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PubMed1994

A comparative study of copper-67 radiolabeling and kinetic stabilities of antibody-macrocycle chelate conjugates.

BACKGROUND: The development of new chelating agents and radiolabeling protocols is essential to progress in radioimmunotherapy with antibody-chelate conjugates. METHODS: Immunoconjugates of four polyazamacrocycles with N-bonded acetate groups were prepared by conjugation via 2-iminothiolane to Lym-1, a murine antilymphoma immunoglobulin G2a MoAb. To optimize 67Cu radiolabeling, complexation conditions were explored. The kinetic stabilities in vitro in human serum of four 67Cu labeled immunoconjugates were investigated. RESULTS: Lym-1-2IT-6-BAT-67Cu, the chelate conjugate of 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane- N,N',N''N'''-tetraacetic acid, exhibited excellent kinetic stability in human serum, while Lym-1-2IT-2-BAT-67Cu, prepared from the structural isomer 2-[p-(bromoacetamido)benzyl]-1,4,8,11- tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid, exhibited a markedly higher rate of loss of radiometal. It was observed that the radiolabeling ratio of Lym-1-2IT-6-BAT-67Cu, in mCi per mg immunoconjugate, was limited solely by the specific activity of the radiometal, which varied significantly from lot to lot. This ratio for a given lot of 67Cu can be predicted by a preliminary titration. CONCLUSIONS: The preparation of 67Cu labeled immunoconjugates of therapeutic quality has been improved by the determination of optimum radiolabeling conditions, and by development of a titration protocol which rapidly and accurately predicts the radiolabeling ratio in mCi per mg immunoconjugate. The surprising difference in the properties of 6-BAT and 2-BAT shows the exquisite dependence of kinetic stability on structure.

Antibodies, Monoclonal↗
PubMed1991

Adriamycin(hydrazone)-antibody conjugates require internalization and intracellular acid hydrolysis for antitumor activity.

Adriamycin hydrazone (ADM-Hzn) immunoconjugates have previously been shown to exhibit antibody-directed antitumor activity in vitro and in vivo. In this report, the biological and biochemical properties of the mAb and linker were investigated. Conjugates prepared with two antibodies 5E9 [anti-(transferrin receptor)] and G28.1 (anti-CD37), (which internalize from the surface of target cells following binding) were more cytotoxic in vitro and had greater antitumor activity against Daudi B lymphoma tumor xenografts than a non-internalizing immunoconjugate prepared with mAb 2H7 (anti-CD20). In addition, the 13-acylhydrazone bond linking the drug to the mAb was labile at pH 5 and released unmodified ADM at a rapid rate (t1/2 = 2.5 h). Immunoconjugates prepared with an oxime linkage at the C-13 position were stable to acid and were not cytotoxic. These findings suggest that internalization of ADM-Hzn immunoconjugates and release of free ADM from the mAb in acidic intracellular compartments were important steps in the mechanism of action of ADM-Hzn immunoconjugates.

Animals↗
PubMed1993

Synthesis of 2'-deoxyuridine and 5-fluoro-2'-deoxyuridine derivatives and evaluation in antibody targeting studies.

Derivatives of 2'-deoxyuridine and of the anticancer agent 5-fluoro-2'-deoxyuridine (FdUR) were linked indirectly via a human serum albumin carrier (HSA) to the murine antiosteosarcoma monoclonal antibody 791T/36. Starting from the 2'-deoxyuridines 1a and 1b, the new nucleosides containing 5'-succinamic acid 7 and 5'-maleamic acid 8 spacers were synthesized from the key intermediate 5'-aminonucleoside 4, and the ribofuronamidobenzoic acid 13 from ribofuranuronic acid 10. These nucleosides were linked via their spacer functionality to HSA. High molar substitution ratios (MSR: moles of drug/mole of HSA) of 25-40 for these derivative-HSA conjugates were achieved. All derivatives were less cytotoxic than the parent drug against both antigen positive osteogenic sarcoma 791T and antigen negative bladder carcinoma T24 cell lines; no IC50 was achieved with any derivative against 791T cells. The fluorodeoxyuridine-HSA conjugates were then further linked via a stable thioether bond to the mouse monoclonal antibody 791T/36. The optimum fluorinated 5'-succinamic acid immunoconjugate exhibited an IC50 of 1 microM against 791T and T24 cells, slightly better than that of fluorodeoxyuridine. The unconjugated derivative 7 was much less cytotoxic than immunoconjugate, with an IC50 of 62 microM on T24 cells, and failed to reach 50% inhibition of 791T cell growth at 290 microM concentration. Derivative 7-HSA conjugate was 10-fold less cytotoxic than the immunoconjugate against both cell lines. Immunoconjugates synthesized with the other 5-fluoro derivatives were unable to effect 50% inhibition of growth of cell lines. Nonfluorinated derivatives and their HSA conjugates and immunoconjugates exhibited no cytotoxicity.

Antibodies, Monoclonal↗
PubMed2002

Monoclonal antibody conjugates of doxorubicin prepared with branched peptide linkers: inhibition of aggregation by methoxytriethyleneglycol chains.

High mole ratio BR96 immunoconjugates were synthesized using branched peptide-doxorubicin linkers designed to liberate doxorubicin following antigen-specific internalization into lysosomes. However, these immunoconjugates are highly prone to noncovalent, dimeric aggregation. We hypothesize that this is due to (1) the hydrophobic nature of the peptides, (2) the loss of positive charge upon amide formation at the 3'-amino group of doxorubicin, and (3) the proximity of the peptide hydrophobic residues to form efficient intermolecular stacking interactions. By introducing a hydrophilic methoxytriethylene glycol chain onto the doxorubicin portion of the branched peptide linkers, aggregation has been eliminated or greatly reduced in the immunoconjugate products. The methoxytriethylene glycol chain was linked to the doxorubicin moiety of the linker via a hydrazone bond that is stable at pH 7 but hydrolyzes rapidly at pH 5 to release free drug. BR96 immunoconjugates synthesized from methoxytriethylene glycol-modified branched peptide-doxorubicin linkers are highly potent and immunospecific in vitro. The data suggest that the methoxytriethylene glycol chain hydrolyzes as designed upon antigen-specific internalization into tumor lysosomes in vitro, where enzymatic degradation of the peptide linker releases free doxorubicin.

Antibodies, Monoclonal↗
PubMed1998

Polylysine-Gd-DTPAn and polylysine-Gd-DOTAn coupled to anti-CEA F(ab')2 fragments as potential immunocontrast agents. Relaxometry, biodistribution, and magnetic resonance imaging in nude mice grafted with human colorectal carcinoma.

RATIONALE AND OBJECTIVES: Immunocontrast agents used for magnetic resonance imaging require antibodies that preserve the immunoreactivity while containing a high number of chelated paramagnetic ions. METHODS: Anti-CEA F(ab')2 fragments were coupled to polylysine-Gd-DOTA and polylysine-Gd-DTPA. A paramagnetic load as high as n = 24 to 28 metal ions per antibody was reached. RESULTS: The immunoreactivity of the gadolinium (Gd)-labeled anti-CEA F(ab')2 immunoconjugates was 80% to 85%. Compared with that of commercial chelates, the relaxivity (R1) increase is as follows: Gd-DTPA < Gd-DOTA < Gd-H2O < PL-Gd-DTPA24-28 < PL-Gd-DTPA24-28 F(ab')2 < PL-Gd-DOTA24-28 < PL-Gd-DOTA24-28 F(ab')2. 1H nuclear magnetic relaxation dispersion data of immunoconjugates showed that the high relaxivity enhancement was the result of a reduction of the molecular tumbling rate. Twenty-four hours after intravenous injection of 50 micrograms (1 mumol Gd/kg) of Gd-labeled immunoconjugates to nude mice grafted with human colorectal carcinoma LS 174T, the tumor uptake was 10% to 15%, resulting in an increase of R1 of up to 15% to 20% versus noninjected mice. No difference was found between PL-Gd-DTPA24-28 F(ab')2 and PL-Gd-DOTA24-28 F(ab')2 immunoconjugates for tumor, liver, and kidney uptake. A high signal intensity of tumor was observed in 50% of the tested mice.

Adenocarcinoma↗
PubMed2004

Streptavidin-biotin crosslinking of therapeutic enzymes with carrier antibodies: nanoconjugates for protection against endothelial oxidative stress.

The streptavidin-biotin system may be used to synthesize immunoconjugates for targeted delivery of drugs, including therapeutic enzymes. The size of antibody-enzyme conjugates, which is controlled by the extent of biotinylation and molar ratio between the conjugate components, represents an important parameter that in some cases dictates subcellular addressing of drugs. This chapter describes the methodology of formation and characterization of polymeric immunoconjugates in the nanoscale range. A theoretical model of streptavidin conjugation based on general principles of polymer chemistry is considered. Factors that influence size and functional characterization of resulting polymer conjugates, as well as advantages and limitations of this approach, are described in detail. The protocols describe the formation of immunoconjugates possessing an antioxidant enzyme, catalase, directed to endothelial cells by anti-platelet endothelial cell adhesion molecule antibodies. However because of the modular nature of the streptavidin-biotin crosslinker system, the techniques herein can be easily adapted for the preparation of nanoscale immunoconjugates delivering other protein drugs to diverse cellular antigens.

Antibodies↗
PubMed1999

Antineoplastic efficacy of doxorubicin enzymatically assembled on galactose residues of a monoclonal antibody specific for the carcinoembryonic antigen.

We have developed a novel procedure to couple enzymatically the antineoplastic agent doxorubicin (Dox) on the galactose residues of a monoclonal antibody specific for the tumor-associated carcinoembryonic antigen. The synthesis of the immunoconjugate consists of covalent attachment of the NH2 terminus of Dox to oxidized galactose residues of desialylated monoclonal antibody, followed by concurrent stabilization of Schiff bases by mild reduction with pyridine borane. The immunoconjugate preserved both antibody specificity and drug cytotoxicity. At equimolar concentrations, the immunoconjugate was 8 times more cytotoxic against two carcinoembryonic antigen-expressing carcinoma cell lines, LoVo and SW-480, than Dox alone. The intracellular drug accumulation was 8-8.5 times higher than that obtained with free Dox, and >50% of the drug delivered by the conjugate was retained for 24 h in the tumor cells. Only 4 days after treatment with a single dose of immunoconjugate carrying 2.5 ng of Dox, LoVo and SW-480 tumor transplants on the chorioallantoic membrane of embryonated hen eggs showed reduced tumor-induced angiogenesis and tumor progression by half, with no detectable damage to surrounding tissues. In contrast, the same amount of free drug induced insignificant changes in tumor progression and tumor-induced angiogenesis. Enzymatically mediated, glycosidic coupling of antineoplastic agents to antibodies specific for tumor-associated antigens may represent a novel platform for the development of more efficient anticancer agents with reduced side effects.

Animals↗
PubMed1995

Radioimmunotherapy of prostatic adenocarcinomas: effects of 131I-labelled E4 antibodies on cells at different depth in DU 145 spheroids.

Spheroids of the human prostatic adenocarcinoma cell line DU 145 were used to study experimental radioimmunotherapy. Spheroids were incubated with the 131I-labelled monoclonal E4 antibody until the radionuclide immunoconjugate had bound the 5 to 6 outermost cell layers of the spheroids. A set of 50 spheroids were exposed, either immediately or 48 hr after antibody incubation and washings, to a dilute trypsin solution with the aim of stripping off cells from the spheroid surface. Stripped cells were collected in fractions corresponding to defined spherical shells. Cells were subsequently plated for clonogenic growth. The technique of automated sequential trypsinization of spheroids followed by a clonogenic survival assay permits studies on therapeutic efficacy for radionuclide immunoconjugates on cells from different layers of spheroids. In addition, the absorbed doses throughout a spheroid were calculated. The binding and retention kinetics of the radionuclide immunoconjugate and the excess of 131I-E4 in the culture medium during incubation are factors that were all accounted for in the calculations. If the calculated absorbed doses were inserted into the linear-quadratic survival model and the low dose rate was taken into account, survival values were well in accordance with the experimentally obtained values. The results demonstrate that the 131I-labelled E4 antibody is capable of sterilizing cultured tumour cells that have bound the radionuclide immunoconjugate and, by means of radiation "cross-fire", those cells located in close proximity.

Adenocarcinoma↗
PubMed1993

Toxin-targeted design for anticancer therapy. II: Preparation and biological comparison of different chemically linked gelonin-antibody conjugates.

To obtain more potent immunotoxins for anticancer therapy a gelonin-AR3 antibody immunoconjugate was prepared with different new linkers and coupling procedures. The gelonin was derivatized with the heterobifunctional thioimidate linkers ethyl-acetyl-3-mercaptopropionthioimidate (AMPT) and 3-(4-carboxamidophenyldithio)propionthioimidate (CDPT), and with the succinimidyl type reagents N-succinimidyl-3-(4-carboxamidophenyldithio)propionate (SCDP) and N-succinimidyl-S-acetyl thiolacetate (SATA). The biological activity of gelonin modified with different linkers (AMPT, CDPT, SCDP, SATA) was determined by a rabbit reticulocyte assay. We found that AMPT was the molecule of choice to derivatize the toxin, confirming the preferability of thioimidate linkers. The monoclonal antibody Mab was derivatized with CDPT and SCDP. Then the following immunoconjugates were prepared with different procedures: Mab-CDPT with gelonin-AMPT; Mab-CDPT with gelonin-CDPT; Mab-SCDP with gelonin-SATA. To verify whether selection of the most suitable coupling procedure could affect the antitumoral activity of the gelonin-AR3 immunoconjugate, the three immunotoxins were tested on target HT-29 human colon carcinoma cells versus nontarget MeWo cells. The gelonin immunoconjugate linked via the AMPT-CDPT thioimidate reagents showed highest antitumoral activity as well as best selectivity for the target cells.

Animals↗
PubMed1999

Comparative cytotoxicity and pharmacokinetics of antimelanoma immunotoxins containing either natural or recombinant gelonin.

Immunotoxins are a class of targeted therapeutic agents under development by various research groups. The murine monoclonal antibody designated ZME-018 recognizes a high molecular weight glycoprotein present on most human melanoma cells and biopsy specimens and has been utilized for clinical imaging studies in patients with melanoma. The plant toxin gelonin is a ribosome-inactivating protein (RIP) with n-glycosidase activity similar to that of ricin A chain. In previous studies by our group, the gelonin toxin was sequenced, cloned and expressed in E. coli. The purified recombinant gelonin (RG) was found to have identical protein synthesis inhibitory activity to that of natural gelonin (NG). For comparative purposes, chemical conjugates of antibody ZME and either RG or NG were produced using the heterobifunctional crosslinking reagents SPDP and SMPT. The ZME-NG and ZME-RG immunotoxins were found to be 10(4)- to 10(5)-fold more cytotoxic to antigen-positive human melanoma cells than free toxin. NG toxin alone was cytotoxic to intact cells (IC(50) = 100 nM) while RG was nontoxic to cells at doses up to 1 microM. Both ZME-NG and ZME-RG immunoconjugates were nontoxic to antigen-negative (Me-180) cells. ZME-RG immunotoxins constructed with the more stable SMPT reagent were slightly more effective in culture than conjugates made with SPDP. Tissue distribution studies in tumor-bearing nude mice demonstrated that tumor uptake of the ZME-RG immunotoxin was similar to that of the intact ZME antibody with reduced distribution to normal organs compared to an immunoconjugate produced with NG. Pharmacokinetic studies showed that the terminal-phase plasma half-life of ZME-RG was similar to that of ZME itself (42 h vs 50 h) and almost threefold higher than that of ZME-NG (11.5 h). The area under the concentration curve (Cxt) for ZME-RG was 50% lower than that for ZME due to an increased apparent volume of distribution (Vd(a)) but was almost tenfold higher than the Cxt for ZME-NG. These studies suggest that immunoconjugates comprising RG demonstrate identical in vitro cytotoxic effects to immunoconjugates produced with NG and immunotoxins with RG display improved in vivo pharmacodynamics and tissue distribution compared to immunotoxins containing NG.

Animals↗
PubMed1991

Adjuvant-independent immunization by immunotargeting antigens to MHC and non-MHC determinants in vivo.

Using avidin as a model protein antigen, and biotinylated monoclonal antibodies as a convenient means of forming stable complexes with avidin, we have investigated the adjuvant-independent immunization of three mouse strains, C57BL/6, C3H and (C57BL/6 x C3H)F1, with immunoconjugates targeted to different class II MHC and non-MHC sites. The results confirm the effectiveness of anti-I-Ak and anti-I-Ab immunoconjugates with respect to priming for secondary IgG responses in (H-2b x H-2k)F1 mice, while indicating a lack of response in strains which are homozygous for the targeted allele. In terms of non-MHC targets in the monocyte-macrophage lineage, neither anti-MAC-1 nor anti-MAC-2 immunoconjugates were effective in any of the three strains. However, the 33D1 anti-dendritic cell antibody gave significant responses in all three strains, with the F1 response being more than 10-fold greater than the anti-class II immunoconjugates in either strain. These findings indicate that immunotargeting a protein antigen to a non-MHC determinant on dendritic cells in vivo can be an effective means of inducing an adjuvant-independent serological response, and that this approach can have significant advantages over anti-class II MHC immunotargeting.

Adjuvants, Immunologic↗
PubMedDate not supplied

Maleimido derivatives of diethylenetriaminepentaacetic acid and triethylenetetraaminehexaacetic acid: their synthesis and potential for specific conjugation with biomolecules.

Immunoconjugates sometimes suffer changes in immunoreactivity and tumor targeting because the chelators used interfere with antigen binding. To try to circumvent such problems, two new homobifunctional chelating agents, 2,6-bis[p-[(beta-maleimidopropionyl) amino]benzyl]diethylenetriamine- N,N,N',N",N"-pentaacetic acid (MPBz-DTPA) and 2,9-bis [p-(beta-maleimidopropionyl)amino]benzyl] triethylenetetraamine-N,N,N',N',N",N"-hexaacetic acid (MPBz-TTHA), were synthesized for chelation of 111In and 90Y metal ions. Each of the new chelators contains two maleimido functional groups substituted at the carbon backbone. In this study, the overall chemical yields for MPBz-DTPA and MPBz-TTHA were approximately 5 and 4%, respectively. The intermediate and final compounds were purified by flash chromatography and fully characterized by 1H-NMR, 13C-NMR, and mass spectroscopy. Chemical modification of the maleimido group on each of these derivatives allowed specific conjugation with a sulfhydryl group at the hinge region of an antibody molecule and conjugation with other peptides. For instance, the two Fab' fragments, through their hinge-region sulfhydryl groups, could covalently attach to a homobifunctional chelator via thioether linkage to generate a Fab'-S-chelator-S-Fab' immunoconjugate. By design, immunoconjugates containing these new chelators will contain only one chelator derivative at a known region of antibody away from the antigen binding site. Consequently, these chelators may minimize changes in the immunoreactivity and improve tumor targeting of immunoconjugates that contain them.

Chelating Agents↗
PubMed2005

Antibody-cytotoxic agent conjugates for cancer therapy.

Antibody-based delivery of cytotoxic agents, including toxins, to tumours can dramatically reduce systemic toxicity and increase therapeutic efficacy. The advantage of a monoclonal antibody (mAb) is superior selectivity towards antigens expressed on the surface of cancer cells. Recent advances in biotechnology accelerated progress in the pharmaceutical applications of mAbs. A cytotoxic warhead is attached to a mAb in an immunoconjugate via a linker, which is stable in circulation but efficiently cleaved in the tumour tissue. The warhead, mAb and linker play important roles in the successful design of potent and efficient immunoconjugates. To date, one mAb-cytotoxic agent conjugate has been approved by the FDA and several other candidates are in various stages of clinical trials. This review describes the recent progress in the design and development of mAb-based immunoconjugates of cytotoxic agents, and summarises the criteria for the critical choices of a suitable mAb, linker and cytotoxic agent to design an efficacious immunoconjugate.

Animals↗
PubMed2003

Effect of antigenic heterogeneity on the efficacy of enhanced delivery of antibody-targeted chemotherapy in a human lung cancer intracerebral xenograft model in rats.

OBJECTIVE: The SGN-15 monoclonal antibody-doxorubicin immunoconjugate is toxic to Lewis(Y) antigen-expressing cells and is effective against intracerebral tumors in nude rats when delivery is enhanced with osmotic disruption of the blood-brain barrier (BBB). We tested whether doxorubicin released locally in antigen-expressing cells would affect adjacent non-antigen-expressing cells in heterogeneously expressing intracerebral tumors. METHODS: Nude rats with intracerebral xenografts of human small cell lung carcinoma cells with high (n = 10) or low (n = 23) Lewis(Y) antigen expression were treated with SGN-15 at a low (10 mg/kg) or high (140 mg/kg) antibody dose, administered intra-arterially with BBB disruption, and tumor volumes and antigen expression were evaluated after 6 days. RESULTS: BBB disruption-enhanced delivery of SGN-15 (10 mg/kg) reduced the high-expressor tumor volume from 26.1 +/- 3.7 mm(3) (n = 7) in untreated control animals to 6.7 +/- 4.6 mm(3) (n = 3, P < 0.05). Untreated high-expressor tumors exhibited uniform prominent Lewis(Y) antigen staining (97.6 +/- 0.9% positive, n = 4), whereas treated tumors demonstrated areas of nil, moderate, and prominent staining (71.0 +/- 8.5% positive, n = 3, P < 0.05). In intracerebral tumors with low initial antigen expression, BBB disruption-enhanced delivery of a low dose of immunoconjugate was significantly effective, but treated tumors demonstrated low levels of antigen expression. An increase in the immunoconjugate dose did not significantly alter either efficacy or antigen expression. CONCLUSION: Immunoconjugate delivered across the BBB was effective against antigen-positive tumor cells, but there was not an effective chemical bystander effect against antigen-negative tumor cells.

Animals↗
PubMed1994

[Comparative studies of 111In-labeled monoclonal antibody using spacer-containing and non-spacer bifunctional chelates: (II). Biodistribution, metabolism and excretion in vivo].

Indium-111-labeled A7 monoclonal antibodies using two spacer-containing chelates, succinimido-EGS-DTPA (EGS-DTPA: diester spacer) and maleimido-C10-Bz-EDTA (C10-Bz-EDTA: hydrocarbon spacer) were investigated in human LS180 colon tumor bearing nude mice and were compared with two non-spacer chelates, cyclic DTPA dianhydride (cDTPAA) and isothiocyanatobenzyl-EDTA (SCN-Bz-EDTA). Compared with immunoconjugates using non-spacer chelates, immunoconjugates using spacer-containing chelates, especially C10-Bz-EDTA-A7 showed lower 111In activity in normal organs. The radioactivity in the liver for C10-Bz-EDTA-A7 decreased continuously till 96 hrs postinjection, however, this liver radioactivity for EGS-DTPA-A7 showed little change after 24 hrs. Moreover, in liver subcellular distribution study, EGS-DTPA-A7 showed a higher activity retention in mitochondrial fraction which contained lysosome, a place for metabolizing and storing of 111In labeled antibody, than that of C10-Bz-EDTA-A7. The C10-Bz-EDTA-A7 conjugate demonstrated more preferable tumor-to-non tumor contrast on the scintigrams than that found with other three immunoconjugates. Up to 96 hrs postinjection, tumor bearing nude mice injecting with immunoconjugates using spacer-containing chelates excreted twice radioactivity from whole body than that excreted by using non-spacer chelates. Interestingly, different from other three chelates, C10-Bz-EDTA-A7 were mainly excreted via feces. We conclude that the decrease of radioactivity in normal tissues in the case of EGS-DTPA-A7 was duo to the rapid decrease of activity in the blood, while in the case of C10-Bz-EDTA-A7 it was due to the quickly excreted small metabolite through faces. 111In labeled C10-Bz-EDTA conjugate is superior, at least when conjugated with A7, to other three chelate conjugates used in this study.

Animals↗
PubMed1994

[Application of monoclonal antibody for cancer therapy].

Immunoconjugates composed of mouse monoclonal antibody and anticancer drug was applied for the treatment of patients with colorectal cancer. Administration of mouse antibody raised human anti-mouse antibody that may interfere with the effect of immunoconjugates. To resolve this problem, human/mouse chimeric antibody was prepared and immunoconjugate of chimeric antibody and anticancer drug was developed. The characteristics of this new immunoconjugate were described.

Animals↗
PubMed2001

Targeted drug conjugates: principles and progress.

Reports of targeting drugs using antibodies have appeared in the literature since 1958, but exciting clinical results in this field have only been reported in the last few years. Progress in this field has occurred largely through an understanding how drug-immunoconjugates work. The objective of this review is to draw together the fundamental principles on which this field of work is based, to examine the evidence supporting those principles, and the effectiveness and selectivity of targeted drug conjugates. The activity of many drug-immunoconjugates can now largely be accounted for by the underlying principles. Excellent development work, both with conventional anti-cancer agents and very potent drugs have led to a number of interesting clinical trials. In the best Phase I and II trials, good evidence of effectiveness have been reported, which suggest that drug-immunoconjugates may now be heralding a new era for chemotherapy.

Animals↗
PubMed1999

Monoclonal antibody drug conjugates in the treatment of cancer.

Monoclonal antibodies directed to tumor-associated antigens have been chemically conjugated to drugs with different mechanisms of action and different levels of potency. Monoclonal-antibody-directed drug delivery has the potential to both improve efficacy and reduce systemic toxicity. Several immunoconjugates have demonstrated impressive antigen-specific antitumor activity in preclinical models. Phase I trials of a calicheamicin immunoconjugate for treatment of acute myeloid leukemia and a doxorubicin immunoconjugate for treatment of carcinoma have recently been completed.

Antibiotics, Antineoplastic↗