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At least 541 records · Page 30Linked to original sources
PubMed1999

A phase II study of [90Y] yttrium-capromab pendetide in the treatment of men with prostate cancer recurrence following radical prostatectomy.

There is currently no curative therapy for men who have disseminated prostate cancer following failed radical prostatectomy. The purpose of this trial was to investigate systemic radioimmunotherapy in these men. Eight patients with occult metastatic prostate cancer following radical prostatectomy as evidenced solely by a rising serum PSA and evidence of soft tissue lesions outside the prostatic fossa detected by an [111I]indiumcapromab pendetide scan received an infusion of 10 mg of capromab pendetide labeled with 9 mCi/m2 of [90Y]yttrium. Serum PSA was used to measure response rate. There were no complete or partial responses by PSA criteria. Significant unexpected bone marrow toxicity developed in the first 6 of 8 patients treated. The last two patients received co-infusion of edetate calcium disodium in an effort to decrease marrow suppression. In these two patients less marrow toxicity was seen. Repeat 111In-capromab pendetide scans were uninterpretable due to grossly altered whole-body biodistribution of the radioimmunoconjugate. Retrospective analysis of serial PSA values after closure of the study showed a decrease in the log slope PSA for seven of eight patients following radioimmunotherapy, with a statistically significant change in the mean log slope (p = 0.01). The clinical significance of this small but measurable change is uncertain. We conclude that radioimmunotherapy for occult metastatic prostate cancer using 90Y-capromab-pendetide at the dose described does not lower serum PSA, is associated with significant hematologic toxicity, and leads to complexation of the immunoconjugate following subsequent capromab pendetide infusion.

Adenocarcinoma↗
PubMed1998

Single-chain Fv with manifold N-glycans as bifunctional scaffolds for immunomolecules.

Unlike natural antibodies, single-chain Fv (sFv) proteins normally lack asparagine-linked glycosylation. Many designed immunoconjugates and other therapeutics currently employ the advantageous conjugation chemistry or targeting properties provided by the glycoprotein oligosaccharide domain. sFv proteins with engineered N-glycan designs were evaluated in Pichia pastoris for glycosylation efficiency, expression level, oligosaccharide chain length and composition, and affinity. In contrast to nearly all natural glycoproteins, the engineered attachment of N-glycans conveniently near the polypeptide C-terminus was found to produce the optimal results. Furthermore, the percentage modification and chain length of the attached mannose chains were controllable by the use of tandem and overlapping Asn-X-Thr tripeptide sites. The glycosylated sFv mannose chains could be effectively conjugated to polyethylene glycol and the resulting conjugate displayed a 10-fold increased circulating life in mice. The potential to control polymer:sFv or drug:sFv molar ratios by site-specific conjugation may substantially improve the therapeutic efficacy of these minimal antigen-binding molecules.

Animals↗
PubMed1994

Antibodies in the treatment of human cancer.

Monoclonal antibody-based therapy has the theoretic appeal of selective targeting of tumor cells. Most promising is the use of toxins and radioisotope immunoconjugates in the treatment of hematologic malignancies. Obstacles to effective treatment have been defined and solutions are being pursued. The future use of this therapeutic strategy will be determined by creative approaches to enhance delivery, decrease immunogenicity, and maximize potency of antibody reagents.

Antibodies, Monoclonal↗
PubMed2006

Elimination of HIV-1 infection by treatment with a doxorubicin-conjugated anti-envelope antibody.

OBJECTIVE: To test the efficacy of an immunoconjugate against HIV-1. DESIGN: : A murine monoclonal antibody against the envelope antigen of HIV (P4/D10) was conjugated with the conventional anticancer drug, doxorubicin, and tested against infectious virus and infected cells, both in vitro and in vivo. METHODS: P4/D10 antibody was incubated with free virus (neutralization) or HIV-infected cells (inhibition) and the resulting infection was measured by a p24 capture enzyme-linked immunosorbent assay. In an HIV-1/MuLV murine challenge model, the ability of the conjugate to inhibit infection in vivo was measured. RESULTS: Doxorubicin-conjugated P4/D10 neutralized HIV-1IIIB and eliminated intercellular spread and HIV replication in infected Jurkat cells in vitro. The conjugate also protected mice from challenge with HIV-1IIIB/MuLV at an eightfold lower concentration than needed for free antibody, whereas no effects were observed for comparable doses of free drug or irrelevant conjugate controls. CONCLUSION: This indicates that doxorubicin is concentrated to HIV-infected cells by the P4/D10 antibody, significantly (P = 0.0001) contributing to HIV elimination. This concept could also be adapted to eradicate remaining antigen-expressing T cells in patients treated with antiretroviral therapy.

Analysis of Variance↗
PubMed1995

Biotherapy of B-cell precursor leukemia by targeting genistein to CD19-associated tyrosine kinases.

B-cell precursor (BCP) leukemia is the most common form of childhood cancer and the second most common form of acute leukemia in adults. Human BCP leukemia was treated in a severe combined immunodeficient mouse model by targeting of the tyrosine kinase inhibitor Genistein (Gen) to the B cell-specific receptor CD19 with the monoclonal antibody B43. The B43-Gen immunoconjugate bound with high affinity to BCP leukemia cells, selectively inhibited CD19-associated tyrosine kinases, and triggered rapid apoptotic cell death. At less than one-tenth the maximum tolerated dose more than 99.999 percent of human BCP leukemia cells were killed, which led to 100 percent long-term event-free survival from an otherwise invariably fatal leukemia. The B43-Gen immuno-conjugate might be useful in eliminating leukemia cells in patients who have failed conventional therapy.

Animals↗
PubMed2004

First clinical trials of a new heteropolymer technology agent in normal healthy volunteers and patients with systemic lupus erythematosus: safety and proof of principle of the antigen-heteropolymer ETI-104.

BACKGROUND: The heteropolymer technology was developed to remove pathogens from the circulation. OBJECTIVES: To evaluate the safety and tolerability of a single administration and to establish proof of principle for ETI-104 in normal healthy volunteers (NHV) and patients with systemic lupus erythematosus (SLE) METHODS: The drug was given intravenously to 11 NHV and six patients with SLE. Over 28 days, vital signs were noted, a haematological and chemical analysis of blood and urine was carried out, and adverse events were recorded. CR1 receptor numbers, the ability of antigen based heteropolymers to bind to red blood cells (RBCs), and the clearance of high avidity and total anti-dsDNA antibodies were measured by Farr assays and FACS analysis. RESULTS: No safety measure differed significantly from normal in both groups; no drug related serious adverse events occurred. ETI-104 rapidly bound to RBCs in NHV and patients with SLE. Binding of the drug to RBCs of patients with SLE also caused a rapid reduction of circulating anti-dsDNA antibodies in the plasma 15 minutes after administration, with a maximum reduction of 55% (range 43-62). At 28 days statistically significant decreases were maintained in three patients, while in the other three the values had returned to baseline levels. CONCLUSION: These clinical trials established the safety and the proof of principle of the new immunoconjugate ETI-104. This provides the basis for further development of this technology for numerous indications-for example, therapeutic options for autoimmune diseases or viral and bacterial infections.

Adult↗
PubMed2005

Radioimmunotherapy of solid tumors by targeting extra domain B fibronectin: identification of the best-suited radioimmunoconjugate.

PURPOSE: The expression of extra domain B (ED-B) fibronectin is always associated with angiogenic processes and can be exclusively observed in tissues undergoing growth and/or extensive remodeling. Due to this selective expression, ED-B fibronectin is an interesting target for radioimmunotherapy of malignant diseases. The aim of this study was to identify the most appropriate ED-B-targeting radioimmunoconjugate for the therapy of solid tumors. EXPERIMENTAL DESIGN: Three ED-B fibronectin-binding human antibody formats of L19 were investigated: dimeric single-chain Fv (approximately 50 kDa), "small immunoprotein" (SIP, approximately 80 kDa), and immunoglobulin G1 (IgG1, approximately 150 kDa). These L19 derivatives were either labeled with I-125 or with In-111 (using MX-diethylenetriaminepentaacetic acid, MX-DTPA). Pharmacokinetics and tumor accumulation of the radiolabeled immunoconjugates were investigated in F9 (murine teratocarcinoma) tumor-bearing mice. Subsequently, dosimetry for the corresponding therapeutic isotopes I-13-1 and Y-90 was done. After testing the myelotoxicity of I-131-L19-SIP and I-131-L19-IgG1 in non-tumor-bearing mice, the therapeutic efficacy of these iodinated antibody formats was finally investigated in F9 tumor-bearing mice. RESULTS: The most favorable therapeutic index was found for I-131-L19-SIP followed by I-131-L19-IgG1. The therapeutic index of all In-111-labeled derivatives was significantly inferior. Considering the bone marrow as the dose-limiting organ, it was calculated that activities of 74 MBq I-131-L19-SIP and 25 MBq I-131-L19-IgG1 could be injected per mouse without causing severe myelotoxicity. The best therapeutic efficacy was observed using I-131-L19-SIP, resulting in significant tumor growth delay and prolonged survival after a single injection. CONCLUSION: Compared with other L19-based radioimmunoconjugates, I-131-L19-SIP is characterized by superior antitumor efficacy and toxicity profile in the F9 teratocarcinoma animal model. These results indicate that ED-B fibronectin-targeted radioimmunotherapy using I-131-L19-SIP has potential to be applied to treatment of solid cancers.

Animals↗
PubMed2005

Antibodies for targeted cancer therapy -- technical aspects and clinical perspectives.

The efficacy of traditional anti-cancer agents comes with the price of toxicity to normal cells, which limits the success of therapy. In the past 2 decades, greater understanding of the molecular differences between malignant and normal cells has led to the development of therapies that more specifically target human tumors. These include new anti-cancer agents directed against intracellular targets associated with malignant alterations, such as increased proliferation, impaired apoptosis or angiogenesis. In addition, antibodies have been developed that are directed towards tumor-associated antigens and provide tailor-made effector functions by inhibiting cell growth, inducing apoptosis or constituting cytotoxic drug delivery systems. Since the targeted approach of anti-cancer therapies increases the exposure of malignant cells and at the same time reduces the exposure of normal tissues, it offers the promise of enhanced efficacy and lower side effects. Antibodies, immunoconjugates and liposomal drug delivery systems derived thereof are now mainstream cancer therapeutics, and by the end of 2003 17 marketed antibody-based products generated several billion in combined annual sales. This study highlights the most recent breakthroughs in antibody technology and summarizes major achievements in antibody-based cancer therapy in oncology trials.

Antibodies↗
PubMed1997

Immunotoxin therapy of small-cell lung cancer: a phase I study of N901-blocked ricin.

PURPOSE: Immunotoxins could improve outcome in small-cell lung cancer (SCLC) by targeting tumor cells that are resistant to chemotherapy and radiation. N901 is a murine monoclonal antibody that binds to the CD56 (neural cell adhesion molecule [NCAM]) antigen found on cells of neuroendocrine origin, including SCLC. N901-bR is an immunoconjugate of N901 antibody with blocked ricin (bR) as the cytotoxic effector moiety. N901-bR has more than 700-fold greater selectivity in vitro for killing the CD56+ SCLC cell line SW-2 than for an antigen-negative lymphoma cell line. Preclinical studies suggested the potential for clinically significant cardiac and neurologic toxicity. We present a phase I study of N901-bR in relapsed SCLC. PATIENTS AND METHODS: Twenty-one patients (18 relapsed, three primary refractory) with SCLC were entered onto this study. Successive cohorts of at least three patients were treated at doses from 5 to 40 microg/kg/d for 7 days. The initial three cohorts received the first day's dose (one seventh of planned dose) as a bolus infusion before they began the continuous infusion on the second day to observe acute toxicity and determine bolus pharmacokinetics. Toxicity assessment included nerve-conduction studies (NCS) and radionuclide assessment of left ventricular ejection fraction (LVEF) before and after N901-bR administration to fully assess potential neurologic and cardiac toxicity. RESULTS: The dose-limiting toxicity (DLT) of N901-bR given by 7-day continuous infusion is capillary leak syndrome, which occurred in two of three patients at the dose of 40 microg/kg (lean body weight [LBW])/d. Detectable serum drug levels equivalent to effective in vitro drug levels were achieved at the 20-, 30-, and 40-microg/kg(LBW)/d dose levels. Specific binding of the immunotoxin to tumor cells in bone marrow, liver, and lung was observed. Cardiac function remained normal in 15 of 16 patients. No patient developed clinically significant neuropathy. However, a trend was noted for amplitude decline in serial NCS of both sensory and motor neurons. One patient with refractory SCLC achieved a partial response. CONCLUSION: N901-bR is an immunotoxin with potential clinical activity in SCLC. N901-bR is well tolerated when given by 7-day continuous infusion at the dose of 30 microg/kg(LBW)/d. Neurologic and cardiac toxicity were acceptable when given to patients with refractory SCLC. A second study to evaluate this agent after induction chemoradiotherapy in both limited- and extensive-stage disease was started following completion of this study.

Adult↗
PubMed2004

Radiation-guided drug delivery systems.

A primary limiting factor for cancer treatment is normal tissue toxicity. Targeted cancer treatment can potentially maximize cancer cure and minimize normal tissue toxicity. Physical energy can be used to activate inert oncologic drugs. X-rays have an advantage over other forms of physical energy because tissue penetration and precise localization can be achieved. Radiation can be used to control drug delivery through radiation-inducible gene therapy. Radiation-guided drug delivery systems involve the targeting of immunoconjugates to radiation-inducible neoantigens induced by irradiation of neoplasms. Magnetic fields can compliment these technologies by drawing magnetic particles containing oncologic drugs toward an externally applied magnetic field. The field of targeted drug delivery by use of external radiation fields will ultimately bring new delivery systems into clinical trials. This review highlights radiation-guided cancer drug delivery systems, at preclinical and clinical stages of development, to tumors and tumor blood vessels.

Animals↗
PubMed2006

Clinical experiences with G17DT in gastrointestinal malignancies.

The development of new agents for the treatment of gastrointestinal malignancies is increasing in pace and importance. The discovery of novel targets, namely the epidermal growth factor receptor and vascular endothelial growth factor, have sparked an explosion of new agents being tested in gastrointestinal malignancies. Clearly, novel agents and approaches are required. G17DT is a novel immunoconjugate designed to elicit a humoral response against the N-terminal end of G17 gastrin. In this overview, the authors summarize the clinical research focused on gastrointestinal tract cancers to date. In total, there is a clear signal of efficacy with this compound, although further testing is required in order for this efficacy to be demonstrated in a manner that will support regulatory approval.

Animals↗
PubMed1998

The development of monoclonal antibodies for the therapy of cancer.

Monoclonal antibodies (Mabs) were first described by Köhler and Milstein in 1975. Not only did this discovery lead to a Nobel prize, but it created an enormous scientific field that has now become a multimillion dollar industry. Mabs made the transition from laboratory reagents to clinical diagnostics very quickly. However, their development as therapeutic agents was, as predicted, more costly and time-consuming. Indeed, clinicians and scientists were required to learn a new set of rules for using these large, immunogenic, targeted agents in humans. Nevertheless, in 1997 the first Mab was licensed in the U.S. and several others will soon follow. In this review, we discuss Mab-based strategies for the treatment of cancer. We compare native, fragmented, recombinant and chimeric antibodies, bispecific antibodies, immunoconjugates, and immunoliposomes. The rationale for their development, their advantages, their in vitro and in vivo performance, and their clinical usefulness are discussed.

Animals↗
PubMed1999

Selection of an anti-CD20, single-chain antibody by phage ELISA on fixed cells.

Cloning the correct genes that code for antibody-variable domains from hybridomas is often complicated by the presence of several immunoglobulin transcripts, some of them arising from a myeloma cell line. For the rapid functional evaluation of recombinant antibody fragments against cell-surface antigens, we established an efficient expression and screening system using phagemid antibodies and fixed cells. VL and VH-polymerase chain reaction (PCR) products, amplified from hybridoma cDNA, were cloned into the phagemid vector pSEX81. After transduction into E. coli and phage rescue, clones were tested for antigen binding using a phage-enzyme-linked immunosorbent assay (ELISA) procedure with whole cells fixed to ELISA wells. This procedure facilitated the successful cloning of a functional anti-CD20, single-chain antibody from hybridoma cDNA. The CD20 B-lymphocyte surface antigen expressed by B-cell lymphomas is an attractive target for cancer treatment using immunoconjugates or bi-specific antibodies.

Antibodies, Monoclonal↗
PubMed1999

Monoclonal antibody-directed cytotoxic therapy: potential in malignant diseases of aging.

The advent of monoclonal antibodies has allowed the development of tumour directed therapies utilising antibody-dependent effector mechanisms and immunoconjugates (e.g. drug, isotope and toxin coupled antibodies) against human malignancies. Preclinical studies in mouse tumour models have been most impressive and have led to numerous clinical trials. Whereas the majority of these phase I/II trials have been less impressive, a few trials have shown efficacy in highly pre-treated refractory patients and have led to phase III trials. The therapeutic monoclonal antibodies examined in these trials will become clinically available in the near future. In this review, various methods of utilising antibody-directed anticancer strategies are presented, with emphasis on recent advances in the field. The advantages and disadvantages of these methods together with the role of antibody-directed therapeutics in cancer management are discussed.

Aging↗
PubMed2006

Novel therapies for the treatment of small-cell lung cancer: a time for cautious optimism?

Small-cell lung cancer accounts for up to one-fifth of all lung cancers diagnosed. While the response rates to chemotherapy are high, ultimately the majority of patients will relapse and die from their disease. Long-term outcomes are poor. A number of new agents and novel strategies for the treatment of small-cell lung cancer are under evaluation, and this review outlines the current most promising agents and pivotal trials. Oblimersen, an antisense oligonuclide to the oncogene bcl-2, has been safely combined with chemotherapy. The proteosome inhibitor bortezomib has not demonstrated single-agent activity in phase II trials but is now being evaluated with proapoptotic triggers. A number of anti-angiogenic strategies have been evaluated in small-cell lung cancer. The vascular endothelial growth factor (VEGF) antibody bevacizumab and a number of VEGF receptor tyrosine kinase inhibitors are in the early phases of clinical trials. Results from trials have not demonstrated any survival advantage with the addition of matrix metalloproteinase inhibitors. A phase III trial has reported improvements in median survival with the addition of thalidomide to chemotherapy, but toxicity has been problematic. Immunotherapy with p53 vaccines and BEC2 antibodies have shown some promise and require further evaluation to determine whether humoral responses can predict for response. Trials with the immunoconjugate BB-10901 and temirolimus are ongoing.

Animals↗
PubMed2005

Intralesional targeted alpha therapy for metastatic melanoma.

UNLABELLED: This paper reports the development and application of intralesional targeted alpha therapy (TAT) for melanoma, being the first part of a program to establish a new systemic therapy. RATIONALE: Labelling the benign targeting vector 9.2.27 with 213Bi forms the alpha-immunoconjugate (AIC), which is highly cytotoxic to targeted melanoma cells. OBJECTIVE: To investigate the safety and efficacy of intralesional AIC in patients with metastatic skin melanoma. FINDINGS: 16 melanoma patients were recruited. All the patients were positive to the monoclonal antibody 9.2.27. AIC doses from 50 to 450 mCi injected into lesions of different sizes resulted in massive cell death, as observed by the presence of tumour debris. The AIC was very effective in delivering a high dose to the tumour while sparing other tissues. There were no significant changes in blood proteins and electrolytes. There was no evidence of a human-antimouse-antibody reaction. Evidence of significant decline in serum marker melanoma-inhibitory-activity protein (MIA) at 2 weeks post-TAT was observed. CONCLUSIONS: Intralesional TAT for melanoma was found to be quite safe up to 450 mCi, and efficacious at a dose of 200 mCi. MIA, apoptosis and ki67 proliferation marker tests all indicated that TAT is a promising therapy for the control of inoperable secondary melanoma or primary ocular melanoma.

Aged↗
PubMed2005

Radiolabeling and biological evaluation of DOTA-Ph-Al derivative conjugated to anti-EGFR antibody ior egf/r3 for targeted tumor imaging and therapy.

An appropriate bifunctional chelating agent namely DOTA-Ph-Al was developed for the conjugation with biological vectors (anti EGFr antibody). We hereby report the synthesis of p-bromoacetamidobenzyl derivative of DOTA and its conjugation to monoclonal antibody anti-EGFR ior egf/r3. Immunoconjugate was prepared by conjugation of p-bromoacetamidobenzyl derivative of DOTA with ior egf/r3. Modified antibody was purified by size exclusion chromatography. DOTA-Ph-Al-ior egf/r3 exhibited quantitative 99mTc-labeling (>96%) with specific activity 10-20 mCi/mg of protein and 90Y-labeling with specific activity 2-5 mCi/mg. Immunoreactivity was determined by flow cytometry. Receptor ligand assay on murine cell line EAT and human tumor cell line U-87MG showed Kd = 2.87 nM and 4.86 nM respectively. The stability in serum indicated that 99mTc remained bound to antibodies up to 24h and 98% 90Y was associated with the mAb for five days. Biodistribution characteristics of Ab-conjugate radiolabeled to 99mTc and 90Y radionuclide was examined in BALB/c mice grafted with EAT and athymic mice with U-87MG cell line demonstrated high tumor uptake with 5.5 +/- 1.3 and 7.85 +/- 1.2%ID/g at four and 24 h for 99mTc- DOTA-Ph-AI-ior egf/r3 in EAT tumors after post injection respectively. Maximal radiotracer uptake peaked 17.6 +/- 2.5%ID/g in EAT tumor and 12.89 +/- 0.66% ID/g in U-87MG tumor at 48h for 90Y. The drug excreted through renal routes as the activity in the kidneys was 13.42 +/- 0.33%ID/g at 1 h and 4.51 +/- 1.2%ID/g at 4 h for 99mTc- DOTA-Ph-Al-ior egf/r3.

Acetamides↗
PubMed1999

Toxicity, biological activity, and pharmacokinetics of TXU (anti-CD7)-pokeweed antiviral protein in chimpanzees and adult patients infected with human immunodeficiency virus.

The purpose of the present study was to evaluate the toxicity and pharmacokinetics of TXU (anti-CD7)-pokeweed antiviral protein (PAP) in human immunodeficiency virus (HIV)-infected chimpanzees and adult patients. At a total dose of 100 microg/kg, TXU-PAP did not cause severe (grade >/= 3) toxicity in any of the four HIV type 1 (HIV-1)-infected or two healthy chimpanzees. The only side effects were a transient elevation of the liver enzyme alanine aminotransferase between days 2 and 14 without a concomitant rise in total bilirubin levels and a decrease in the serum albumin levels between days 1 and 5 without any concomitant weight gain or peripheral edema. TXU-PAP showed favorable pharmacokinetics in chimpanzees with a plasma elimination half-life of 5.1 to 12.0 h and a systemic clearance of 5.8 to 15.1 ml/h/kg. At 2 months after initiation of the TXU-PAP infusions, the HIV-1 burden was reduced to below-detection levels in three of the four chimpanzees, and in the remaining chimpanzee, the HIV burden was <500 RNA copies/ml at 2 weeks but returned to the pretreatment levels by 2 months. TXU-PAP was well tolerated by HIV-1-infected adult patients who received a single 5 microg/kg i.v. infusion of TXU-PAP. TXU-PAP showed very favorable pharmacokinetics in these patients with a relatively long plasma elimination half-life of 12.4 +/- 1.4 h, a mean residence time of 17.9 +/- 2.0 h, and a slow systemic clearance of 2.7 +/- 0.7 ml/h/kg. Concentrations of TXU-PAP required for effective inhibition of HIV-1 replication in preclinical models were achieved in HIV-1-infected patients at the 5 microg/kg dose level without any adverse reactions, and the mean value for AUC was 3059 +/- 721 ng. h/ml. The 1-h postinfusion plasma samples from TXU-PAP-treated patients showed potent anti-HIV activity in vitro and inhibited the replication of HIV in normal peripheral blood mononuclear cells (PBMCs) even at a 1:100 dilution. Although treatment with TXU-PAP at the 5 microg/kg dose level does not provide sustained therapeutic levels, it was capable of reducing the viral burden in six of six patients evaluated. To our knowledge, this is the first report of a clinical pharmacokinetics study of a PAP immunoconjugate in HIV-infected patients. The favorable long plasma elimination half-life of TXU-PAP in combination with its low toxicity provides the basis for further investigation of TXU-PAP as a potential anti-HIV agent.

Adult↗