[20] Preparation of antibody-linked cytotoxic agents

Ghose, T. K.; Blair, A H; Kulkarni, P. N.

doi:10.1016/s0076-6879(83)93050-1

Cited by 75 publications

(56 citation statements)

References 46 publications

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“…Second, the apparent quantum efficiency of singlet oxygen generation ((A) for SnCe6 has been shown to be 2-fold greater than that of the metal-free chlorin e6 under conditions of matched absorbance at the principal red band for each PS (data not shown). Recent studies of metallo-and metal-free chlorin e6 derivatives have shown that the efficiency of singlet molecular oxygen (1Ad) generation and the chromophore photostability are governed by the identity of the central metal atom (29 As a consequence of non-site-specifc linkage methods, reduced activity of the active agent and the mAb has been reported (2,31,32). Recently, coupling techniques have been developed that exploit the Fc oligosaccharide residues in mAbs (33).…”

Section: Discussionmentioning

confidence: 99%

“…Over the past decade, advances in monoclonal antibody (mAb) technology (1) have provided the opportunity to study the potential of mAbs to selectively deliver a variety of active agents (e.g., drugs, toxins, radioisotopes) to cell surfaces (2)(3)(4)(5)(6)(7)(8). The selectivity of such conjugates can be compromised by shared antigen cross-reactivity or by nonspecific uptake of the conjugates (9,10).…”

mentioning

confidence: 99%

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Antibody-targeted photolysis: in vitro studies with Sn(IV) chlorin e6 covalently bound to monoclonal antibodies using a modified dextran carrier.

Rakestraw

Tompkins

Yarmush

1990

Proc. Natl. Acad. Sci. U.S.A.

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A monoclonal antibody-dextran-Sn(IV) chlorin e6 immunoconjugate was prepared by a technique involving the site-specific covalent modification of the monoclonal antibody oligosaccharide moiety. Dextran carriers were synthesized with a single chain-terminal hydrazide group, which was used as the coupling point between the carrier and the monoclonal antibody carbohydrate. Selective in vitro photolysis of SK-MEL-2 human malignant melanoma cells was accomplished using several conjugates prepared from anti-melanoma 2.1 (chromophore:antibody molar ratios, 6.8 and 11.2). MATERIALS AND METHODSSynthesis of SnCe6-Dextran Carrier. The synthetic schemes used in the current work are outlined in Fig. 1 (17). Dextran (Pharmacia T-40; weight average molecular weight =35,000) was chosen as the carrier polymer because it is water soluble, is nontoxic, and possesses a single reducing terminus. A reactive hydrazide group was added to the reducing terminus via reductive amination with a large excess of apidic dihydrazide in the presence of sodium cyanoborohydride (18,19). Titration of the reducing end in I using the dinitrosalicylate method (20) showed a 92% modification of the terminal aldehyde relative to unaltered dextran. To prevent modification of the chain-terminal hydrazide in I prior to linkage to the antibody, a Trt protection group was introduced via the active ester TCPPH to yield II. In addition to providing a protected terminal hydrazide, the TCPPH was also designed to introduce a six-carbon spacer group on the dextran terminus in order to facilitate subsequent linkage to the mAb.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Antibody-targeted photolysis: in vitro studies with Sn(IV) chlorin e6 covalently bound to monoclonal antibodies using a modified dextran carrier.

Rakestraw

Tompkins

Yarmush

1990

Proc. Natl. Acad. Sci. U.S.A.

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“…Ghose and colleagues successfully conjugated many drugs, such as chlorambucil, adriamycin, daunomycin, methotrexate, trenimon, vindesine and others, without sacrificing the cytotoxicity of drugs or specificity of antibodies (37,(45)(46)(47)(48)(49). All these conjugates showed activity and effectiveness against cancer cell lines in vitro, but were less potent than the free drug (50)(51)(52).…”

Section: Drug-antibody Conjugatesmentioning

confidence: 99%

Monoclonal antibodies in drug targeting

Panchagnula

Dey

1997

Journal of Clinical Pharmacy and Therapeutics

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SUMMARYThe objective of drug targeting is to deliver drugs to a specific site of action through a carrier system. In cancer chemotherapy, cytotoxic drugs kill cancerous cells but also damage normal cells. Monoclonal antibodies generated against specific antigens, when conjugated to cytotoxic drugs, can selectively deliver drugs to cancer cells while minimizing damage to normal cells. Of all the carrier systems available, monoclonal antibodies are gaining importance because of their high specificity. The purpose of this review is to provide a comprehensive account of the use of monoclonal antibodies in drug targeting, highlighting their scope and limitations.

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“…Void volume fractions containing MBSA-DXR were pooled and subjected to extensive dialysis. The amount of DXR int he conjugate was determined by measuring the absorbance at 495 nm [16]. Protein was estimated by bicinchoninic acid (BCA) reagent [17].…”

Section: Coniugation Of Dxr To Mbsamentioning

confidence: 99%

Enhanced intracellular delivery of doxorubicin by scavenger receptor‐mediated endocytosis for preferential killing of histiocytic lymphoma cells in culture

et al. 1994

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A conjugate of the antineoplastic drug doxorubicin (DXR) with maleylated bovine serum albumin (MBSA) was taken up by a human histiocytic lymphoma cell line (U937) through the high efficiency process of scavenger receptor-mediated endocytosis resulting in a sixfold higher intracellular concentration of the drug compared to that obtained when the free drug was administered. Compared to the free drug, the drug conjugate showed significantly higher cytotoxicity towards U937 cells presumably because of intracellular availability of a pharmacologically active form of the drug. The intracellular product released after lysosomal degradation of the drug conjugate was chromatographically identical to free DXR. These findings merit serious consideration in the development of new chemotherapeutic agents for the treatment of histiocytic malignancies.

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[20] Preparation of antibody-linked cytotoxic agents

Cited by 75 publications

References 46 publications

Antibody-targeted photolysis: in vitro studies with Sn(IV) chlorin e6 covalently bound to monoclonal antibodies using a modified dextran carrier.

Antibody-targeted photolysis: in vitro studies with Sn(IV) chlorin e6 covalently bound to monoclonal antibodies using a modified dextran carrier.

Monoclonal antibodies in drug targeting

Enhanced intracellular delivery of doxorubicin by scavenger receptor‐mediated endocytosis for preferential killing of histiocytic lymphoma cells in culture

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