N-acetyl-γ1i, in which the rhamnose residue is present but the amino sugar residue of the parent drug is either missing or modified, significantly inhibited tumor growth over a 4-fold dose range and produced long-term tumor-free survivors. Sterically hindering methyl groups adjacent to the disulfide in the linker further increased the therapeutic window of these potent conjugates.
