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PubMed1994

Comparison of two anthracycline-based prodrugs for activation by a monoclonal antibody-beta-glucuronidase conjugate in the specific treatment of cancer.

Antibody-directed enzyme prodrug therapy (ADEPT) may improve the therapeutic index of cytostatic agents. We compared two prodrugs, epirubicin-glucuronide (Epi-glu) and doxorubicin-spacer-glucuronide (Dox-sp-glu), for their cytotoxicity on activation by a monoclonal antibody-enzyme conjugate bound to tumor cells. The results showed that the prodrugs were 10 (Dox-sp-glu) and 100 (Epi-glu) times less toxic than the parent drugs against OVCAR-3 cells. This difference was a result of the hydrophilic property of the prodrugs resulting in a reduced cellular uptake. The enzyme-catalyzed hydrolysis of Dox-sp-glu by E. coli-derived beta-glucuronidase (GUS) (Km 500 microM, Vmax 21,000 mumol/min/g) was much more efficient than that of Epi-glu (Km 10 microM, Vmax 40 mumol/min/g). Incubation of OVCAR-3 cells with an enzyme-immunoconjugate prepared from monoclonal antibody 323/A3 and E. coli-derived GUS before treatment with prodrugs completely restored the cytotoxicity of the prodrugs to the level of the parent drugs.

Antibodies, Monoclonal↗
PubMed1999

Novel approaches to the treatment of small-cell lung cancer.

Small-cell lung cancer (SCLC) is characterized by its initial responsiveness to chemotherapy and the appearance of early metastases. Although combination chemotherapy, in some instances together with radiation, has improved the prognosis of this disease, in most patients SCLC ultimately recurs in a drug-resistant form. Several new strategies for the eradication of SCLC are being explored at the preclinical level. The identification of selective target molecules on the surface of SCLC cells, together with the progress made in antibody engineering, have provided new generations of antibodies and immunoconjugates as well as growth factor antagonists and inhibitors. In addition, recent advances in understanding the biology of SCLC have stimulated new investigations searching to counter the molecular basis underlying the increased proliferation and the apoptosis deficiency of SCLC cells. This can be achieved using antisense oligodeoxynucleotides that repress the expression of growth factor receptors and anti-apoptosis genes, or by gene replacement to compensate for the loss or inactivation of tumor suppressor genes.

Antibodies, Neoplasm↗
PubMed2004

Active immunization against nicotine alters the distribution of nicotine but not the metabolism to cotinine in the rat.

We have previously shown that active immunization with the nicotine immunoconjugate IP18-KLH attenuates the reinforcing effects of nicotine, i.e., suppresses the nicotine-induced brain dopamine release and prevents reinstatement of the nicotine-seeking behavior in rats. These effects are thought to be due to an alteration of the kinetics of nicotine distribution by the antibodies, resulting in an attenuated nicotine distribution to the brain. In this study, the distribution of nicotine administered at doses corresponding to those used in our previous studies, was investigated in immunized rats and controls. Male Wistar rats received two immunizations with IP18-KLH in Freund's incomplete adjuvant, 21 days apart, and experiments were performed 7-11 days post-immunization under chloral hydrate anesthesia. Blood samples were collected to determine antibody titer and nicotine selectivity using enzyme-linked immunosorbent assay (ELISA) techniques. The animals received an intravenous nicotine dose and were sacrificed either 3 min or 60 min after nicotine administration. Trunk blood was collected and the brains were removed for analysis of nicotine content. The results showed that immunization against nicotine increases the nicotine concentration in blood and significantly decreases the amount of nicotine that reaches the brain. The present findings thus demonstrate an altered distribution of nicotine after immunization with IP18-KLH. Despite the sustained nicotine binding by the antibodies, the active immunization did not alter the metabolism of nicotine to cotinine, the major nicotine metabolite. In conclusion, the attenuation of the reinforcing effect of nicotine after immunization with IP18-KLH, shown previously, is indeed associated with an altered distribution of nicotine.

Animals↗
PubMed2005

Antibody-targeted chemotherapy of B-cell lymphoma using calicheamicin conjugated to murine or humanized antibody against CD22.

Antibody-targeted chemotherapy with immunoconjugates of calicheamicin is a clinically validated strategy in cancer therapy. This study describes the selection of a murine anti-CD22 mAb, m5/44, as a targeting agent, its conjugation to a derivative of calicheamicin (CalichDM) via either acid-labile or acid-stable linkers, the antitumor activity of CalichDM conjugated to m5/44, and its subsequent humanization by CDR grafting. Murine IgG1 mAb m5/44 was selected based on its subnanomolar affinity for CD22 and ability to be internalized into B cells. CalichDM conjugated to m5/44 caused potent growth inhibition of CD22+ human B-cell lymphomas (BCLs) in vitro. The conjugate of m5/44 with an acid-labile linker was more potent than an acid-stable conjugate, a nonbinding conjugate with a similar acid-labile linker, or unconjugated CalichDMH in inhibiting BCL growth. CalichDM conjugated to m5/44 caused regression of established BCL xenografts in nude mice. In contrast, both unconjugated m5/44 and a nonbinding conjugate were ineffective against these xenografts. Based on the potent antitumor activity of m5/44-CalichDM conjugates, m5/44 was humanized by CDR grafting to create g5/44, an IgG4 anti-CD22 antibody. Both m5/44 and g5/44 bound CD22 with subnanomolar affinity. Competitive blocking with previously characterized murine anti-CD22 mAbs suggested that g5/44 recognizes epitope A located within the first N-terminal Ig-like domain of human CD22. Antitumor efficacy of CalichDM conjugated to g5/44 against BCL xenografts was more potent than its murine counterpart. Based on these results, a calicheamicin conjugate of g5/44, CMC-544, was selected for further development as a targeted chemotherapeutic agent for the treatment of B-cell malignancies.

Amino Acid Sequence↗
PubMed2006

Effect of pH and human serum albumin on the cytotoxicity of a glucuronide prodrug of 9-aminocamptothecin.

PURPOSE: 9-aminocamptothecin glucuronide (9ACG) is a prodrug of 9-aminocamptothecin (9AC) that displays potent antitumor activity against human tumor xenografts in nude mice. Camptothecins exist in a pH dependent equilibrium between active lactone and inactive carboxy forms that can be altered by binding to human serum albumin (HSA). Here we investigated the influence of pH and HSA on the lactone-carboxy equilibrium, HSA binding, and cytotoxicity of 9ACG. METHODS: Microfiltration and HPLC were used to measure the influence of pH on lactone to carboxy conversion and HSA binding of 9ACG as compared to other camptothecins. In vitro cytotoxicity of drugs was determined against EJ human bladder carcinoma cells and CL1-5 human lung cancer cells. RESULTS: The rate of lactone to carboxy conversion was similar for 9ACG and 9AC. Decreasing the pH from 7.6 to 6.0 increased the equilibrium levels of the lactone forms of the drugs from 20 to almost 95% of total drug. HSA moderately diminished the amount of free 9ACG lactone but did not change the ratio of 9ACG lactone to 9ACG carboxy. Consistent with the effect of pH on lactone levels, lowering the pH of EJ human bladder carcinoma cells from 7.6 to 6.8 decreased the IC(50) of 9ACG from 480 to 98 nM and 9AC from 33 to 12 nM. Activation of 9ACG by human beta-glucuronidase anchored on the surface of EJ cells further decreased its IC(50) value to 26 nM. Although HSA significantly decreased the cytotoxicity of 9AC and 9ACG, activation of 9ACG at cancer cells with an antibody-beta-glucuronidase immunoconjugate produced greater cytotoxicity than 9AC. CONCLUSIONS: Acidification and targeted delivery of beta-glucuronidase can enhance 9ACG cytotoxicity even in the presence of HSA.

Antineoplastic Agents, Phytogenic↗
PubMed1995

Detection of human IgG antibodies against free N-acetyl-L-cysteine.

Human antibodies of the IgG type reacting with free N-acetyl-cysteine are detectable with an appropriate immunoconjugate. Free cysteine, homocysteine and glutathione, but not cystine, interfere with the antibodies. The interference with cysteine and homocysteine is frequently reduced after nitrosylation of these amino acids. The interference with glutathione is frequently amplified after nitrosylation of this oligopeptide. The antibodies react weakly with whole red blood cells. Autoantibodies of this type may explain the wasting observed in untreated tuberculosis patients and in AIDS patients.

Acetylcysteine↗
PubMed2006

Multiple myeloma: monoclonal antibodies-based immunotherapeutic strategies and targeted radiotherapy.

Multiple myeloma (MM) is an incurable B-cell malignancy of terminally differentiated plasma cells. Besides conventional treatments, several targeted therapies are emerging for MM. We review recent developments in monoclonal antibodies (MoAbs) and (radio)immunoconjugates-based targeted immunotherapeutic (serotherapies) strategies, as well as skeletal targeted radiotherapy (STR) in MM. MoAbs-based strategies include the targeting of cytokines and their receptors as well as toxins, drugs or radionuclide delivery to MM cells. Both targeted radioimmunotherapy (RIT) and STR have proved efficient in the treatment of radiosensitive tumours. We conclude that there is a need for more mechanistic investigations of drug action to identify novel therapeutic targets in myeloma cells, as well as in the bone marrow microenvironment.

Antibodies, Monoclonal↗
PubMed2005

Phosphorothyoate oligodeoxynucleotides block nonspecific binding of Cy5 conjugates to monocytes.

Cy5-based monoclonal antibody conjugates, including those containing PE-Cy5 and Cy5 alone, are used widely for multi-color flow cytometry in both research and clinical applications. One problem with these conjugates is they bind to monocytes and macrophages irrespective of antibody specificity. This effect, which is thought to be due to binding of the Cy5 itself to the human high affinity receptor for IgG (FcgammaRI, CD64), can complicate interpretion of flow cytometric results. In the present study we demonstrate that phosphorothioate oligodeoxynucleotides (PS-ODN) suppress this nonspecific binding in a manner that is independent of PS-ODN sequence. Binding of FITC-labeled PS-ODN to monocytes was blocked by CD64-specific monoclonal antibodies, suggesting CD64 is a PS-ODN-binding protein. We conclude PS-ODN can be used as an effective, simple and low-priced reagent to prevent nonspecific binding of Cy5-based immunoconjugates to monocytes. This effect appears to be mediated by PS-ODN binding to CD64 thereby blocking the binding of Cy5 to this receptor.

Antibodies, Monoclonal↗
PubMed2004

Efficacy of different targeting agents in the photolysis of interleukin-2 receptor bearing cells.

The multichain interleukin-2 receptor (IL-2R) has been proposed as a target for immunotherapy in the treatment of certain cancers including adult T-cell leukemia and cutaneous T-cell lymphoma as well as certain autoimmune diseases. The IL-2R is abnormally expressed on cells associated with each of these diseases; while normal, non-activated T-cells do not express the receptor. This report describes the selective photolysis of activated and non-activated IL-2R expressing cells using several immunoconjugates synthesized with one of two photosensitizers, hematoporphyrin (HP) or chlorin-e(6) (Ce(6)), covalently linked to IL-2 or an anti-IL-2R antibody. Destruction of IL-2R bearing cells was achieved after photosensitizer internalization and irradiation using all tested photosensitizer conjugates. Chlorin containing conjugates were more effective, by a factor of 4 or more, than HP containing conjugates. Conjugates made with IL-2 were up to 30 times more effective than conjugates that used a monoclonal antibody against the IL-2R for targeting. Activation of the cells to increase IL-2R expression decreased the internalization time required for optimal therapeutic efficacy; however, stimulation of the cell to increase IL-2 secretion greatly reduced conjugate effectiveness. This work could lead to the development of more effective strategies to treat T-cell diseases.

Animals↗
PubMed2005

Phase II pilot trial of gemtuzumab ozogamicin (GO) as first line therapy in acute myeloid leukemia patients age 65 or older.

The prognosis of acute myeloid leukemia (AML) in older adults is generally poor. Standard cytotoxic chemotherapy is usually poorly tolerated and provides dismal results in this patient population. Gemtuzumab ozogamicin (GO) is an immunoconjugate that has activity in the relapsed and refractory setting. We hypothesized that administering this agent, as an initial treatment in AML patients over the age of 65 would have, at least, similar efficacy to standard therapy, but at much less toxicity. We report on the first 12 patients that were treated solely with GO as induction, consolidation, and maintenance therapy as part of a single institution clinical trial. The treatment was well tolerated, with a response rate of 27%. Toxicities were acceptable, although five patients (41%) developed cardiac toxicity three of which had grade 3 and/or 4. Responses were present regardless of the karyotype, and lasted for a median of 7.6 months. These early results suggest that the option of single agent monoclonal antibody therapy is viable in this patient population and that additional studies are warranted with this agent either alone or in combination as initial therapy.

Acute Disease↗
PubMed1995

Photoimmunotherapy of human uveal melanoma cells.

To examine whether tumor-reactive monoclonal antibodies can be used to enhance photodestruction of human uveal melanoma cells, we conjugated photosensitizer chlorin e6 monoethylenediamine monoamide (CMA) with a melanoma-reactive monoclonal antibody IG12 and evaluated the effectiveness of this immunoconjugate (IC) in the destruction of OCM431 human uveal melanoma cells in vitro. RPMI1846 melanoma cells do not react with IC and were used as non-target cells. For control, target and non-target cells were treated with IC or light alone. The effects of IC and free CMA in the destruction of melanoma cells were compared. Cell survival was assessed by a colorimetric assay using tetrazolium salt MTT. Target (OCM431) cells preincubated with IC and irradiated with 5-40 J cm-2 showed light dose-dependent decrease in cell survival. At 40 J cm-2, OCM431 cells preincubated with IC showed only 6 +/- 1.4% viability. Under same treatment, non-target (RPMI1846) cells showed much less phototoxicity; cell survival was 54 +/- 2.1%. Treatment with free CMA and light at 40 J cm-2 showed similar phototoxicity to both target and non-target cells, with cell survival being 24.3 +/- 3.5% and 23.7 +/- 1.5%, respectively. These results show that our IC is effective in causing photodestruction of human uveal melanoma cells in vitro. The phototoxicity is selective and more potent than free CMA.

Antibodies, Monoclonal↗
PubMed1998

Carbohydrates engineered at antibody constant domains can be used for site-specific conjugation of drugs and chelates.

To improve the efficiency of site-specific conjugation of chelates and drugs to antibodies, and to minimize the incidence of immunoreactivity perturbation to the resultant immunoconjugates, Asn-linked oligosaccharide moieties were designed and engineered into the constant domains of a humanized anti-CD22 monoclonal antibody, hLL2. From 10 potential glycosylation mutants, two CH1 domain glycosylation sites, HCN1 and HCN5, were identified that were positioned favorably for glycosylation. The carbohydrate (CHO) chains attached at these sites were differentially processed so that HCN5-CHOs were physically larger than HCN1-CHOs. Although both the CH1-appended CHOs, and the LL2 Vkappa-appended CHOs conjugated efficiently with small chelates, the HCN5-CHOs, due to the structural and positional superiority, appear to be a better conjugation site for large drug complexes, such as 18 kDa doxorubicin (DOX)-dextran.

Amino Acid Sequence↗
PubMed2002

In vitro testing of the leukaemia monoclonal antibody WM-53 labeled with alpha and beta emitting radioisotopes.

We report the preparation and testing of a new alpha emitting radio-immunoconjugate (RIC) against acute myeloid leukaemia (AML) using CD33 positive monoclonal antibody WM-53 (specific for HL-60 cell line). Using cyclic anhydride of diethylenetriaminepentacetic acid (cDTPAa) as chelator, antibody was labeled with 213Bi (alpha), 149Tb (alpha), 153Sm (beta) and 152Tb (positron). In vitro testing showed high labeling efficiency (90-95%) and stability (11-19% leaching) with immunoreactivity virtually the same before and after labeling. DNA synthesis data and MTS cell survival were compared for all RICs. Only the alpha emitter was found to be capable of inhibiting DNA synthesis and had selective cell kill with activity as low as 2-3 microCi. The high stability and outstanding cytotoxicity of the 213Bi conjugate provides the basis for targeted alpha therapy for the control of metastatic and disseminated cancer such as AML.

Acute Disease↗
PubMed1996

Proposal for translational analysis and development of clinical radiolabeled immunoglobulin therapy.

BACKGROUND AND PURPOSE: Radiolabeled immunoglobulin therapy (RIT) can be a selective, effective, low-toxicity outpatient cancer therapy. A consensus on the best approach for the preclinical and clinical development of RIT reagents needs to be developed. We report the M.D. Anderson Cancer Center prior experience in translating RIT from laboratory to clinic for the treatment of Hodgkin's disease and propose a flow diagram for the development of RIT for other malignancies. MATERIAL AND METHODS: Three different animal models are described: nude mice bearing human tumor xenografts, normal beagle dogs, and normal rhesus monkeys. We produced and purified antibodies and prepared chelate-immunoconjugates reactive with six different human tumor-associated antigens. The Igs used were derived from rabbits, mice, and humans (human-derived RIT reagents being less immunogenic in human patients). Eighty patients with refractory Hodgkin's disease were treated with radiolabeled antiferritin. RESULTS: We recommend a two-injection scheme using, (1) an indium-111-labeled radioimmunoconjugate for diagnosis, pharmacokinetic studies, and dosimetry, and (2) a yttrium-90-labeled radioimmunoconjugate for therapy. The animal models provide useful data on tumor targeting, radiotoxicology, and undesirable biodistributions. A 70% response rate is obtained in patients with advanced recurrent Hodgkin's disease. More extensive preclinical testing allows for safer and more effective clinical RIT studies. CONCLUSIONS: We recommend, (1) preclinical optimization of chelation chemistry, Ig size, Ig origin, route of administration, and fractionation, (2) new clinical Phase I-III studies more appropriate for RIT development than the classical Phase I-III studies used for the development of chemotherapeutic agents, and (3) more extensive preclinical testing of RIT reagents.

Animals↗
PubMed2003

Enabling ScFvs as multi-drug carriers: a dendritic approach.

To enable scFvs as multi-drug carriers, we designed and synthesized dendritic linker molecules bearing up to nine chlorambucil residues at the branch ends. A maleimide group was used at the focal point of the dendron for easy linkage to the scFv. Originally designed molecules showed poor water solubility. To address this problem, a lysine residue with an unprotected carboxylic acid group was inserted into the dendron branches. The new molecules showed excellent water solubility and are now suitable for conjugation. Such dendritic molecules will allow studies to understand the relationship between the drug/antibody ratio and the potency of the immunoconjugates. The dendritic approach could also be applied to drugs other than chlorambucil and carriers other than scFvs to greatly increase the drug/carrier ratio.

Chlorambucil↗
PubMed2002

In vivo comparison of macrocyclic and acyclic ligands for radiolabeling of monoclonal antibodies with 177Lu for radioimmunotherapeutic applications.

The studies reported herein present the first in vitro and in vivo comparison of radioimmunoconjugates (RIC) radiolabeled with 177Lu using the acyclic CHX-A"-DTPA ligand and the macrocyclic ligands, C-DOTA and PA-DOTA. The in vivo studies include pharmacokinetics and biodistribution of the formed 177Lu-labeled immunoconjugates in a tumor bearing murine model with engineered monoclonal antibody HuCC49DeltaCH2. The in vitro analysis indicated that the CHX-A" RIC was superior with respect to immunoreactivity, radiolabeling with 177Lu, and specific activity. The in vivo pharmacokinetic data by itself indicated that the Lu(III)-PA-DOTA complex may not be as stable as Lu(III) complexes with CHX-A" or C-DOTA. All three RICs demonstrated tumor targeting of human colon carcinoma xenografts in athymic mice. In these biodistribution studies, there appears to be no overall pattern or trend of one RIC over the other two. Based on these in vitro and in vivo studies, the CHX-A" DTPA ligand should be considered a suitable bifunctional chelate for the radiolabeling of monoclonal antibodies with 177Lu for radioimmunotherapy applications.

Adenocarcinoma↗
PubMed1999

Preparation, biodistribution, and dosimetry of 188Re-labeled MoAb ior cea1 and its F(ab')2 fragments by avidin-biotin strategy.

The biotinylated monoclonal antibody (MoAb) ior cea1 and its F(ab')2 fragments were labeled with Re-188 by combination of avidin-biotin strategy. 188Re-MoAb, 188Re-MoAb-biotin, 188Re-F(ab')2, and 188Re-F(ab')2-biotin preparations were produced for these studies with specific activities of 1.30+/-0.18 GBq/mg and from instant freeze-dried kit formulations using ethane-1-hydroxy-1,1-diphosphonic acid (EHDP) as a weak competing ligand. There were no significant differences (p > 0.05) between the biodistribution in mice of biotinylated and unbiotinylated 188Re-labeled immunoconjugates. When avidin was injected as a chase after injection of 188Re-MoAb-biotin or 188Re-F(ab')2-biotin, the blood radioactivity level decreased approximately 75% (cumulated activity) and the effective dose decreased almost 25% with respect to that of the radioimmunoconjugates in which the chase effect was not used. Our results suggest that 188Re-labeled biotinylated MoAb ior ceal and its F(ab')2 fragments prepared by this method are stable complexes in vivo.

Animals↗
PubMedDate not supplied

In vitro and preclinical targeted alpha therapy for melanoma, breast, prostate and colorectal cancers.

Targeted alpha therapy (TAT) can inhibit the growth of micrometastases by selectively killing isolated and preangiogenic clusters of cancer cells. The alpha emitting radioisotopes Tb-149 and Bi-213 were chelated to cancer specific monoclonal antibodies to form alpha-immunoconjugates (AIC) against melanoma, leukaemia, prostate and colorectal cancer, and to the plasminogen activator inhibitor type-2 (PAI2) to form alpha-PAI2 (API) against breast and prostate cancer. These conjugates were found to be highly stable, specific and cytotoxic in vitro. Melanoma and breast cancer tumour growth was observed in nude mouse models for untreated controls and non-specific AIC/API at 2 days post-subcutaneous inoculation of cancer cells. Complete inhibition of melanoma and breast cancer growth was found for local injections of AIC and API, respectively. Intra-lesional TAT of established melanoma showed that all melanomas regressed with 100 microCi injections of AIC. These results point to the potential application of local and systemic TAT in the management of metastatic cancer.

Alpha Particles↗