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PubMedDate not supplied

Carbohydrate-directed conjugation of cobra venom factor to antibody by selective derivatization of the terminal galactose residues.

Cobra venom factor (CVF) can cause cell death by complement-mediated bystander cell lysis. Several studies have investigated CVF for application in cancer therapy by conjugating CVF to antibodies against tumor cell surface-specific antigens via the side-chain amino acid residues. In most cases, the activity of CVF was markedly impaired, presumably by modification of the factor B binding domain due to random derivatization. Since CVF is a glycoprotein and its oligosaccharide chains are distal to the factor B binding domain, coupling of CVF to antibodies through its oligosaccharide chains is expected to yield immunoconjugates with retention of CVF activity and elimination of the immunoreactivity of the terminal alpha-galactosyl residues. In this study, we investigated the carbohydrate site-directed conjugation of CVF to a monoclonal IgG specific to a cell-surface antigen of human ovarian cancer cells. The terminal galactosyl residues of CVF were selectively modified at C-6 by treatment with galactose oxidase, and the generated aldehyde groups were derivatized in situ with hydrazides containing either protected thiol or maleimide functional groups. The CVF derivatives were allowed to react with thiol groups introduced to the antibody by derivatization with 2-iminothiolane to yield carbohydrate site-directed CVF-antibody conjugates. In both cases, 30-40% of the antibody cross-linked to CVF to yield predominantly monovalent CVF-antibody conjugates. The purified immunoconjugates retained 70-75% of CVF activity and significant level of antigen-binding capacity. This is the first study to exploit the oligosaccharide chains of CVF for the preparation of active immunoconjugates.

Animals↗
PubMed2002

Monoclonal antibody therapies in leukemias.

Significant advances in the development of monoclonal antibodies (unconjugated) and monoclonal antibodies conjugated to potent toxins or cytotoxic agents (immunoconjugates) have enabled improved targeting of leukemic cells with acceptable toxicities. Gemtuzumab ozogamicin, a calicheamicin-conjugated anti-CD33 monoclonal antibody, has demonstrated substantial efficacy in patients with acute myeloid leukemia (AML) and has induced remissions in patients with favorable-, intermediate-, and poor-risk cytogenetics. The immunoconjugate BL-22, comprised of an anti-CD22 monoclonal antibody fused to a fragment of pseudomonas exotoxin PE38, has produced high response rates in patients with purine analog-resistant hairy cell leukemia. Campath-1H (Wellcome, Beckenham, UK, and Ilex Oncology, San Antonio, TX), an anti-CD52 monoclonal antibody, has demonstrated significant activity in patients with previously untreated, relapsed, or refractory chronic lymphocytic leukemia (CLL), as well as in patients with T-cell prolymphocytic leukemia. The anti-CD20 monoclonal antibody rituximab also is effective in treating CLL and is being evaluated in combination with chemotherapeutic agents (cyclophosphamide) and fludarabine. Monoclonal antibodies may sensitize cells to chemotherapy. The optimal role of targeted therapy with monoclonal antibodies and immunoconjugates in acute and chronic leukemias has not yet been determined, but these novel therapies are beginning to fulfill their promise.

Antibodies, Monoclonal↗
PubMed2001

In vivo evaluation of bismuth-labeled monoclonal antibody comparing DTPA-derived bifunctional chelates.

Among the radionuclides considered for radioimmunotherapy, alpha-emitters such as the bismuth isotopes, 212Bi and 213Bi, are of particular interest. The macrocyclic ligand, DOTA, has been shown to form stable complexes with bismuth isotopes. The kinetics of the complexation of bismuth with the DOTA chelate, however, are slow and impractical for use with 212Bi and 213Bi that have half-lives of 60.6 and 45.6 min. The study described herein compares six DTPA derived bifunctional chelates with the goal of identifying an alternative to the DOTA ligand for radiolabeling with bismuth. Radioimmunoconjugates comprised of MAb B72.3, each of the six DTPA chelates, and radiolabeled with 206Bi, which facilitated the evaluation due to its readily detectable gamma-emission. In vitro studies showed that each of the radioimmunoconjugates retained immunoreactivity that was comparable to its 125I-labeled counterpart. The 206Bi- and 125I-labeled immunoconjugates were then co-injected i.p. into normal athymic mice. Injection of Afree@ 206Bi demonstrated that the kidneys were the critical organ to evaluate for retention of bismuth in the chelate complex. Major differences were identified among the six preparations. The CHX-A and -B immunoconjugates were found to have 1) the lowest %ID/gm in the kidney; 2) a level of 206Bi in the kidney that was comparable to that of 125I-B72.3; and 3) no significant uptake of 206Bi evident in other organs such as bone, lung and spleen. The results described herein suggest that either of the cyclohexyl derivatives of DTPA may be suitable candidates for the labeling of immunoconjugates with alpha-emitting bismuth isotopes for radioimmunotherapeutic applications.

Animals↗
PubMed2003

Identification of a protein fragment of interleukin 2 responsible for vasopermeability.

BACKGROUND: The cytokine interleukin 2 (IL-2) is involved in the activation of T cells and has been shown to play a central role in cancer immunotherapy. The full therapeutic potential of IL-2, however, has not been realized because of its dose-limiting systemic toxicity. We sought to identify a region of IL-2 that is responsible for the induction of vasopermeability (leaky tumor endothelium), a property associated with the toxicity of the molecule. METHODS: Intact IL-2 or overlapping synthetic peptides of IL-2 that were chemically conjugated to tumor-targeting monoclonal antibodies (TNT-1 or Lym-1) were injected into groups of mice (n = 4) that had previously been xenotransplanted with human tumor cells (ME-180 cervical carcinoma and Raji lymphoma). Two hours later, mice received intravenous injections of radiolabeled tracer antibody, and 3 days later they were subjected to biodistribution analysis to measure the ability of each immunoconjugate to enhance tumor uptake of the tracer antibody (i.e., vasopermeability activity). The cytokine activity of the immunoconjugates was determined by assaying their ability to promote the proliferation of a mouse IL-2-dependent cell line. RESULTS: Pretreatment of mice with an antibody/IL-2 immunoconjugate resulted in an approximately fourfold increase in radiolabeled tracer antibody uptake in the xenograft tumor as compared with uptake in mice injected with antibody alone. One synthetic fragment consisting of amino acids 22-58 contained 100% of the vasopermeability activity of IL-2 and was designated permeability-enhancing peptide (PEP). PEP had vasopermeability activity only when conjugated to a tumor-targeting antibody, had maximal activity as a dimer, and was devoid of cytokine activity. CONCLUSIONS: The identification of PEP should aid in the discovery of ways to decrease the toxicity of IL-2. Moreover, PEP is a promising candidate for the generation of agents that can enhance the delivery of antibodies and drugs to tumors.

Animals↗
PubMed2000

Organ donor or graft pretreatment to prolong allograft survival: lessons learned in the murine model.

Permanent donor-specific tolerance to allografts is the goal of transplantation research. Currently, morbid immunosuppressive therapy is used to mitigate rejection initiated in part by Ia-bearing interstitial graft dendritic or antigen-presenting cells (APCs) that are thought to migrate into the host after transplantation. We hypothesized that donor or organ immune modulation directed against graft APCs might influence graft immunogenicity and promote prolonged graft acceptance in histoincompatible hosts in the absence of immunosuppressive therapy. Haplotype-specific monoclonal antibodies (mAb), mAb specific to graft APC, adhesion or costimulatory molecules and anti-LFA-1-Ricin and anti-Iak-Ricin immunoconjugates (IC) were prepared and administered in varying doses and time intervals to donor C3H/HeJ (H-2k) mice. Thereafter, their spleens and hearts were removed at varying time intervals and used either as stimulator cells in one-way mixed lymphocyte reaction or transplanted into naive Balb/c (H-2d) recipients, respectively. Explanted C3H hearts were pretreated with anti-Iak mAb on the Langendorf apparatus. Hearts were also used from major histocompatibility complex (MHC) class I, MHC class II, and MHC class I- and II-deficient "knockout" mice. Splenocytes exposed to at least 500 microg of anti-Iak mAb in vivo for more than 4 hr were able to inhibit the mixed lymphocyte reaction to almost background levels, but only after incubation with rabbit complement in vitro. Similarly pretreated cardiac allografts (both in vivo or explanted and pretreated on the Langendorf apparatus) did not experience prolonged survival in nonimmunosuppressed Balb/C recipients when compared with control solutions, regardless of the concomitant use of complement. Splenocytes from immunoconjugate pretreated donors inhibited the mixed lymphocyte reaction completely without the use of complement; however, hearts from these donors also did not experience prolonged survival nor donor hearts exposed to mAb specific for graft APC, adhesion or costimulatory molecules. Only hearts from MHC class I and class II "knockout" mice survived significantly longer than controls. We conclude that donor or graft pretreatment with haplotype-specific anti-Ia mAb, haplotype-specific immunoconjugates, or mAb directed against graft APC, adhesion or costimulation molecules have little efficacy in promoting acceptance of cardiac allografts in nonimmunosuppressed recipients. The enhanced survival of hearts from MHC class I- and class II-deficient donors suggest that novel methods to effect the immunogenicity of the graft will be required if long-term allograft acceptance is to be achieved in the absence of host immunosuppression.

Animals↗
PubMed2001

Monoclonal antibody therapy for cancer.

Monoclonal antibody therapy has emerged as an important therapeutic modality for cancer. Unconjugated antibodies show significant efficacy in the treatment of breast cancer, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia. Promising new targets for unconjugated antibody therapy include cellular growth factor receptors, receptors or mediators of tumor-driven angiogenesis, and B cell surface antigens other than CD20. Immunoconjugates composed of antibodies conjugated to radionuclides or toxins show efficacy in non-Hodgkin's lymphoma. One immunoconjugate containing an antibody and a chemotherapy agent exhibits clinically meaningful antitumor activity in acute myeloid leukemia. Numerous efforts to exploit the ability of antibodies to focus the activities of toxic payloads at tumor sites are under way and show early promise. The ability to create essentially human antibody structures has reduced the likelihood of host-protective immune responses that otherwise limit the duration of therapy. Antibody structures now can be readily manipulated to facilitate selective interaction with host immune effectors. Other structural manipulations that improve the selective targeting properties and rapid systemic clearance of immunoconjugates should lead to the design of effective new treatments, particularly for solid tumors.

Antibodies, Monoclonal↗
PubMed1995

Immunoselective targeting of an anti-thrombin agent to the surface of cytokine-activated vascular endothelial cells.

An immunoconjugate was designed to target hirudin, a potent and specific inhibitor of thrombin, to the surface of activated endothelial cells. Hirudin was covalently cross-linked to the monoclonal antibody H18/7 that recognizes the extracellular domain of E-selectin (CD62E), an endothelium-leukocyte adhesion molecule that is expressed only on cytokine-activated endothelium. The hirudin-H18/7 immunoconjugate selectively bound to interleukin-1-activated but not to unactivated cultured human umbilical vein endothelial cells with a temporal profile similar to that of inducible cell-surface procoagulant activity. When bound to activated endothelial cells, the hirudin-H18/7 immunoconjugate significantly inhibited endogenous thrombin activity generated from coincubated human plasma and fibrin clot formation on the monolayer surface. Cellular responses that are mediated via the thrombin receptor, such as increases in cytoskeletal F-actin content, also were significantly downregulated, and monolayers were protected from thrombin-induced disruption by this treatment. The ability to selectively antagonize thrombin-dependent processes at the endothelium-blood interface may provide new insights into complex pathophysiological processes, such as thrombosis, inflammation, and atherogenesis. These studies also demonstrate the general feasibility of selective targeting of therapeutic agents to endothelial cells based on recognition of an activation-dependent surface phenotype.

Actins↗
PubMed2004

[Gemtuzumab ozogamicin and targeted cancer therapy].

Recently, anti-cancer antibodies have been launched in Japan and also immunoconjugates with a cytotoxic compound or a radioisotope have been launched in the USA. Gemtuzumab ozogamicin is a conjugate of anti-CD33 antibody and a cytotoxic calicheamicin derivative. After binding the CD33-positive leukemia cells, gemtuzumab ozogamicin is internalized and releases the calicheamicin derivative. The calichemicin derivative breaks DNA and kills the cells. Gemtuzumab ozogamicin was effective and well tolerated in clinical trials in patients with acute myeloid leukemia (AML) in relapse. It was approved in 2000 by the FDA, and Wyeth K.K. has submitted it as an anti-tumor drug for CD33 positive AML. Two kinds of immunoconjugates, anti-CD20 antibodies with radioisotopes, recently have been launched in the USA for CD20-positive non-Hodgkin's lymphoma. These conjugates showed efficacy in patients who are refractory to the conventional chemotherapies. Targeted therapy with the immunoconjugate that can deliver cytotoxic compounds to specific cells is promising for use in oncology.

Aminoglycosides↗
PubMed1998

Large scale manufacturing of B43(anti-CD19)-genistein for clinical trials in leukemia and lymphoma.

We have conjugated the murine monoclonal anti-CD19 antibody B43 to the tyrosine kinase inhibitor genistein to construct an effective immunoconjugate against CD19 antigen positive hematologic malignancies. The scaled-up production and purification of B43 antibody, genistein, and B43-Genistein immunoconjugate permitted the manufacturing of a highly purified clinical-grade B43-Genistein preparation. In clonogenic assays, B43-Genistein elicited selective and potent cytotoxicity against CD19 antigen positive human leukemia cells. To our knowledge, this work represents the first effort of producing a clinical-grade genistein immunoconjugate for treatment of B-lineage leukemia and lymphoma.

Antibodies, Monoclonal↗
PubMed2001

Monoclonal antibody-mediated drug targeting to choroidal neovascularization in the rat.

PURPOSE: Active drug targeting mediated by monoclonal antibodies (mAbs) of vascular endothelial cells in tumors is a new concept in cancer therapy. Integrin alphavbeta3 has been reported to be strongly expressed in vascular endothelial cells of surgically excised choroidal neovascular membranes and is thought to be a potential antigen for mAb-mediated drug targeting of choroidal neovascularization (CNV). The objective of this study was to evaluate the efficacy of drug targeting mediated by anti-integrin alphavbeta3 mAbs in a laser-induced CNV rat model. METHODS: The mitomycin C (MMC)-dextran (MMCD) conjugate was synthesized with a carbodiimide-catalyzed reaction. The mAb was conjugated with MMCD (MMCD-mAb). To evaluate the feasibility of mAb-mediated drug targeting in vitro, we investigated the effect of the immunoconjugates involving dextran-binding MMC on the proliferation of human umbilical vein endothelial cells (HUVECs). CNV was induced by laser photocoagulation in male Brown Norway rats. Immunolocalization of integrin alphavbeta3 in CNV lesions was assessed immunohistochemically with the anti-von Willebrand factor antibody as an endothelial cell marker. Intravenous administration of saline (n = 7), 1 mg/day mAb (n = 7), 100 microg/kg per day free MMC (n = 7), MMCD with irrelevant Ab (n = 7), unconjugated MMCD with unconjugated mAb (MMCD+mAb; n = 7), or MMCD with mAb (MMCD-mAb; n = 8) containing an equal amount of free MMC, was performed daily for 3 days from day 14 after CNV induction. CNV was assessed by fluorescein angiography 2 weeks after treatment. Fluorescein leakage was scored on a four-grade scale. The animals were killed 2 weeks after treatment, and the lesions were evaluated histologically. RESULTS: The inhibition of immunoconjugates on the proliferation of HUVECs was enhanced specifically by the mediatory effect of the mAb. Endothelial cells demonstrated strong immunoreactivity of integrin alphavbeta3 in the CNV. In the vehicle-treated group, fluorescein leakage equal to that before treatment was observed 2 weeks after treatment, with an average score of 2.00 +/- 0.17 (mean +/- SEM). MMCD-mAb significantly inhibited the development of CNV in rats (P < 0.01). Moreover, the thickness of the lesions was significantly reduced in the MMCD-mAb-treated group (P < 0.01). CONCLUSIONS: Immunoconjugates effectively inhibited progression of CNV in this model. The results suggest that mAb-mediated drug targeting may be beneficial in the treatment of CNV.

Animals↗
PubMed2001

Pronounced antitumor efficacy of doxorubicin when given as the prodrug DOX-GA3 in combination with a monoclonal antibody beta-glucuronidase conjugate.

A glucuronide doxorubicin prodrug N-[4-doxorubicin-N-carbonyl (oxymethyl) phenyl] O-beta-glucuronyl carbamate (DOX-GA3) has been developed to improve the antitumor effects of doxorubicin (DOX). The prodrug was originally designed to be activated into drug by human beta-glucuronidase (GUS) released from tumor cells in necrotic areas of tumor lesions. The aim of this study was to further improve the antitumor effects of DOX-GA3 by means of antibody-directed enzyme prodrug therapy (ADEPT). We thus investigated if the administration of an enzyme-immunoconjugate prepared from the pancarcinoma Ep-CAM specific monoclonal antibody (MAb) 323/A3 and beta-glucuronidase would result in improved antitumor effects because of additional enzyme localization in tumor tissue. In vitro, the prodrug DOX-GA3 was found to be 12-times less toxic than the parent drug DOX in a human ovarian cancer cell line. Immunospecific and complete activation of the prodrug took place when the cells were pretreated with 323/A3-beta-glucuronidase conjugate. In nude mice bearing s.c. human ovarian cancer xenografts (FMa) the maximum tolerated dose (MTD) of DOX-GA3 (500 mg/kg weekly x 2) was much higher when compared with that of DOX (8 mg/kg weekly x 2). In mice bearing well-established FMa xenografts, the standard treatment of DOX at the MTD (8 mg/kg weekly x 2) resulted in a tumor growth inhibition of 67%. Treatment with DOX-GA3 at a single dose of 500 mg/kg resulted in a better tumor growth inhibition of 87%. The combination of DOX-GA3 (500 mg/kg) with 323/A3-mGUS conjugate and anti-GUS MAb 105, to clear circulating conjugate, improved the antitumor effect even further to 98%. At the lower dose of 250 mg/kg DOX-GA3 tumor growth inhibition (34%) was not better than that of DOX. The combination, however, of DOX-GA3 at 250 mg/kg and 323/A3-mGUS conjugate plus MAb 105 again greatly improved the antitumor effect (growth inhibition of 93%). DOX given at 8 mg/kg weekly x 2 did not result in tumor regressions. As a result of ADEPT, the number of regressions of tumors improved from 0 out of 12 to 9 out of 11 at a dose of 250 mg/kg DOX-GA3. At the higher prodrug dose (500 mg/kg) the number of regressions improved from 2 out of 12 to 9 out of 10 as a result from the addition of enzyme-immunoconjugate. Our studies show that the efficacy of the widely used anti-cancer agent DOX may be improved by using the prodrug DOX-GA3, in combination with the tumor-specific enzyme-immunoconjugate 323/A3-mGUS and a conjugate clearing antibody.

Animals↗
PubMed1988

Immunotoxins containing single-chain ribosome-inactivating proteins.

We have summarized what is currently known about the distribution, biological role, and the mechanism of action of the single chain ribosome-inactivating proteins and described the purification of one of them, gelonin, as an example. ITs have been made with several of these proteins and, depending upon the antibody used for conjugation, these immunoconjugates can show specific in vitro cytotoxicity which is similar to that shown by equivalent ITs prepared with ricin A chain. The most potent of these conjugates have shown antitumor efficacy in a variety of animal tumor models, including both syngeneic rodent tumors and xenografts in nude or immunosuppressed mice. An important point needs to be addressed, however, before concluding that ITs containing single chain toxins will be clinically useful. A major problem with this approach is that it is likely that both the antibody and the toxin components of these conjugates will be immunogenic. Both antitoxin and antixenogenic immunoglobulin responses have been shown to occur in animals after infusion of IT, although it has not yet been clearly demonstrated that such antibody responses adversely effect the pharmacokinetics or the efficacy of immunoconjugates. Thus, preliminary enthusiasm over the efficacy of these new reagents must be tempered with the knowledge that their use in the clinic may be limited by the host immune responses or other as yet undefined factors. The fact that there are many immunologically distinct single chain ribosome-inactivating proteins does suggest one way of evading the antitoxin response, by a sequential treatment with a panel of immunoconjugates, each containing a different single chain toxin.

Animals↗
PubMed1989

In vivo antitumor effect of methotrexate conjugated to a monoclonal IgM antibody specific for stage-specific embryonic antigen-1, on MH-15 mouse teratocarcinoma.

Methotrexate (MTX) was coupled to an IgM monoclonal antibody specific for stage-specific embryonic antigen-1 (SSEA-1), and the resulting immunoconjugate (MTX-anti-SSEA-1) was used for in vivo drug targeting in mice bearing MH-15 teratocarcinoma. Immunoconjugates having an average of 65 mol MTX/mol antibody retained full antigen-binding capacity. Mice bearing well-established tumors (approx. 1 g) were treated i.v. using the immunoconjugate. MTX-anti-SSEA-1 at 15 mg/kg of drug had significant antitumor activity with no significant systemic toxicity. Neither an irrelevant isotype-matched conjugate, MTX-MOPC-104E, prepared from the MOPC 104E myeloma protein, nor free MTX injected alone or with either antibody had any significant antitumor effect. These results indicate that IgMs can be effective drug carriers for tumor targeting in spite of their high molecular mass, and that antigens that are selectively accessible in tumors, even though present in normal tissues, can be suitable targets for in vivo chemoimmunotherapy.

Antibodies, Monoclonal↗
PubMed1992

Frequent anti-V-region immune response to mouse B72.3 monoclonal antibody.

The immune response of 56 colorectal cancer patients to a single infusion of 1 mg of radiolabeled (111In) mouse B72.3-GYK-DTPA immunoconjugate was examined using a double-antigen radiometric assay system. The incidence of antibody response was 48% to polyclonal mouse IgG, 71% to mouse B72.3, and 62% to chimeric B72.3. Twelve patients (23%) had an antibody response to B72.3 V region in the absence of binding to polyclonal mouse IgG. An antiidiotype response was demonstrated in sera from 36% of 25 patients examined and correlated well with chimeric B72.3-GYK-DTPA immunoconjugate binding (r = 0.72, moderately well with mouse B72.3 binding (r = 0.56), and not at all with polyclonal mouse IgG binding (r = 0.28). The peak antibody response occurred most frequently 2 weeks postinfusion, although a "delayed" peak response to chimeric B72.2 occurred in 29% of patients. This study suggests that mouse B72.3 causes an immune response in the majority of patients and that antibody response to the V region is common. Understanding the physiological significance of these antibody responses will require correlation with the kinetics and tumor localization of repeat infusions of such immunoconjugates.

Animals↗
PubMed1994

Modification of monoclonal antibody carbohydrates by oxidation, conjugation, or deoxymannojirimycin does not interfere with antibody effector functions.

Site-specific attachment of metal chelators or cytotoxic agents to the carbohydrate region of monoclonal antibodies results in clinically useful immunoconjugates [Doerr et al. (1991) Ann Surg 214: 118, Wynant et al. (1991) Prostate 18: 229]. Since the capacity of monoclonal antibodies (mAb) to mediate tumor cell lysis via antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) may accentuate the therapeutic effectiveness of immunoconjugates, we determined whether site-specific modification of mAb carbohydrates interfered with these functions. The chemical modifications examined consisted of periodate oxidation and subsequent conjugation to either a peptide linker/chelator (GYK-DTPA) or a cytotoxic drug (doxorubicin adipic dihydrazide). mAb-associated carbohydrates were also modified metabolically by incubating hybridoma cells in the presence of a glucosidase inhibitor deoxymannojirimycin to produce high-mannose antibody. All four forms (unaltered, oxidized, conjugated and high-mannose) of murine mAb OVB-3 mediated tumor cell lysis via CDC. Similarly, equivalent ADCC was observed with native and conjugated forms of mAb OVB-3 and EGFR.1. ADCC was achieved with different murine effector cells such as naive (NS), poly (I*C)- and lipopolysaccharide-stimulated (SS) spleen cells, or Corynebacterium-parvum-elicited peritoneal cells (PEC). All murine effector cell types mediated tumor cell lysis but differed in potency such that PEC > SS > NS. Excellent ADCC activity was also demonstrable by human peripheral blood mononuclear cells with OVB-3-GYK-DTPA and high-mannose OVB-3 mAb. ADCC activity was detectable in vivo: both native and conjugated OVB-3 inhibited growth of OVCAR-3 xenografts in nude mice primed with C. parvum. In conclusion, modification of mAb carbohydrates did not compromise their in vivo or in vitro biological functions. Therefore, combination therapy using immunomodulators to enhance the effector functions of site-specific immunoconjugates could be seriously contemplated.

1-Deoxynojirimycin↗
PubMed1990

Effective drug-antibody targeting using a novel monoclonal antibody against the proliferative compartment of mammalian squamous carcinomas.

mAb 174H.64, which selectively recognizes an epitope expressed on the proliferating cells of mammalian squamous carcinomas, was covalently coupled to daunomycin (DM) by an acid-sensitive linker and tested for its selective cytotoxicity for squamous carcinomas. A murine lung squamous carcinoma model for chemoimmunotherapy using mAb 174H.64-DM conjugates was developed. This model utilizes the KLN-205 cell line, which metastasizes to the lungs following i.v. injection and shows a pattern of growth similar to those of spontaneous squamous carcinomas, characterized by highly proliferative cells at the periphery of the tumor (reactive with 174H.64) with the keratinized differentiated cells toward the center (not reactive with 174H.64). 174H.64-DM conjugates showed marked and specific cytotoxicity against KLN-205 cells both in vitro and following i.v. injection of the immunoconjugate in mice with established lung metastases. The conjugate was nearly as effective as daunomycin alone when incubated in vitro with KLN-205 cells and much more effective than daunomycin alone in vivo or other control immunoconjugates, which were ineffective. Finally, while the free 174H.64 mAb produced a significantly increased time of survival of mice bearing KLN-205 metastases, a much greater survival was found with mice treated with the 174H.64-DM immunoconjugate, some mice apparently demonstrating long-term survival (greater than 100 days). We conclude that mAb 174H.64 may have potential therapeutic benefit against squamous carcinoma.

Animals↗
PubMed1992

Antitumour activity of a sterically blocked ricin immunotoxin on a human colorectal adenocarcinoma grafted subcutaneously in nude mice.

We prepared a ricin-antibody conjugate, lacking the ability to bind the galactosidic residues of Sepharose 6B, a so-called blocked immunotoxin. The monoclonal antibody AR-3 was cross-linked to ricin through a thioether bond. Further studies showed that the immunoconjugate suppressed the tumour growth of HT-29 cells in intraperitoneally grafted nude mice, without showing any undesirable ricin toxicity. In this work, to demonstrate the therapeutic activity of the AR-3-ricin conjugate injected into mice bearing subcutaneous tumour, we first evalauted its pharmacokinetic behaviour and biodistribution. The behaviour of the immunoconjugate injected intravenously was almost intermediate between that of the antibody and ricin. Moreover, when the immunotoxin was intravenously administered to nude mice bearing subcutaneous tumour, no therapeutic effects appeared, in accordance with the relatively low permeability of the immunotoxin from the blood to the skin. In contrast, peritumoral treatment produced a strong reduction of the neoplastic nodules without substantial regrowth of the malignant cells. This result was also achieved when the immunotoxin treatment was performed on a well-established tumour. This finding was strictly related to the specifcity of the immunoconjugate, since the analogous treatment with an irrelevant immunotoxin showed therapeutic failure.

Adenocarcinoma↗
PubMed1993

Introduction of five potentially metabolizable linking groups between 111In-cyclohexyl EDTA derivatives and F(ab')2 fragments of anti-carcinoembryonic antigen antibody--II. Comparative pharmacokinetics and biodistribution in human colorectal carcinoma-bearing nude mice.

The five linker-containing immunoconjugates described in the preceding paper were labeled with 111In and tested for their biodistribution, pharmacokinetics and immunoscintigraphic imaging properties in tumor-xenografted nude mice. The results were compared with DTPADA and CDTAMA for reference. Results showed that, for immunoscintigraphy, the derivatives in decreasing order of effectiveness were: aliphatic (tumor/liver > 4.5 and tumor/kidney > 6.5 at 96 h), thioether (tumor/liver > 3 and tumor/kidney > 1.2 at 24 h), ethylene glycol succinate (tumor/liver > 1.7 and tumor/kidney > 0.5 at 24 h) and disulfide (tumor/liver > 0.5 and tumor/kidney > 0.6 at 96 h). Pharmacokinetic results were complementary with those of the biodistribution studies and provide a basis for the study of in vivo metabolic mechanisms of linker-immunoconjugates. Indium-111-labeled linker-immunoconjugates appear promising for tumor imaging with better contrast than what is obtained with the use of the conventional 111In-DTPA dianhydride chelate.

Adenocarcinoma↗