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PubMed2002

Early phase I/II trials with gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia.

Relapsed acute myeloid leukemia (AML) carries a poor prognosis. Treatment options are limited, and their toxicities are substantial. There is an urgent need for novel therapies that are effective and have acceptable side effects. Gemtuzumab ozogamicin (Mylotarg) is an immunoconjugate targeted against CD33, which is expressed on more than 90% of myeloid leukemic blasts. The antibody is attached to calicheamicin, a potent cytotoxic enediyne antibiotic that inhibits DNA synthesis and induces apoptosis. In vitro studies showed excellent activity of gemtuzumab ozogamicin in leukemic cell lines and encouraged the evaluation of this agent in patients. In this review, early phase I/II studies that led to the US Food and Drug Administration approval of this immunoconjugate for older patients with relapsed AML are discussed. Potential adverse events reported with this agent, particularly the recent data of possible veno-occlusive disease and increased hepatotoxicity, are addressed. This agent is currently being investigated in many clinical trials as a front-line approach in previously untreated individuals, and it is likely that it will have many more indications in the near future.

Aminoglycosides↗
PubMed1989

Monoclonal antibodies for treating cancer.

PURPOSE: To assess the current status of in-vivo use of monoclonal antibodies for treating cancer. DATA IDENTIFICATION: Publications appearing between 1980 and 1988 were identified by computer searches using MEDLINE and CANCERLIT, by reviewing the table of contents of recently published journals, and by searching bibliographies of identified books and articles. STUDY SELECTION: More than 700 articles, including peer-reviewed articles and book chapters, were identified and selected for analysis. DATA EXTRACTION: The literature was reviewed and 235 articles were selected as relevant and representative of the current issues and future applications for in-vivo monoclonal antibodies for cancer therapy and of the toxicity and efficacy which has been associated with clinical trials. RESULTS OF DATA SYNTHESES: Approaches include using antibody alone (interacting with complement or effector cells or binding directly with certain cell receptors) and immunoconjugates (antibody coupled to radioisotopes, drugs, toxins, or other biologicals). Most experience has been with murine antibodies. Trials of antibody alone and radiolabeled antibodies have confirmed the feasibility of this approach and the in-vivo trafficking of antibodies to tumor cells. However, tumor cell heterogeneity, lack of cytotoxicity, and the development of human antimouse antibodies have limited clinical efficacy. Although the immunoconjugates are very promising, heterogeneity and the antimouse immune response have hampered this approach as has the additional challenge of chemically or genetically coupling antibody to cytotoxic agents. CONCLUSIONS: As a therapeutic modality, monoclonal antibodies are still promising but their general use will be delayed for several years. New approaches using human antibodies and reducing the human antiglobulin response should facilitate treatment.

Animals↗
PubMed1999

Studies on the red marrow dosimetry in radioimmunotherapy: an experimental investigation of factors influencing the radiation-induced myelotoxicity in therapy with beta-, Auger/conversion electron-, or alpha-emitters.

Usually, the red marrow (RM) is the first dose-limiting organ in radioimmunotherapy. However, several studies have obtained only poor correlations between the marrow doses and the resulting toxicities. Furthermore, RM doses are mostly not determined directly but are derived from blood doses by assuming a ratio that is, over time for the respective conjugates, more or less constant between blood and marrow activities. The aim of this study was to determine, in a mouse model, this RM:blood activity ratio for various immunoconjugates, to investigate whether there may be differences between complete IgG and its fragments with various labels ((125/131)I versus (111)In, (88/90)Y, or 213Bi), and to analyze, in more detail, factors other than just total dose, such as dose rate or relative biological effectiveness factors, that may influence the resulting myelotoxicity. The maximum tolerated activities (MTAs) and doses (MTDs) of several murine, chimeric, and humanized immunoconjugates as complete IgG or fragments (F(ab)2 and Fab), labeled with beta(-)-emitters (such as 131I or 90Y), Auger electron-emitters (such as 125I or (111)In), or alpha-emitters (such as 213Bi) were determined in nude mice. Blood counts were monitored at weekly intervals; bone marrow transplantation was performed to support the assumption of the RM as dose-limiting. The radiation dosimetry was derived from biodistribution data of the various conjugates, accounting for cross-organ radiation; besides the major organs, the activities in the blood and bone marrow (and bone) were determined over time. Whereas no significant differences were found for the RM:blood ratios between various IgG subtypes, different radiolabels or various time points, differences were found between IgG and bi- or monovalent fragments: typically, the RM:blood ratios were approximately 0.4 for IgG, 0.8 for F(ab')2, and 1.0 for Fab'. Nevertheless, at the respective MTAs, the RM doses differed significantly between the three conjugates: e.g., with 131I-labeled conjugates, the maximum tolerated activities were 260 microCi for IgG, 1200 microCi for F(ab)2, and 3 mCi for Fab, corresponding to blood doses of 17, 9, and 4 Gy, respectively. However, initial dose rates were 10 times higher with Fab as compared to IgG, and still 3 times higher as compared to F(ab)2; interestingly, all three deliver approximately 4 Gy within the first 24 h. The MTDs of all three conjugates were increased by BMT by approximately 30%. Similar observations were made for 90Y-conjugates. Higher RM doses were tolerated with Auger-emitters than with conventional beta(-)-emitters, whereas the MTDs were similar between alpha- and beta(-)-emitters. In accordance to dose rates never exceeding those occurring at the single injection MTA, two subsequent injections of two doses of 80% of the single shot MTA of 131I- or 90Y-labeled Fab' and two doses of 100% of the single shot MTA of 213Bi-labeled Fab' were tolerated without increased lethality, if administered 24-48 h apart. In contrast, reinjection of bivalent conjugates was not possible within 6 weeks. These data suggest that the RM:blood activity ratios differ between IgG and fragments, although there is no anatomical or physiological explanation for this phenomenon at this point. In contrast to the current opinion, indication for a strong influence of the dose rate (or dose per unit time), not only total dose, on the resulting toxicity is provided, whereas the influence of high-linear energy transfer (alpha and Auger/conversion electrons) versus low-linear energy transfer (beta and gamma) type radiation seems to be much lower than expected from previous in vitro data. The lower myelotoxicity of Auger-emitters is probably due to the short path length of their low-energy electrons, which cannot reach the nuclear DNA if the antibody is not internalized into the stem cells of the RM.

Alpha Particles↗
PubMed2001

Technology evaluation: C242-DM1, ImmunoGen Inc.

C242-DM1 is a tumor-activated immunotoxin under development by GlaxoSmithKline plc (formerly SmithKline Beecham plc), under licence from ImmunoGen Inc, as a potential treatment for colon tumor. It consists of a colon cancer-specific humanized antibody, C242, conjugated to the maytansine derivative DM1. In preclinical studies, C242-DM1 caused complete tumor regression in animal models of both human pancreatic and non-small cell lung cancer (NSCLC) at non-toxic doses. C242-DM1 has also been evaluated in an immunoconjugate combination with J-591 (Cornell University). The J591-DM1 immunoconjugate demonstrated effective, antigen-specific delivery of a highly cytotoxic drug to PSMA-positive Pca cells in vitro and in vivo with low systemic toxicity. Results from studies in monkeys showed that C242-DM1 had no significant toxicity or side effects, when administered at doses higher than those that were previously shown to completely eradicate human colon tumors in mice [271420]. ImmunoGen acquired the right to evaluate, and an option to license, technology related to maytansines from Takeda. In February 1999, ImmunoGen and SmithKline Beecham signed a US $45 million development and commercialization agreement for C242-DM1 [313493]. In August 1997, Immunogen received an SBIR grant to advance development of huC242-DM1 [258356]. EP-00425235, held by ImmunoGen, covers conjugated forms of ansamitocin (maytansine) derivatives. Takeda holds several patents for the production of ansamitocin and its analogs, the first one being JP-53124692.

Animals↗
PubMed1992

Therapeutic advantage of high-affinity anticarcinoma radioimmunoconjugates.

The effect of the relative affinity (Ka) on the antitumor efficacy of monoclonal antibodies (MAbs) has been questioned. It has previously been shown in experimental models that the use of MAbs with higher relative Kas manifests itself in a higher percentage of injected dose of MAb bound to tumor. On the other hand, mathematical models have proposed that the use of higher affinity MAbs may be disadvantageous for antitumor effects, since higher Ka MAbs would bind more antigen and prevent penetration of MAb through tumor. To test this hypothesis, three MAbs reacting to the human pancarcinoma antigen TAG-72 were used as radioimmunoconjugates for therapeutic efficacy versus the LS-174T human colon carcinoma xenograft. MAbs B72.3, CC49, and CC83 have all been shown by depletion studies to react to the same molecule and to all react with overlapping epitopes. While the relative Ka of B72.3 is 2.5 x 10(9) M-1, the relative Kas of CC49 and CC83 are 16.2 and 27.7 x 10(9) M-1, respectively. Each MAb was radiolabeled with 131I, and each radioimmunoconjugate was assayed at five dose levels for therapeutic efficacy using the human xenograft model. The results of these studies demonstrate substantial therapeutic advantage of the higher affinity MAbs CC49 and CC83 versus B72.3 at every dose level. While 500 microCi of B72.3 were required to reduce tumor growth in only a minority of tumor-bearing animals, the use of the same amount or less of the radioimmunoconjugates of CC49 or CC83 resulted in strong antitumor effects in 80 to 100% of tumor-bearing animals. Thus, stronger antitumor effects were seen using as little as 2.5- to 3-fold less of the higher Ka immunoconjugates CC49 and CC83 as compared with B72.3. While we acknowledge the potential disadvantages of higher Ka MAbs in some situations, at least the experimental studies and model system described here show that a distinct therapeutic advantage exists with the use of higher affinity immunoconjugates.

Adenocarcinoma, Mucinous↗
PubMed1992

Antigen-specific activity of carcinoma-reactive BR64-doxorubicin conjugates evaluated in vitro and in human tumor xenograft models.

The anticarcinoma antibody BR64 was conjugated to a doxorubicin derivative, doxorubicin 13-[3-(2-pyridyldithio)propionyl]hydrazone, and the resulting conjugates (BR64-DOX) were evaluated for activity and immunological specificity in vitro and in human tumor xenograft models. The BR64-DOX immunoconjugates retained immunoreactivity and cytotoxicity and demonstrated antigen-specific cytotoxicity in vitro. The potency of BR64-DOX immunoconjugates in vitro was related to the drug:monoclonal antibody mole ratio of the conjugates. The antitumor activity of BR64-DOX conjugates was consistently superior to the maximal activity obtained with the parent drug, doxorubicin (DOX), in established human lung and human breast carcinoma xenograft models. The superior antitumor activity of BR64-DOX conjugates was reflected both in tumor growth inhibition and in regressions and cures of established tumors following the administration of tolerated doses of BR64-DOX. The antitumor activity of BR64-DOX conjugates was not the result of synergism between monoclonal antibody BR64 and DOX, because mixtures consisting of monoclonal antibody and optimized DOX were not more active than an equivalent dose of DOX administered alone. The antitumor activity of BR64-DOX conjugates was antigen specific; equivalent doses of nonbinding isotype-matched conjugates were not active against established tumor xenografts.

Adenocarcinoma↗
PubMed2003

Enhanced therapeutic index of radioimmunotherapy (RIT) in prostate cancer patients: comparison of radiation dosimetry for 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)-peptide versus 2IT-DOTA monoclonal antibody linkage for RIT.

PURPOSE: Radioimmunotherapy delivered by radiometal immunoconjugates and followed by marrow support is dose limited by deposition of radioactivity in normal organs. To increase elimination of radioactivity from the liver and body and, thus, minimize hepatic radiation dose, a peptide having a specific cathepsin B cleavage site was placed between the radiometal chelate DOTA (1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid) and the monoclonal antibody m170, and the comparative pharmacokinetics was evaluated in prostate cancer patients. EXPERIMENTAL DESIGN: (111)In-DOTA-2IT-m170 and (111)In-DOTA-peptide-(GGGF)-m170, representing the same monoclonal antibody and chelate with and without the cleavable linkage, were studied in comparable groups of prostate cancer patients (17 with In-2IT-BAD-m170 and 8 with In-DOTA-peptide-m170). Pharmacokinetics over 7 days, calculated yttrium-90 radiation dosimetry, therapeutic index, and projected maximum tolerated injected yttrium-90 dose were evaluated. RESULTS: The radioimmunoconjugates pharmacokinetics and calculated tumor and normal organ absorbed radiation dose (rads/mCi) were similar, except for a significant decrease in the mean dose to the liver (31%; P < 0.01) and lungs (31%; P < 0.01) with the DOTA-peptide immunoconjugates. Because mean tumor dose was not statistically different, this peptide linkage provided a significant increase in the therapeutic index for this tumor targeting radiopharmaceutical. If marrow support is adequate, the radiation dose historically tolerated by normal organs other than marrow would allow a 30% increase in the administered dose, resulting in a mean dose of 9500 rads to metastatic prostate cancer.

Antibodies, Monoclonal↗
PubMed1992

Development of humoral immune responses against a macrocyclic chelating agent (DOTA) in cancer patients receiving radioimmunoconjugates for imaging and therapy.

The development of stable immunoconjugates by the advent of macrocyclic metal chelating agents (DOTA) has enabled us to study the ability of 111In-DOTA-labeled monoclonal antibodies to detect tumor lesions in a pilot radioimmunolocalization study, as well as to evaluate the kinetics, toxicity, and efficacy of i.p. administered 90Y-DOTA-labeled murine monoclonal antibody in a Phase I/II clinical trial of advanced ovarian cancer. The development of serum sickness-like reactions in three of six treated patients, in the absence of previous monoclonal antibody administration, led us to study the potential immunogenicity of the new chelate. Six patients with ovarian cancer received 25 mg of HMFG1 monoclonal antibody coupled with 90Y-DOTA (doses of radioactivity, 15 to 25 mCi), administered i.p. Eight patients with various malignant tumors received low doses (220 micrograms to 1 mg) of monoclonal antibodies, labeled with 111In-DOTA, i.v. for imaging studies. Using a solid-phase enzyme-linked immunosorbent assay method, the immunogenicity of DOTA was evaluated. Serial dilutions of patients' sera, before and after imaging or therapy with DOTA-coupled monoclonal antibodies, as well as sera from patients who did not receive DOTA-coupled antibody, were screened on enzyme-linked immunosorbent assay plates coated with human serum albumin (HSA), HSA-2-iminothiolane, and HSA-2-iminothiolane-benzyl-DOTA. All patients treated with i.p. monoclonal antibody developed anti-DOTA antibodies. Four of eight patients who received i.v. "imaging" doses of DOTA-coupled monoclonal antibody developed antibodies against DOTA. The levels of anti-DOTA response correlated with the amount of injected radioimmunoconjugate (r = 0.889, P less than 0.001). None of the patients who received DOTA-coupled antibody had detectable antibodies against the macrocycle before immunoconjugate administration. We then addressed further the restriction of the immune response against the macrocycle. We found that there was no or very low response against the aromatic ring attached to DOTA. Most, if not all, of the immune response is directed against the DOTA ring structure. Affinity purification of anti-DOTA antibody from serum enabled quantitation of these antibodies in the serum of patients. An inverse, statistically significant correlation was observed between the percentage of binding inhibition of a patient's serum to DOTA, by HSA-2-iminothiolane-DOTA (100 micrograms/ml) and the level of anti-DOTA immunoglobulin in the serum.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1991

A specific and potent immunotoxin composed of antibody ZME-018 and the plant toxin gelonin.

Murine monoclonal antibody ZME-018 recognizes a 240 Kda glycoprotein present on the surface of most human melanoma cells and on over 80% of human biopsy specimens tested. Gelonin is a ribosome-inactivating plant toxin similar in nature and rivaling the activity of ricin A chain. ZME-018 was coupled to purified gelonin using the reagents SPDP and 2-iminothiolane. The ZME-gelonin conjugate was purified by S-300 Sephacryl and Blue Sepharose chromatography, removing unreacted gelonin and antibody, respectively. PAGE analysis showed that ZME was coupled to 1, 2, or 3 gelonin molecules. The ZME-gelonin conjugate was 10(6)-fold more active than gelonin itself in inhibiting the growth of log-phase human melanoma cells in culture. The immunoconjugate was not cytotoxic to antigen negative T-24 (human bladder carcinoma) cells. Treatment of melanoma cells with recombinant IFN-alpha or TNF substantially augmented the cytotoxicity of the immunoconjugate while treatment with IFN-gamma had a minor effect. Using the human tumor colony assay of melanoma cells obtained from fresh biopsy specimens, greater than 90% growth suppression was observed in 2 of 4 samples tested at a concentration of 250 ng/ml. In addition, 25% growth suppression was observed with a third sample tested, and no growth suppression was observed in 1 sample. Thus, clonogenic melanoma cells are sensitive in vitro to the cytotoxic activity of this immunotoxin at concentrations which we presume are pharmacologically relevant.

Antibodies, Neoplasm↗
PubMed1991

Antibody-mediated delivery of tumor necrosis factor (TNF-alpha): improvement of cytotoxicity and reduction of cellular resistance.

Recombinant human tumor necrosis factor-alpha (TNF-alpha) is a macrophage-derived, non-glycosylated (17 kDa) peptide that has a remarkably broad range of biological and immunological effects including antiviral action and cytotoxic and cytostatic effects. TNF-alpha was coupled to murine antibody ZME-018, which recognizes a 240 kDa glycoprotein present on over 80% of melanoma cells. The crosslinking was accomplished using the heterobifunctional crosslinking reagent, N-succimindyl 3-(2-pyridyldithio)proprionate (SPDP). After purification on gel-permeation and affinity columns, the resulting eluate was analyzed by non-reducing SDS-PAGE, which confirmed that the product was a mixture of ZME-018 coupled to one or two TNF-alpha molecules. The ZME-TNF conjugate was titered against murine L-929 cells to demonstrate the presence of active TNF. ELISA of the conjugate against target BRO human melanoma cells or non-target T-24 cells demonstrated specific binding only to target cells. Melanoma BRO cells were killed by the immunoconjugate (IC50 of 10 units/mL), whereas native TNF-alpha had no effect at concentrations greater than 50,000 units/mL. The immunoconjugate and TNF-alpha were inactive against T-24 non-target cells. These studies suggest that the sensitivity of cells to TNF was dramatically augmented by specific antibody mediated delivery to tumor cells.

Animals↗
PubMedDate not supplied

Preparation and biological characterization of conjugates consisting of ricin and a tumor-specific non-internalizing MAb.

MOv18, a non-internalizing monoclonal antibody (MAb) with restricted tumor specificity, was conjugated to ricin toxin (RT). According to their ability to bind to galactose residues of Sepharose 6B, the immunoconjugates were fractionated into Bound and Unbound MOv18-RT. The two conjugates could be distinguished by SDS-PAGE, in vivo toxicity and agglutination capability. When the binding activity of both fractions was compared by solid-phase RIA to that of native MAb, it proved to be similar on the relevant target cells but significantly increased on the non relevant cells. On the latter, galactose totally cancelled the binding of the Unbound immunoconjugate, whereas it could only partially reverse that of the Bound MOv18-RT. By in vitro cytotoxic activity, either in the presence or absence of galactose, only a slight selectivity for relevant versus non-relevant target cells was observed for both conjugates. It seems that in the presence of a MAb which is incapable of internalization, the conjugate cytotoxicity could only be attributed to RT, with a loss of the MAb's specificity.

Animals↗
PubMed1990

Selective elimination in vitro of alloresponsive T cells to human transplantation antigens by toxin or radionuclide conjugated anti-IL-2 receptor (Tac) monoclonal antibody.

The human allogeneic mixed lymphocyte reaction is the in vitro correlate of graft rejection. Cytotoxic effector cells generated during an allogeneic mixed lymphocyte reaction were previously shown to express the human p55 IL-2 receptor subunit, whereas resting cells do not express this receptor peptide. In this study, we asked whether Pseudomonas exotoxin or bismuth-212 (an alpha-particle emitting radionuclide) coupled to the anti-IL-2 receptor mAb, anti-Tac, were able to selectively eliminate alloresponsive cells generated during an allogeneic mixed lymphocyte reaction. After assembly, anti-Tac immunoconjugates retained their binding integrity, specificity, and selectivity. Deletion of alloresponsive cells was shown by the removal of alloproliferating cells as assessed by quantitating cell recovery and by measurement of thymidine incorporation into newly synthesized DNA. Both toxin and radionuclide immunoconjugates eliminated established cytotoxic effector cells generated in an allogeneic mixed lymphocyte reaction, while leaving intact the PHA-inducible mitogenic response of the nonactivated cells. The addition of excess anti-Tac blocked all of the effects of these cytotoxic reagents. The therapeutic reagents in vitro were most effective when added just prior to the peak of the alloproliferative response, when receptor expression would be close to maximum. Thus, anti-Tac conjugated either with toxin or radionuclide is effective in vitro in specifically eliminating cytotoxic effector cells.

ADP Ribose Transferases↗
PubMed1990

Monoclonal antibody therapy of lymphoproliferative disorders.

Monoclonal antibodies, either alone or as immunoconjugates, are now being utilized to treat patients with a wide range of hematologic malignancies. The aim of early studies was to delineate the feasibility of this form of therapy, assess toxicities, and identify potential obstacles. These trials demonstrated that MoABs can be safely administered, and that clinically significant and durable responses occur. Areas of future research include the development of more potent immunoconjugates, the study of MoABs in conjunction with other treatment modalities, and the evaluation of approaches that may eliminate the human anti-mouse antibody response. Methods using MoABs to block growth factor receptors or as vaccines are being considered. At present, MoAB therapy remains investigational and should be restricted to patients with diseases refractory to standard therapies. We are encouraged, however, by the therapeutic results witnessed in early Phase I/II trials.

Antibodies, Monoclonal↗
PubMed1986

Preclinical trials with combinations and conjugates of T101 monoclonal antibody and doxorubicin.

We investigated the potential for additive therapy for malignancy using an anti-human T-cell monoclonal antibody, T101, and the chemotherapy agent doxorubicin (DOX). We compared the efficacy of T101 alone, DOX alone, T101 and DOX covalently linked to dextran to form an immunoconjugate, T101 plus DOX mixed together and injected, T101 and DOX injected separately, and nonspecific murine IgG2A plus DOX mixed together. Inhibition of [3H]thymidine was examined in vitro, and the clinical efficacy of each treatment was tested on human T-cell tumors growing in athymic mice. In vitro experiments confirmed retention of immunoreactivity and cytotoxicity by the immunoconjugate, but it was not superior to DOX alone. In efficacy experiments, all therapeutic arms were superior to placebo treatment (P less than 0.05). However, the best results in the animal tumor model were obtained with T101 mixed with DOX, perhaps because of formation of weak complexes via hydrophobic bonds. This mixture was superior to all other treatments, both by growth curve analysis (P less than 0.05) and by analysis of complete regression of tumor (P less than 0.01). T101 mixed with DOX was superior to a mixture of nonspecific mouse immunoglobulin and DOX and superior to a combination of T101 injected i.v. and DOX injected i.p. The antitumor effect of T101 mixed with DOX was blocked by premodulating the target antigen with T101. These data suggest that further exploration into monoclonal antibody-anthracycline complexes is warranted.

Animals↗
PubMed1988

Cytotoxic effects of anti-CD5 radioimmunotoxins on human tumors in vitro and in a nude mouse model.

An immunoconjugate, consisting of both toxin and radionuclide on the same antibody molecule, was synthesized by cross-linking the phytotoxin ricin to the T101 monoclonal antibody recognizing the CD5 cluster expressed on normal and malignant T-cells. The hybrid molecule was then labeled with iodine-125 by an iodine monochloride procedure. This radioimmunotoxin (RIT), which selectively bound to the CD5-positive CEM human leukemia cell line, was selectively inhibitory to antigen-positive cells in protein synthesis inhibition assays. RIT was only 3.0-7.8-fold less toxic and was 1.1-1.6-fold slower than unlabeled immunotoxin in inhibiting protein synthesis. Because of the radionuclide moiety, the RIT also provided information related to biodistribution and pharmacokinetics. Four days following intratumoral injection, more than 125-fold greater activity was found in CEM tumors implanted in nude mice as compared to normal tissues. The mean blood half-life for RIT was 25.7 h and for radiolabeled antibody, 91.3 h. Intratumoral injections of RIT selectively induced regression of established CEM tumors. To our knowledge, these studies are the first to demonstrate that a single immunoconjugate can combine the advantages of both a catalytic toxin and radionuclide for cancer therapy.

Animals↗
PubMed1989

[Specific binding and internalization of anti-CCT2 monoclonal antibody and bleomycin A6 conjugate in human leukemia cells].

The immunoconjugate of anti-CCT2 monoclonal antibody linked to bleomycin A6 was adsorbed on colloidal gold particles (McAb-A6-Au). Binding and internalization of McAb-A6-Au particles in human leukemia CEM cells were examined by electron microscopy. After 60 min at 4 degrees C, McAb-A6-Au particles were bound to the surface membrane of 78% of CEM cells. Transferring to 37 degrees C for 15 min, McAb-A6-Au particles were found to be 56% inside the CEM cells and about one third of the cells contained particles in the nucleus. After 4 h at 37 degrees C the percentage of CEM cells containing McAb-A6-Au particles increased to 72%. However, only 14% of the antigenically irrelevant U937 cells contained these particles and none of them was found in the nucleus. Preincubation with unconjugated anti-CCT2 monoclonal antibody markedly blocked the McAb-A6-Au particle uptake in CEM cells. The McAb-A6-Au particles were internalized through the formation of endocytotic vesicles. In addition, some McAb-A6-Au particles were able to penetrate the plasma membrane directly into cytoplasma and notably into the nucleus. Results indicate that the immunoconjugate of monoclonal antibody linked to bleomycin A6 showed selective binding to target cells and entered the cells specifically and rapidly.

Antibodies, Monoclonal↗
PubMed1989

[Immunotherapy and cancer: the role of monoclonal antibodies].

Monoclonal antibodies, produced in vitro from hybridoma supernatants, may be administered to cancer patients either directly or after coupling to an anticancer agent (immunoconjugates). Monoclonal antibodies concentrate in tumor site, where they initiate an anti-tumor effect, either by activation of the patient's immune system or by the cytotoxic agent which is present at high concentration within the tumor, while systemic concentrations of this agent remain low. Monoclonal antibodies which are radiolabelled also allow the immunoscintigraphic study of the immunoconjugates' diffusion within the body. Given certain precautions of administration, the clinical and biological tolerance of this type of treatment is satisfactory, most of the side effects correspond to an allergic response to the murine antibodies used. Clinical studies performed in patients with leukemias have demonstrated a significant antitumor effect although this effect is transitory. Studies performed on small series of patients with solid tumors (gastrointestinal neoplasms, melanoma, leptomeningeal localizations, ovarian peritoneal carcinosis) have shown a few cases of major responses and/or complete remissions having lasted up to periods of many months. These studies as well as the perspectives for the development of this type of therapy are presented and discussed.

Adjuvants, Immunologic↗
PubMed1987

[Use of monoclonal antibodies in the treatment of cancer].

Monoclonal antibodies directed against antigens borne by tumors have already been the object of clinical trials in patients with leukemia or solid tumors. These antibodies, generally obtained from murine hybridomask, are used alone or as immunoconjugates, i.e. coupled to a non-specific antimitotic agent. Under the proper conditions they may be administered with a satisfactory clinical and biological tolerance. The antimitotic action of these antibodies, which is specifically directed against neoplastic cells, has been demonstrated in vitro and in animal models and is found inconstantly in leukemias. Studies have been performed in patients bearing solid tumors, with large initial tumoral mass, showing partial regression in a few cases. A number of parameters, including modalities of administration, types of immunoconjugates and mechanisms of action in vivo, must be explored to increase the antineoplastic potential of monoclonal antibodies.

Antibodies, Monoclonal↗