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PubMed1999

Receptor-mediated and enzyme-dependent targeting of cytotoxic anticancer drugs.

This review is a survey of various approaches to targeting cytotoxic anticancer drugs to tumors primarily through biomolecules expressed by cancer cells or associated vasculature and stroma. These include monoclonal antibody immunoconjugates; enzyme prodrug therapies, such as antibody-directed enzyme prodrug therapy, gene-directed enzyme prodrug therapy, and bacterial-directed enzyme prodrug therapy; and metabolism-based therapies that seek to exploit increased tumor expression of, e.g., proteases, low-density lipoprotein receptors, hormones, and adhesion molecules. Following a discussion of factors that positively and negatively affect drug delivery to solid tumors, we concentrate on a mechanistic understanding of selective drug release or generation at the tumor site.

Antibodies, Monoclonal↗
PubMed2002

Enhanced tumor cell selectivity of adriamycin-monoclonal antibody conjugate via a poly(ethylene glycol)-based cleavable linker.

A novel linker consisting of poly(ethylene glycol) (PEG) and dipeptide was used for conjugation of adriamycin with tumor-specific monoclonal antibody, NL-1, to confirm that the linker can be cleaved selectively with the tumor specific enzyme to express cytotoxicity of the anti-tumor agent. Initially, adriamycin-conjugated PEG linkers through different amino acid compositions, alanyl-valine (Ala-Val), alanyl-proline (Ala-Pro), and glycyl-proline (Gly-Pro) sequences, were prepared to confirm selective digestion with model enzymes. Adriamycin was released by particular model endoproteases, thermolysin and proline endopeptidase, from the linkers with different efficiency. When conjugates were prepared using these adriamycin-bound linkers, conjugates had no loss of binding affinity and specificity for common acute lymphoblastic leukemia antigen (CALLA) expressed on the Daudi cell surfaces as the target of NL-1 antibody. In addition, adriamycin release from the conjugates was also confirmed by incubating them with specific proteases. Tumor cell growth was inhibited dose-dependently for the conjugates carrying Ala-Val and Gly-Pro linkers, whereas significant inhibitory effect was abolished for the conjugate carrying Ala-Pro linker, indicating that cytotoxic effect can be controlled by specificity of antibody and composition of linker peptide. IC(50) for Ala-Val linked conjugate was approximately 3.5 microg/ml and that for Gly-Pro linked conjugate was 5.2 microg/ml. PEG-dipeptidyl linker demonstrated here will be an effective tool for the preparation of immunoconjugate, especially specific activation of anti-tumor agents at desired tumor tissues.

Antibodies, Monoclonal↗
PubMed2003

Effective drug delivery by PEGylated drug conjugates.

The current review presents an update of drug delivery using poly(ethylene glycol) (PEG), that focuses on recent developments in both protein and organic drugs. Certainly the past 10 years has resulted in a renaissance of the field of PEG drug conjugates, initiated by the use of higher molecular weight PEGs (M(w)>20,000), especially 40,000 which is estimated to have a plasma circulating t(1/2) of approximately 10 h in mice. This recent resuscitation of small organic molecule delivery by high molecular weight PEG conjugates was founded on meaningful in vivo testing using established tumor models, and has led to a clinical candidate, PEG-camptothecin (PROTHECAN), an ester based prodrug currently in phase II trials. Additional applications of high molecular weight PEG prodrug strategies to amino containing drugs are presented: similar tripartate systems based on lower M(w) PEG and their use with proteins is expounded on. The modification of a benzyl elimination tripartate prodrug specific for mercaptans is presented, and its successful application to 6-mercaptopurine giving a water soluble formulation is discussed. Recent novel PEG oligonucleotides and immunoconjugates are also covered. Clinical results of FDA approved PEGylated proteins are also presented.

Animals↗
PubMed2002

Design and construction of novel molecular conjugates for signal amplification (I): conjugation of multiple horseradish peroxidase molecules to immunoglobulin via primary amines on lysine peptide chains.

Immunoconjugates are widely used for indirect detection of analytes (such as antibodies or antigens) in a variety of immunoassays. However, the availability of functional groups such as primary amines or free sulfhydryls in an immunoglobulin molecule is the limiting factor for optimal conjugation and, therefore, determines the sensitivity of an assay. In the present study, an N-terminal bromoacetylated 20 amino acid peptide containing 20 lysine residues was conjugated to N-succinimidyl-S-acetylthioacetate (SATA)-modified IgG or free sulfhydryl groups on 2-mercaptoethylamine (2-MEA)-reduced IgG molecules via a thioether (S[bond]CH(2)CONH) linkage to introduce multiple reactive primary amines per IgG. These primary amines were then covalently coupled with maleimide-activated horseradish peroxidase (HRP). The poly-HRP-antibody conjugates thus generated demonstrated greater than 15-fold signal amplification upon reaction with orthophenyldiamine substrate. The poly-HRP-antibody conjugates efficiently detected human immunodeficiency virus (HIV)-1 antibodies in plasma specimens with significantly higher sensitivity than conventionally prepared HRP-antibody conjugates in an HIV-1 solid-phase enzyme immunoassay and Western blot analysis. The signal amplification techniques reported here could have the potential for development of highly sensitive immunodiagnostic assay systems.

HIV Antigens↗
PubMed2000

Double-masked prospective ocular safety study of a lens epithelial cell antibody to prevent posterior capsule opacification.

PURPOSE: To evaluate the intraocular safety of an immunoconjugate (MDX-RA) developed to prevent posterior capsule opacification (PCO) in human eyes. SETTING: St. Thomas's Hospital Eye Department, London, United Kingdom. METHODS: Twenty-six patients had phacoemulsification and implantation of an intraocular lens (IOL). All were randomly allocated at the end of surgery to receive a 0.1 mL placebo or 0.1 mL of the immunotoxin MDX-RA intracamerally. Two doses of the drug were tested: 8 patients with a low dose (50 units), 9 patients with a high dose (100 units), and 9 with placebo. Follow-up at days 1, 14, 30, 60, 90, and 180 consisted of visual acuity measured by the Early Treatment of Diabetic Retinopathy Study test, contrast sensitivity, aqueous flare, specular microscopy of the IOL's anterior surface, and corneal endothelial counts. The percentage area of PCO was measured from retroillumination images of the posterior capsule. RESULTS: There was no decrease in corneal endothelial cell count in toxin-treated patients. Early postoperative flare, anterior chamber cell count, and corneal pachymetry were higher in toxin-treated patients. The median percentage area of PCO at 1 year was 32.0 in the placebo group, 3.8 in the low-dose group, and 7.4 in the high-dose group (P = .06). CONCLUSION: This prospective, randomized, placebo-controlled trial confirmed that MDX-RA is safe for intraocular use and is of potential value for further clinical trials of the prevention of PCO.

Aged↗
PubMed1996

Treatment of relapsed Hodgkin's disease.

High-dose chemotherapy with peripheral stem cell or bone marrow transplantation has quickly become accepted as the standard of care for patients with Hodgkin's disease (HD) who are chemotherapy induction failures or who relapsed after a short initial remission. The majority of studies would indicate that high-dose therapy is most effective when used early. As a result of promising pilot studies, high-dose therapy is also being used more frequently in patients at initial relapse after a long remission. Future approaches to improve the efficacy of high-dose therapy in marrow transplantation will require more effective chemotherapeutic agents. Recent studies with the taxanes and camptothecins suggest that these agents may be useful (Devizzi et al, 1994). Biological approaches with CD30 based antibodies and immunotoxins may also be helpful adjuncts to conventional-dose debulking regimens. Radio-immunoconjugates may augment the delivery of myelo-ablative doses of radiation therapy selectively to tumours. When patients relapse after high-dose therapy, there has been no standard approach to management. However, single agent chemotherapy (e.g. weekly low-dose vinblastine) has the potential for significant palliation, occasionally for prolonged periods.

Antineoplastic Agents↗
PubMed1998

Development of electrochemical immunosensing systems with renewable surfaces.

The repeated use of immunochemically modified solid phases in electrochemical immunosensor analysis is the driving interest of this work. Two new strategies have been developed. One of these strategies is aimed at the development of a manual methodology. It comprises the construction of amperometric immunosensors based on rigid biocomposites. These biocomposites are formed by a conducting polymer composite matrix that acts as a reservoir of an immobilized immunologic material. The surface of the biocomposite can be renewed by a simple polishing procedure. The second strategy involves the design of an automatic methodology. It features an immunochemical analytical system using flow injection techniques. The potentiometric detection uses a solid phase formed by immunologic reagents immobilized in magnetic particles. These particles are fixed to the sensor with the use of a magnetic field. The renewal of the reactive surface is achieved by the release and activation of the restraining magnetic field and the manipulation of the flow. The analytical properties of these immunosensors were evaluated measuring RIgG using a competitive technique and measuring GaRIgG with a sandwich methodology. The labelling enzymes of the immunoconjugates were peroxidase in amperometric measurements and urease in potentiometric measurements.

Animals↗
PubMed1993

Tumour necrosis factor increases tumour uptake of co-administered antibody-carboxypeptidase G2 conjugate.

Increased tumour uptake of antibodies and antibody-drug conjugates has been demonstrated following pretreatment of animals with recombinant human tumour necrosis factor-alpha (rTNF-alpha) and interleukin 2 immunoconjugates. The experiments reported here were performed to determine whether improved tumour localisation of antibody-carboxypeptidase G2 conjugates could be achieved, with a view to applying this technology to antibody-directed enzyme-prodrug therapy (ADEPT). B6CF1 mice bearing the Ly-2.1+ murine thymoma E3 were simultaneously injected with 2.0 micrograms rTNF-alpha and 3.5 micrograms (74kBq) 125I-labelled murine anti-Ly-2.1-CPG2 conjugate. Mice in control groups received phosphate buffered saline in place of rTNF-alpha. The conjugate corresponded in molecular weight to a mixture of 1:1 and 2:1 (CPG2:IgG) conjugate and retained its antigen binding specificity and enzymic activity in vitro. A significant increase in tumour uptake was observed 24 h after administration when rTNF-alpha-treated animals were compared to controls (28.1 +/- 9.7%/g and 11.6 +/- 2.3%/g, respectively). Other tissues, most notably gut, skin and kidney also showed an increased localisation of conjugate. By 48 h, analysis of tissue:blood ratios demonstrated that although tumour:blood ratios were significantly higher in rTNF-alpha-treated animals (P < 0.05), all the other tissue:blood ratios were not significantly different between the two groups.

Animals↗
PubMed2003

BR96 conjugates of highly potent anthracyclines.

The 6-maleimidocaproylhydrazone derivatives of highly potent antitumor agents 5-Diacetoxypentyldoxorubicin and Morpholinodoxorubicin were synthesized and conjugated to monoclonal antibody BR96 and control IgG. Immunoconjugate molar ratios were generally 7.5-8.5, and dimer aggregate levels were low. The linkers released parent drug at lysosomal pH 5, while they remained stable at neutral pH. BR96 conjugates were highly potent and antigen specific in vitro. The BR96-DAPDOX conjugate demonstrated an IC(50) of 0.03 micrometer and was at least 300-fold more potent than a non-binding IgG-DAPDOX control conjugate.

Anthracyclines↗
PubMed1998

Cathepsin B-sensitive dipeptide prodrugs. 2. Models of anticancer drugs paclitaxel (Taxol), mitomycin C and doxorubicin.

Substrates containing doxorubicin (DOX), paclitaxel (taxol), and mitomycin C (MMC) attached to the cathepsin B-sensitive dipeptide Phe-Lys via a self-immolative spacer were prepared as model compounds for internalizing anticancer immunoconjugates. Cathepsin B-mediated release rates of free drug, rat liver lysosomal susceptibility and human plasma stability were measured for each.

Animals↗
PubMed1997

Crystal structure of carboxypeptidase G2, a bacterial enzyme with applications in cancer therapy.

BACKGROUND: Carboxypeptidase G enzymes hydrolyze the C-terminal glutamate moiety from folic acid and its analogues, such as methotrexate. The enzyme studied here, carboxypeptidase G2 (CPG2), is a dimeric zinc-dependent exopeptidase produced by Pseudomonas sp. strain RS-16. CPG2 has applications in cancer therapy: following its administration as an immunoconjugate, in which CPG2 is linked to an antibody to a tumour-specific antigen, it can enzymatically convert subsequently administered inactive prodrugs to cytotoxic drugs selectively at the tumour site. CPG2 has no significant amino acid sequence homology with proteins of known structure. Hence, structure determination of CPG2 was undertaken to identify active-site residues, which may in turn provide ideas for protein and/or substrate modification with a view to improving its therapeutic usefulness. RESULTS: We have determined the crystal structure of CPG2 at 2.5 A resolution using multiple isomorphous replacement methods and non-crystallographic symmetry averaging. Each subunit of the molecular dimer consists of a larger catalytic domain containing two zinc ions at the active site, and a separate smaller domain that forms the dimer interface. The two active sites in the dimer are more than 60 A apart and are presumed to be independent; each contains a symmetric distribution of carboxylate and histidine ligands around two zinc ions which are 3.3 A apart. This distance is bridged by two shared zinc ligands, an aspartic acid residue and a hydroxyl ion. CONCLUSIONS: We find that the CPG2 catalytic domain has structural homology with other zinc-dependent exopeptidases, both those with a single zinc ion and those with a pair of zinc ions in the active site. The closest structural homology is with the aminopeptidase from Aeromonas proteolytica, where the similarity includes superposable zinc ligands but does not extend to the rest of the active-site residues, consistent with the different substrate specificities. The mechanism of peptide cleavage is likely to be very similar in these two enzymes and may involve the bridging hydroxyl ion ligand acting as a primary nucleophile.

Aminopeptidases↗
PubMed1998

Lysine-directed conjugation of ethidium homodimer to B72.3 antibody: retention of immunoreactivity but altered tumor targeting.

Ethidium homodimer (EHD) was conjugated to B72.3 monoclonal antibody using a method whereby 85-90% of the conjugated EHD remains available for DNA intercalation. Antibody was thiopropionylated by reaction with N-succinimidyl 3-(2-pyridyldithio)propionate and reduction of pyridyldithio groups with dithiothreitol. EHD was maleimido-functionalized with succinimidyl-4-(N-maleimidoethyl)cyclohexane-1-carboxylate and treated with thiopropionylated antibody to obtain a conjugate containing approximately 3.4 EHD per antibody molecule. For biologic studies, 14C-labeled EHD was synthesized by reductive amination and conjugated as above. In vitro the conjugate maintained chemical integrity and immunoreactivity, while in vivo its targeting of LS174T tumors was reduced compared with that of iodinated antibody. A decrease in isoelectric point of the immunoconjugate was also observed.

Adenocarcinoma↗
PubMed1997

Role of delivery vehicles for photosensitizers in the photodynamic therapy of tumours.

The use of photosensitizing drugs associated with different types of delivery vehicle has received strong interest within the field of the photodynamic therapy of tumours. Lipid-based delivery vehicles, such as liposomes and oil emulsions, allow the administration of water-insoluble photosensitizers, widening the choice of photosensitizers potentially useful for treating tumours. In some cases, these delivery vehicles increase the selectivity of tumour targeting by favouring photosensitizer uptake in tumour tissue. However, a higher selectivity of tumour targeting could be obtained through the association of photosensitizers with delivery vehicles which can interact preferentially or specifically with tumour cells. With this aim in mind, low-density lipoproteins (LDLs) and monoclonal antibodies, in particular, are regarded as the most promising delivery systems for anticancer drugs. Some pharmacokinetic studies with LDL-associated photosensitizers have demonstrated a higher tumour uptake compared with the same photosensitizers delivered with other formulations. Monoclonal antibody-coupled photosensitizers have been tested mainly in vitro, and have shown a high selectivity towards cells expressing specific antigens. Only a limited number of reports are available on the biodistribution of immunoconjugated photosensitizers and on their selectivity in vivo, so that their importance for the selectivity of tumour targeting has not yet been defined.

Antibodies, Monoclonal↗
PubMedDate not supplied

The clinical role of prostate-specific membrane antigen (PSMA).

Prostate cancer remains the most common cancer type in men in the United States. Efforts are increasing to evaluate and to discover diagnostic and therapeutic markers for prostate cancer patients. One of these, prostate-specific membrane antigen (PSMA), is a transmembrane protein highly expressed in all types of prostatic tissue, especially cancer. The radio-immunoconjugate form of the anti-PSMA monoclonal antibody (mAb) 7E11, known as the ProstaScint scan, is currently being used to diagnose prostate cancer metastasis and recurrence. Early promising results from various Phase I and II trials have utilized PSMA as a therapeutic target. Recently, PSMA expression in endothelial cells of tumor-associated neovasculature has been described. PSMA's possible role in malignant angiogenesis newly expands the realm of its possible beneficial uses, especially as new anti-PSMA mAbs continue to be developed and refined.

Antibodies, Monoclonal↗
PubMedDate not supplied

Antibody-targeted chemotherapy of acute myeloid leukemia using gemtuzumab ozogamicin (Mylotarg).

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and accounts for 20% of pediatric leukemia. Although conventional chemotherapy induces clinical remissions in most patients with AML, recurrent leukemia represents the major obstacle to cure. Conventional chemotherapy reinduction is associated with limited efficacy and substantial toxicity. Chemotherapy specifically targeted to leukemic cells by monoclonal antibodies might enable patients to achieve remissions more safely than conventional approaches. After evaluating a series of phase II studies, the U.S. Food and Drug Administration approved Mylotarg (gemtuzumab ozogamicin) for the treatment of patients with CD33-positive AML in first relapse who are 60 years of age or older and who are not considered candidates for other types of cytotoxic chemotherapy. Among 277 adult patients with CD33-positive AML in first relapse, 26% experienced an overall response after Mylotarg monotherapy. Despite the fact that myelosuppression, hyperbilirubinemia, and elevated hepatic transaminases were commonly observed, the incidences of severe infections and mucositis were relatively low in comparison with conventional chemotherapeutic treatment. Preliminary reports in pediatric patients also report Mylotarg to be reasonably well tolerated. Recently, data from study regimens combining Mylotarg and conventional chemotherapy suggest an unusually high remission induction rate in de novo AML patients. Information assembled from prospective, ongoing studies in the United States and the United Kingdom should help us use this novel immunoconjugate in a safe and effective manner.

Acute Disease↗
PubMed2003

Inhibitors of epidermal-growth-factor receptors: a review of clinical research with a focus on non-small-cell lung cancer.

Despite aggressive surgical and chemotherapeutic interventions, non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death in men and women with overall cure rates of less than 15%. Recent advances in our understanding of cellular signalling and its critical role in tumorigenesis has led to the development of novel therapies which may offer new hope. In particular, the epidermal growth-factor receptor superfamily is an attractive therapeutic target because it is commonly overexpressed in malignant disease, regulates many vital cellular processes, and seems to be a negative prognostic indicator. Several selective inhibitors of this family of receptors are currently being evaluated in several cancers including NSCLC. In this review we examine current preclinical and clinical evidence on monoclonal antibodies (cetuximab, ABX-EGF, EMD72000, MAb ICR62, h-R3, MDX-447, MDX-H210, trastuzumab, and 2C4), immunoconjugates (Y10, Ua30:2, Mab806), anti-EGF vaccine (YMB2000), and tyrosine kinase inhibitors (gefitinib, erlotinib, CI1033, GW572016, EKB 569, PKI166, PD158780, and TAK 165).

Antibodies, Monoclonal↗
PubMedDate not supplied

N-terminal modification of immunoglobulin polypeptide chains tagged with isothiocyanato chelates.

Conjugates of monoclonal antibodies with drugs, toxins, radionuclides, and other agents are in widespread use in therapeutic trials and as clinical research tools. The characterization of these immunoconjugates generally does not include determining the individual sites at which such agents are attached. We have begun to explore the attachment of the bifunctional chelating agent isothiocyanatobenzyl-EDTA (CITC1) to the N-termini of the light chains of the Lym-1 monoclonal antibody. The similarity between this bifunctional chelating agent and Edman's reagent, phenyl isothiocyanate, led us to develop methods to distinguish between chelate-conjugated alpha-amino groups and epsilon-amino groups by Edman degradation. Practically all the N-terminal Asp alpha-NH2 groups of Lym-1 can be modified at neutral pH, while attachment at lysine side chains predominates at pH 9. Comparison of the immunoreactivities of Lym-1-CITC conjugates with and without N-terminal conjugation shows that both are almost fully active. This implies that modification of light-chain N-termini has little or no effect on immunoreactivity, despite the fact that these residues lie near the antigen-binding sites.

Amino Acid Sequence↗