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PubMed1999

An Epstein-Barr virus-infected lymphoblastoid cell line (D430B) that grows in SCID-mice with the morphologic features of a CD30+ anaplastic large cell lymphoma, and is sensitive to anti-CD30 immunotoxins.

BACKGROUND AND OBJECTIVE: In this study we describe a newly established CD30+ Epstein Barr virus (EBV)-infected B cell line derived from an EBV-infected B cell culture (utilized, once irradiated, as a feeder) which showed a B clonal rearrangement and strong CD30 antigen expression. DESIGN AND METHODS: The cells injected into SCID mice were able to grow giving rise to CD30+ solid tumors with the morphologic features of an anaplastic large cell lymphoma (ALCL). Thus we tried to establish a model to investigate the potency of immunoconjugates containing a CD30 monoclonal antibody (Ber-H2) and ribosome-inactivating proteins (saporin, momordin and ricin A-chain) as toxic moieties. RESULTS: We observed a strong cytotoxic activity of the anti-CD30 immunotoxins on the in vitro growth of D430B cells. High levels of anti-tumor activity were also observed in vivo, in the SCID mouse model. INTERPRETATION AND CONCLUSIONS: The antitumor immunotoxin therapy was sccessful in our chosen animal model, the effecacy seeming to be associated with strength of CD30 expression. Our data suggest that immunotoxins should be tested (before use) on the tumor cells of the subject to be treated and that immunotoxins should be directed to different tumor-associated antigens to avoid selection of cell populations with different antigenic mosaics.

Animals↗
PubMed1999

Treatment of therapy-refractory B-lineage acute lymphoblastic leukemia with an apoptosis-inducing CD19-directed tyrosine kinase inhibitor.

Seven children and eight adults with CD19+ B-lineage acute lymphoblastic leukemia, as well as one adult with chronic lymphocytic leukemia, were treated with the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein. All patients had failed previous chemotherapy regimens, and six patients had relapsed after bone marrow transplantation. B43-Genistein was administered as a 1-hour i.v. infusion at 0.1-0.32 mg/kg/day dose levels for 10 consecutive days or 3 consecutive days weekly for a total of nine doses. B43-Genistein was well tolerated by all patients with no life-threatening side effects. There were six episodes of grade 2-3 fever, two of which were clearly drug related, one episode each of grade 3 myalgia, grade 2 sinus tachycardia, and grade 2 vascular leak syndrome. There was one durable complete remission and two transient responses. Pharmacokinetic analyses in 12 patients revealed a plasma half-life of 20 +/- 5 h, mean residence time of 24 +/- 5 h, and a systemic clearance rate of 20 +/- 3 ml/h/kg. Moderate levels of human antimouse antibody (HAMA) ranging from 20-87 ng/ml were detected in the day 28 blood samples from three of nine cases examined. Treatment of these three HAMA-positive patients with a second course of B43-Genistein did not yield measurable immunoconjugate levels in the plasma, indicating that the administered B43-Genistein molecules were rapidly cleared from circulation due to the HAMA. On the basis of its acceptable toxicity profile and its ability to elicit objective responses at nontoxic dose levels, B43-Genistein may provide the basis for an effective treatment strategy for B-lineage acute lymphoblastic leukemia patients who have failed standard therapy.

Adolescent↗
PubMed2000

The combined use of an immunotoxin and a radioimmunoconjugate to treat disseminated human B-cell lymphoma in immunodeficient mice.

Immunoconjugates (ICs) consist of a targeting moiety and a toxic moiety and have the specificity that traditional cancer therapy lacks. At appropriate doses, ICs are safe and effective in treating various cancers in experimental animals and in humans. However, because cures are rarely achieved using single agents, regimens involving combinations of agents with different mechanisms of action must be evaluated. In this study, we explored the efficacy and toxicity of a combination of two IC therapies, radioimmunotherapy (RIT) and immunotoxin (IT) therapy, to treat advanced, disseminated human lymphoma in immunodeficient mice. We proposed to use the bystander effect of RIT to reduce large tumor burdens, followed by an IT to eliminate residual tumor cells. Our results indicate that, when used alone, both RIT and IT therapy were safe and effective, but not curative. When the two therapies were combined, efficacy and toxicity became dependent on the temporal order of administration. Thus, with the doses used in this study, when RIT was administered after IT therapy, the regimen was curative. In contrast, when RIT was administered before IT therapy, the combination was highly toxic or even lethal. Both RIT and IT therapy induced pulmonary vascular leak, but with different kinetics. When RIT was given prior to IT therapy, the pulmonary vascular leak became life-threatening but not when the two agents were administered in the reverse order.

Animals↗
PubMed2000

[Radioimmunotargeting: diagnosis and therapeutic use].

Monoclonal antibodies labeled with a radionuclide make feasible the in vivo radioimmunotargeting of tumor cells. This targeting could be performed for diagnosis, using gamma emitters, or for therapeutic purpose when antibodies are labeled with beta- and in the future alpha-emitters. Diagnosis applications (tumor detection and caracterization), i.e. immunoscintigraphy, have been widely investigated during 20 last years. This technic appeared quite interesting, complementary of morphological imaging, and clinically useful, but difficult on a practical point of view because of several pharmacological and immunological limitations. For these reasons, despite several consequent improvements (especially two-steps or pre-targeting methods), immunoscintigraphy is currently not widely used; furthermore, other scintigraphic methods, mainly positron emission tomography with 18F-fluorodeoxyglucose, are efficient and easier to perform. On the other hand, knowledge of the biodistribution of radiolabeled antibodies allows the development of their therapeutic use, i.e. radioimmunotherapy, which represents a new method of cancer treatment. Radioimmunotherapy has several particular radiobiological and dosimetric aspects, which remain widely under investigation. Understanding of these aspects, together with a better delineation of the indications, allow to be really optimist concerning this new way of cancer treatment, as shown by clinical results that have been obtained in non Hodgkin's lymphoma. Radiolabeled immunoconjugates appears as a growing field in nuclear medicine, which sustains numerous preclinical and clinical studies.

Antibodies, Monoclonal↗
PubMed2000

Monoclonal antibody treatment of solid tumors: a coming of age.

Over the past 5 years there has been a renewed interest in the use of monoclonal antibodies and immunoconjugates in the treatment of nonhematologic malignancies. This enthusiasm has stemmed from advances in recombinant technology allowing for the production of chimeric and humanized antibodies, from Food and Drug Administration approval of radioimmunoconjugates for use in diagnosis and staging in colorectal, ovarian, and prostate cancer, from studies demonstrating durable response rates in lymphoma and breast cancer, and from trials demonstrating marked efficacy of radiolabeled antibodies in the treatment of non-Hodgkin's lymphoma. Part of the success of chimeric and humanized antibodies in treating solid tumors relates to the lack of human antimouse antibody formation along with enhanced immunogenic effector mechanisms. The pitfalls underlying early trials of murine monoclonal antibodies in solid tumors and newer antibody approaches using unique antigen targets, bifunctional constructs, and alternative routes of antibody administration will be discussed.

Animals↗
PubMed1997

[A monoclonal antibody directed against an enediyne antitumor antibiotic and its preliminary application].

C1027, composed of an enediyne chromophore and an apoprotein of 110 amino acid residues, is a new highly potent macromolecular antitumor antibiotic. In order to prepare monoclonal antibodies (McAb) against C1027 by hybridoma technique, natural C1027 was inactivated by ultraviolet and coupled with human serum albumin, then immunized BALB/c mice. After cell fusion and screening by ELISA, a hybridoma secreting anti-C1027 McAb designated as F9 was obtained. McAb F9 specifically reacted with C1027 as determined by immunoblot assay. No obvious difference was observed between the reactivity of McAb F9 to natural C1027 and that of McAb F9 to ultraviolet inactivated C1027. This result indicates that the ultraviolet-sensitive chromophore of C1027 may not participate in the epitope for McAb F9. The isotype of F9 is IgG1 and its affinity constant was found to be (2.2 +/- 0.47) x 10(7) L.mol-1 according to Beatty's method. By clonogenic assay, McAb F9 neither affected the cytotoxicity of C1027 to KB cells nor blocked the activity of the chromophore. McAb F9 also specifically reacted with the recombinant truncated C1027 apoprotein in which 16 amino acid residues at the C terminus were deleted. This study suggests that F9 is a valuable McAb for the research of C1027 apoprotein engineering, C1027 related immunoconjugates and screening of new macromolecular antitumor substances with homology to the protein part of C1027.

Aminoglycosides↗
PubMed2001

Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia.

PURPOSE: Gemtuzumab ozogamicin (Mylotarg; Wyeth Laboratories, Philadelphia, PA) consists of a semisynthetic derivative of calicheamicin, a cytotoxic antibiotic linked to a recombinant monoclonal antibody directed against the CD33 antigen present on leukemic myeloblasts in most patients with acute myeloid leukemia (AML). In this study, we review the preclinical and clinical profiles of this immunoconjugate and the regulatory review that led to marketing approval by the United States Food and Drug Administration. EXPERIMENTAL DESIGN: From the literature and manufacturer's data, we review the activity, tolerability, and pharmacokinetics of gemtuzumab ozogamicin in preclinical and Phase I studies and its activity, efficacy, and side effects in three Phase 2 trials of 142 patients with relapsed AML. RESULTS: In Phase I studies, the major toxicity was myelosuppression, especially neutropenia and thrombocytopenia, resulting from the expression of CD33 on myeloid progenitor cells. The Phase 2 dose was 9 mg/m(2) infused i.v. over 4 h, repeated on day 14. A minority of patients experienced acute infusion-related symptoms, usually transient and occasionally requiring hospitalization. The complete response (CR) rate with full recovery of hematopoiesis was 16%. A subset of patients [CRs with incomplete platelet recovery (CRps)] was identified with blast clearance and neutrophil recovery but incomplete platelet recovery. The duration of responses of CRps appeared to be similar to those of the CRs, although the numbers were small. The question of the equivalence of these response groups was a central issue in the review of this new drug application (NDA). After considerable discussion, the Oncology Drugs Advisory Committee recommended allowing inclusion of CRps resulting in an overall response rate in the Phase 2 studies of 30%. In the subgroup of patients over 60 years of age, the overall response rate was 26%. Response duration was difficult to establish because of the high prevalence of postremission therapies. Tolerability and ease of administration may be improved compared with conventional chemotherapy, except for hepatotoxicity, with 31% of patients exhibiting abnormal liver enzymes. One patient died of liver failure in the Phase 2 trials. CONCLUSIONS: Marketing approval of gemtuzumab ozogamicin was granted on May 17, 2000 by the United States Food and Drug Administration under the Accelerated Approval regulations. Gemtuzumab ozogamicin is indicated 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 cytotoxic chemotherapy. The approved dose was 9 mg/m(2) i.v. over 4 h and repeated in 14 days. Completion of the ongoing studies of gemtuzumab ozogamicin in relapsed AML and initiation of randomized clinical trials comparing the effects of gemtuzumab ozogamicin in combination with conventional induction chemotherapy to conventional chemotherapy alone on survival are mandated to confirm clinical benefit under the accelerated approval Subpart H regulations. Postmarketing reports of fatal anaphylaxis, adult respiratory distress syndrome (ARDS), and hepatotoxicity, especially venoocclusive disease (VOD) in patients treated with gemtuzumab ozogamicin, with and without associated hematopoietic stem cell transplantation (HSCT), have required labeling revisions and the initiation of a registration surveillance program. Tumor lysis and ARDS have been reported in patients with leukocytes above 30,000/ml treated with gemtuzumab ozogamicin; therefore, the reduction of leukocyte counts to below 30,000/ml is recommended prior to treatment. Patients should be carefully monitored for acute hypersensitivity, hypoxia, and delayed hepatotoxicity following treatment with gemtuzumab ozogamicin.

Adolescent↗
PubMed2001

Angiogenesis and metastasis marker of human tumors.

Tumor growth and metastasis are dependent on angiogenesis. Therefore, certain angiogenesis markers may be useful as metastasis markers and/or the targets for antiangiogenic therapy. We and others have been studying endoglin(EDG; CD105) for such purposes. EDG is a proliferation-associated antigen of endothelial cells and essential for angiogenesis. In addition, EDG is a component of the transforming growth factor(TGF)-beta receptor complex. Expression of EDG is up-regulated in tumor-associated angiogenic vasculature compared with normal tissue vasculature. Microvessel density detected for EDG expression in breast cancer tissues showed a statistically significant correlation with overall and disease-free survival. In addition, elevated serum EDG was associated with metastasis in patients with colorectal, breast, and other solid tumors. On the other hand, We have been targeting EDG on tumor vasculature to suppress tumor growth and metastasis by systemic(i.v.) administration of anti-EDG monoclonal antibodies(mAbs) and immunoconjugates(IMCs). To thid end, we have been using three animal models, i.e., severe combined immunodeficient(SCID) mouse model of MCF-7 human breast cancer, human skin/SCID mouse chimera model bearing MCF-7 tumor, and syngeneic metastasis model of colon-26 adenocarcinoma cells in BALB/c mice. In addition, antiangiogenic activities of anti-EDG mAbs and IMCs were evaluated in mice using the dorsal air sac assay. The IMCs were prepared by coupling deglycosylated ricin A-chain or 125I to individual anti-EDG mAbs. These anti-EDG IMCs and mAbs showed substantial antitumor efficacy and antimetastatic activities without showing severe toxicity. Recently, we generated a recombinant human/mouse chimeric anti-EDG mAb to facilitate clinical application of the mAb.

Animals↗
PubMed2001

Preparation and Use of a Monoclonal Antibodyagainst Luffin b.

Luffin b is one of the most toxic single chain plant ribosome inactivating proteins. It has been successfully used to prepare an immunotoxin against human melanoma cells. Two strains of hybridomas (1E5 and 2E1) were screened out using cell fusion technique which steadily secreted monoclonal antibodies against luffin b. These antibodies specifically reacted with luffin b. The affinity constants of 1E5 and 2E1 monoclonal antibodies were determined to be 1.1x10(9) mol(-1).L and 7.5x10(8) mol(-)1.L, by RIA,respectively. An immunoaffinity gel composed with the 1E5 monoclonal antibody and Sepharose 4B was prepared. The luffin b was successfully purified by one step immunoaffinity chromatography from the crude extract of Luffa cylindrica seeds. An immunoconjugate 1E5-HRP was also prepared and it was successfully used in Western blotting for detection of recombinant luffin b from E.coli total proteins.

Journal Article↗
PubMed2002

Radioimmunodetection of cervical carcinoma xenografts with (111)In-labeled MAb Cx-99 detected by a hand-held gamma detector.

PURPOSE: To establish a radioimmunodetection (RAID) system for localization of cervical cancer by labeling 111-indium ((111)In) to a monoclonal antibody against cytokeratin 19 (MAb Cx-99), and detecting it with a hand-held gamma detector in an animal model. METHODS: MAb Cx-99 was labeled with 111-Indium by the DTPA chelating method. From the second day to the seventh day after injection of this immunoconjugate into athymic nude mice bearing cervical cancer cell line CC7T xenografts, the biodistribution ratios of tumor and non-tumor radioactivity were detected by a hand-held gamma detector. Data were also correlated with the data detected by the conventional gamma counter. RESULTS: The labeling efficiency of this (111)In-labeled MAb Cx-99 and (111)In-labeled MOPC was 91.6% and 95.5%, respectively. After injection, the liver, kidney and lung were initially noticed to have high radioactivity, but the localization of tumor/tissue ratios increased progressively as time passed, indicating the effect of delayed detection for distinguishing tumor from non-tumor tissues. Except for the spleen, the range of tumor/tissue ratios was 1.18-32.7 and 1.14-39.35 for the fourth day and the seventh day, respectively. The tumor/spleen ratio remained low until the seventh day after injection, thus indicating that the spleen might have a different excretion rate. CONCLUSION: This study indicated the feasibility of a hand-held detection system in the localization of cervical cancer after injection of (111)In-labeled MAb Cx-99. The effect of delayed detection was obvious by the decreasing high bindings in the liver, spleen and kidney, with the applicable detection time being four to seven days after injection.

Animals↗
PubMed2002

[Rapid immunotitration of individual toxins from Androctonus australis venom].

Passive immunotherapy against scorpion envenomations is facilitated by the preliminary titration of circulating toxins in envenomed patients. Currently, routinely used ELISA tests allow only the titration of the whole venom, without reference to the toxins which compose the venom and spread variably within the tissue. Taking as a model one of the three toxins responsible for the lethal effects of Androctonus australis hector (Aahl) venom, we developed an ELISA sandwich test based on a fragment of recombining antibody (scFv) consisting of the variable chains of the monoclonal IgG 9C2 coupled to a decapeptide showing high affinity for streptavidine. Conjugate scFvlStrep-tag was prepared by genetic engineering. It was produced in the periplasm of recombining bacteria, in a reproducible way, in a soluble form, at low cost and with an output, after purification, of 0.8 mg/L of bacterial culture. The recombinant protein, of small size (28 kDa), is bifunctional. It preserves a very high affinity for the toxin Aah I (Kd of 2.3 10(-10) M, very close to that of IgG 9C2), yet recognises streptavidine and its conjugate (streptavidine-peroxidase). The titration of the Aahl toxin used an ELISA sandwich test in which the toxin was captured in a specific way by a monoclonal antibody; the immunocomplexes were then detected by recombinant immunoconjugate, thus conferring a high specificity on titration. The test is quick (90 mn), reproducible and sensitive, with a limit of detection of 0.6 toxin (ng.ml-1). This method could be extended to two other lethal toxins of the venom of the scorpion Androctonus australis hector and to those of other species. New perspectives are thus possible for the diagnosis of the envenomations.

Animals↗
PubMed2003

Radiolabeled monoclonal antibodies specific to the extracellular domain of prostate-specific membrane antigen: preclinical studies in nude mice bearing LNCaP human prostate tumor.

UNLABELLED: Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein, is highly expressed by virtually all prostate cancers. PSMA is also expressed on the tumor vascular endothelium of virtually all solid carcinomas and sarcomas but not on normal vascular endothelium. PSMA is currently the focus of several diagnostic and therapeutic strategies. We have previously reported on the radiolabeling and in vitro binding properties of monoclonal antibodies (mAbs) (J415, J533, and J591) that recognize and bind with high affinity to the extracellular domain of PSMA (PSMA(ext)). This article reports on the in vivo behavior and tumor uptake of (131)I- and (111)In-labeled antiPSMA(ext) mAbs (J415, J533, and J591) and their potential utility for radioimmunotherapy. METHODS: In nude mice bearing PSMA-positive human LNCaP tumors, the pharmacokinetics, biodistribution, and tumor uptake of these antibodies was compared with (111)In-7E11 mAb, specific to the intracellular domain of PSMA (PSMA(int)). Autoradiographic studies were done to identify intratumoral distribution of radiolabeled mAbs. RESULTS: With (131)I-labeled antibodies, the net tumor retention of radioactivity by day 6 was significantly higher with J415 (15.4% +/- 1.1%) and 7E11 (14.5% +/- 1.7%) than with J591 (9.58% +/- 1.1%). By contrast, the tumor uptake of (111)In-1,4,7,10-tetraazacyclododecane-N,N',N", N"'-tetraacetic acid-labeled J415 and J591 gradually increased with time and was quite similar to that of 7E11. In addition, the blood clearance of (111)In-labeled J415 and J591 antibodies was relatively faster than that of radiolabeled 7E11. As a consequence, the tumor-to-blood ratios with J415 and J591 were higher than that of 7E11. The localization of radiolabeled anti-PSMA(ext) antibodies in PSMA-positive LNCaP tumors was highly specific because the tumor uptake of (131)I-labeled J415 and J591 was more than twice that of a nonspecific antibody. Furthermore, the tumor uptake of (131)I-J591 was almost 20 times higher in PSMA-positive LNCaP tumors than in PSMA-negative PC3 and DU145 tumor xenografts. Autoradiographic studies suggested that 7E11 (anti-PSMA(int)) distinctly favors localization to areas of necrosis whereas J415 and J591 (anti-PSMA(ext)) demonstrated a distinct preferential accumulation in areas of viable tumor. CONCLUSION: These results clearly demonstrate that PSMA-specific internalizing antibodies such as J415 and J591 may be the ideal mAbs for the development of novel therapeutic methods to target the delivery of beta-emitting radionuclides ((131)I, (90)Y, and (177)Lu) for the treatment of PSMA-positive tumors. In addition, because J591 and J415 mAbs are specific to PSMA(ext), thus targeting viable tumor, these immunoconjugates are better candidates for targeted radioimmunotherapy than are antibodies targeting PSMA(int).

Animals↗
PubMedDate not supplied

Demonstration of monoclonal anti-carcinoembryonic antigen (CEA) antibody internalization by electron microscopy, western blotting and radioimmunoassay.

One of the important factors affecting the action of monoclonal antibodies (Mabs) or immunoconjugates on tumour sites depends on whether the Mab is internalized by the cancer cells in question. The underexplored subject of internalization is discussed in this paper, and a number of in vitro techniques for investigating internalization are evaluated, using a model which consists of a well characterized anti-carcinoembryonic antigen (anti-CEA) Mab and a number of CEA expressing human cancer cell lines. Employing two alternative radiolabeling assays, evidence for internalization of the anti-CEA Mab by a CEA-positive colorectal cancer cell line (LS174T) was obtained throughout the time intervals examined (5 min to 150 min). Electronmicroscopy employing horseradish-peroxidase labeled anti-CEA Mab and control antibody permitted direct visualization of anti-CEA Mab-related staining in intracellular compartments of a high CEA-expressor human colorectal cell line (SKCO1). Finally Western blots of samples derived from cytosolic and membrane components of solubilized cells from lung and colonic cancer cell lines provided evidence for internalized anti-CEA Mab throughout seven half hour intervals, starting at 5 minutes. Internalized anti-CEA was detected in all CEA expressing cell lines (LS174T, SKCO1, BENN) but not in the case of a very low CEA expressor line (COLO 320).

Antibodies, Monoclonal↗
PubMed1992

Demonstration of clonality, by X-linked DNA analysis, in chronic natural killer cell lymphocytosis and successful therapy with oral cyclophosphamide.

The expanded lymphocyte population in large granular lymphocyte (LGL)-leukemia carries the phenotypic characteristics of either cytotoxic T lymphocytes (CD3+,CD8+) or natural killer (NK) cells (CD3-,CD15+). In the former subset, clonality has been demonstrated by T-cell receptor gene rearrangement studies. Since NK cells do not rearrange T-cell receptor genes, the neoplastic nature of chronic NK cell lymphocytosis has not been well defined. We used X-linked DNA analysis to study the clonal nature of an expanded NK cell population in a patient with a 3-year history of relative lymphocytosis associated with anemia and neutropenia. Southern blot analysis showed no clonal T-cell receptor gene rearrangement. The majority of the circulating lymphocytes had a NK cell phenotype and demonstrated both direct NK cell-mediated cytotoxicity and antibody-dependent cellular cytotoxicity. However, the in vitro growth characteristics of these cells did not suggest that they were polyclonal expansions of normal NK cells. To determine directly the clonal origin of these cells, we performed X-linked DNA analysis. Density gradient centrifugation methods were used to isolate mononuclear cells, and NK cells were positively selected by CD16-immunoconjugated magnetic beads. The DNA of these cells was analyzed by restriction fragment length polymorphism-methylation strategy and showed a monoclonal pattern of X-chromosome inactivation while a polyclonal pattern was obtained in corresponding skin tissue. Treatment of the patient with oral cyclophosphamide resulted in complete hematologic remission. We conclude that chronic NK lymphocytosis may be clonal and responsive to immunosuppressive therapy.

Aged↗
PubMed1992

Local administration of monoclonal antibody-drug conjugate: a new strategy to reduce the local recurrence of colorectal cancer.

This report investigates the application of monoclonal antibody A7 and its drug conjugate in locally controlling colorectal cancer. The experimental protocol consisted of local retention, lymphatic delivery, normal organ distribution, systemic toxicity, and tumoricidal effects. When 125I-labeled monoclonal antibody (Mab) A7 was injected into the pelvis and the thigh of Balb/c mice, a high local retention unrelated to antigen-antibody interaction was observed at the injected site for 24 h after injection. An analysis of local retension properties related to antigen-antibody interaction, conducted by intratumorally or peritumorally injecting 125I-Mab A7 into the tumor-bearing athymic nude mice, revealed a significantly higher tumor localization of Mab A7 in comparison to i.v. injection. 125I-Mab A7 accumulated to a great extent in the ipsilateral regional lymph node but not in the contralateral regional lymph node. Normal organ accumulation of Mab A7 was lower in the locally injected group than in the i.v. injected group. Intratumoral injection of Mab A7-neocarzinostatin (A7-NCS) led to the complete remission of established tumor in 5 of 6 antigen-positive xenograft-bearing mice but exhibited a complete remission in only 1 of 6 antigen-negative xenograft-bearing mice. A single local injection of A7-NCS inhibited tumor development in 12 of 16 and 5 of 15 antigen-positive tumor-bearing mice and antigen-negative tumor-bearing mice, respectively, whereas neither a systemic injection of A7-NCS and NCS nor a local injection of NCS and saline had a notable inhibitory effect on tumor development. Systemic toxicity of NCS was markedly reduced when it was locally administered in the antibody-conjugated form. These findings indicate that local injection of immunoconjugate is a promising new field for controlling the local recurrence of colorectal cancer.

Animals↗
PubMed1992

[Antitumor activity of new antitumor antibiotic C1027 and its monoclonal antibody assembled conjugate].

C1027, a new macromolecular peptide antitumor antibiotic produced by Streptomyces globisporus C1027, shows extremely potent cytotoxicity to cultured cancer cells. The antibiotic is composed of an apoprotein and a chromophore and the latter serves as the active part of the compound. C1027 was separated into apoprotein and chromophore by methanol extraction and the separated parts can be reconstituted to form the active C1027 molecule in phosphate buffer. For determination of the specificity of C1027 reconstitution, the apoprotein was incubated with epirubicin and the chromophore was incubated with H16, a McAb directed against hepatoma cells. Notably, the reconstitution of C1027 occurred neither between apoprotein and epirubicin nor between chromophore and IgG molecule. In addition, bovine serum albumin showed no competition with C1027 apoprotein in binding to the chromophore. Various methods for linking C1027 to McAb were studied and two kinds of immunoconjugates have been prepared: (1) direct conjugate was made by linking C1027 to McAb, using SPDP as a linker agent, (2) assembled conjugate was made by linking and reconstitution, including 3 steps. Firstly, the chromophore was extracted with methanol and stored at -70 degrees C in drak. Secondly, the apoprotein was conjugated to McAb by SPDP and finally the extracted chromophore was added to the McAb-apoprotein conjugate. Determined by clonogenic assay, the IC50 values for hepatoma cells were 42 pmol/L, and 5.5 pmol/L, respectively, for direct conjugate and assembled conjugate. The IC50 value of M3-C1027 assembled conjugate prepared by linking the irrelevant McAb M3 to C1027 was 1,400 pmol/L.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoglycosides↗
PubMed1992

A gelonin-containing immunotoxin directed against human breast carcinoma.

Toxins may be specifically directed to tumor cells and the toxins' potency greatly increased by covalent conjugation to monoclonal antibodies recognizing tumor-associated antigens. Antibody 15A8, an immunoglobulin G1 (IgG1) subclass anti-human breast carcinoma murine monoclonal antibody and gelonin, a plant toxin, were covalently modified with N-succimindyl 3-(2-pyridyldithio) proprionate and iminothiolane, respectively, and allowed to cross-link. 15A8-gelonin conjugates were purified from unreacted antibody and free gelonin by gel filtration and blue sepharose chromatography. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that the final product contained two bands corresponding to antibody:gelonin conjugates of 1:1 (predominant) and 1:2. There were no contaminating amounts of free antibody or free toxin in the preparation. The yield of the final purified 15A8-gelonin conjugate was approximately 20% based on the amount of starting antibody. The protein synthesis inhibitory activity of the immunoconjugate was assessed by in vitro rabbit reticulocyte translation assay. This functional activity was normalized to that of unmodified gelonin for use in in vitro antiproliferative assays against antigen-negative (Hs294t human melanoma) and antigen-positive (ME-180 human cervical carcinoma) cell lines. Antigen-negative Hs294t cells incubated for 72 hours with 15A8-gelonin immunotoxin showed no increased cytotoxicity compared with HS294t cells exposed to free gelonin alone. However, the immunotoxin was preferentially toxic to antigen-positive ME-180 cells; over 5 logs greater cell kill was observed after 72 hours exposure to 15A8-gelonin than after the same exposure to gelonin alone. Various lysosomotropic agents augmented 15A8-gelonin cytotoxicity; the most effective potentiating agent appeared to be monensin. In addition, the chemotherapeutic agents L-phenylalanine mustard (L-PAM), 5-fluorouracil, vincristine, and bleomycin, and the biological response modifiers interferon-alpha and tumor necrosis factor-alpha were shown to augment 15A8-gelonin cytotoxicity. Should in vivo pharmacology and therapeutic studies confirm these in vitro findings, 15A8-gelonin conjugate may be a potent agent for therapy of cancer in man.

Antibodies, Neoplasm↗
PubMed2004

Sequential administration of gemtuzumab ozogamicin and conventional chemotherapy as first line therapy in elderly patients with acute myeloid leukemia: a phase II study (AML-15) of the EORTC and GIMEMA leukemia groups.

BACKGROUND AND OBJECTIVES: Acute myeloid leukemia (AML) in the elderly is associated with low rates of response to conventional chemotherapy and long-term survival, highlighting the need for innovative treatment strategies. Gemtuzumab ozogamicin (GO) is an immunoconjugate that has shown activity in relapsed AML with a favorable safety profile. The aim of this collaborative trial was to assess the feasibility, safety, and antileukemic activity of administering GO followed by conventional chemotherapy as first line therapy in patients aged 61-75 years with AML. DESIGN AND METHODS: Eligible patients received frontline treatment with GO 9 mg/m2 infused intravenously on days 1 and 15. Following response assessment to GO, patients were started on conventional chemotherapy consisting of the MICE regimen (mitoxantrone, cytarabine, etoposide). No further treatment was planned for complete responders. RESULTS: Among the 57 evaluable patients, 38 (67%) completed the entire sequential treatment as planned. The overall response rate to the entire induction sequence was 54.4% (31/57), with complete remission (CR) in 35.1% and complete remission with incomplete platelet recovery (CRp) in 19.3%. Rates of failure due to treatment-related mortality or resistant disease were 14.1% (3 toxic deaths during the GO segment, 5 during MICE) and 29.9%, respectively. An initial response to GO was documented in 20 patients (35.1%), with CR in 22.8% and CRp in 12.3%; 6 additional patients entered a partial remission. Reversible myelosuppression and liver toxicity were the main adverse events during both segments of induction. Frontline GO was associated with modest mucosal and gastrointestinal toxicity, but grade 3-4 pancytopenia was universal and prolonged. Hepatic veno-occlusive disease developed in 3 patients after GO and 2 after MICE, resulting in 4 deaths from liver failure. One-year survival at follow-up was 34%. Twelve patients continue in CR/CRp after a median of 226 days. INTERPRETATION AND CONCLUSIONS: The sequential combination of GO and conventional chemotherapy is a feasible and active treatment strategy for older patients with untreated AML. This novel regimen is now being compared in a phase III trial (AML-17).

Acute Disease↗