Antibodies Conjugated to Potent Cytotoxins as Specific Antitumor Agents

Moolten, Frederick L.; Schreiber, Barbara M.; Zajdel, S.

doi:10.1111/j.1600-065x.1982.tb00389.x

Cited by 16 publications

(4 citation statements)

References 55 publications

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“…Verification of the monosubstitution was accomplished by TLC and elemental analysis. Reverse-phase TLC produced a single spot, and elemental analysis of a sample crystallized from ethyl acetate as the monohydrochloride gave the following values: C36H43N605C1 (675.22): C, 63.82%; H, 6.69%; N, 11.46%. Expected values were as follows: C, 64%; H, 6%; N, 12.45%.…”

Section: Resultsmentioning

confidence: 99%

“…The selectivity ofmAb-directed treatment may be reduced, however, by cross-reactivity due to shared antigens on normal tissues and by nonspecific tissue uptake (5,6). These problems can be obviated by utilizing mAbs that carry light-activated molecules (i.e., photosensitizers, PSs), which are innocuous without illumination but which produce toxic or reactive species such as singlet oxygen (102) upon absorbing light.…”

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confidence: 99%

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Antibody-targeted photolysis: selective photodestruction of human T-cell leukemia cells using monoclonal antibody-chlorin e6 conjugates.

Oseroff

Ohuoha

Hasan

et al. 1986

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

147

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Selective in vitro photodestruction of HPB-ALL human T-cell leukemia cells was accomplished using the photosensitizer chlorin e6 coupled through dextran molecules to an anti-T-cell monoclonal antibody (mAb), anti-Leu-1.Conjugates with mAb/chlorin molar ratios as high as 1:36 retained mAb binding activity, and the absorption spectrum and quantum efficiency for singlet oxygen production of bound chlorin (0.7 ± 0.2) were unchanged from that of the free photosensitizer. Phototoxicity, as measured by a clonogenic assay and by uptake of ethidium bromide, was dependent on the doses of both mAb-chlorin and 630-to 670-nm light, was enhanced by 2H20, and was observed only in target populations that bound the mAb. Similarly, free chlorin e6 in solution had no photodynamic effect in amounts 100 times more than that carried by the mAb. For this antibody-targeted system, approximately 1010 molecules of singlet oxygen were necessary to kill a cell.A principal objective in the development of chemotherapeutic strategies is to devise modalities that are capable of selectively acting on the offending cells while sparing normal tissues. Selectivity may be provided by the preferential action of a particular agent or by preferential localization of molecules that act nonspecifically. Monoclonal antibodies (mAbs) that bind to cell surface antigens have great promise for directing cytotoxic agents to appropriate sites; and a substantive body of literature has already accumulated on the use of monoclonal antibodies to enhance selectivity of cytotoxic drugs, radioisotopes, or toxins (1-4).The selectivity ofmAb-directed treatment may be reduced, however, by cross-reactivity due to shared antigens on normal tissues and by nonspecific tissue uptake (5, 6). These problems can be obviated by utilizing mAbs that carry light-activated molecules (i.e., photosensitizers, PSs), which are innocuous without illumination but which produce toxic or reactive species such as singlet oxygen (102) upon absorbing light. By confining illumination to areas containing specifically bound PSs, toxicity can be limited to target cells. Nontarget cells, which adventitiously bind the mAb-PS but which are outside the illuminated volumes, would be spared.The present report describes selective cytolysis of human T-cell leukemia cells in vitro using mAb conjugated to the PS chlorin e6, which has a molar extinction coefficient of about 59,000 M-1-cm-1 at 660 nm (7). Chlorin/mAb conjugation ratios of approximately 30:1 were achieved, and mAb and chlorin activities were retained. Selective destruction of target T cells was accomplished by irradiation of cells containing mAb-PS conjugates bound to their cell surface. MATERIALS AND METHODSChromophore Preparation. In brief, chlorin e6-monoethylenediamine monoamide (chlorin e6-A) was prepared as follows: A monoactivated species (mixed anhydride) was formed by sequential addition oftriethylamine and ethyl chloroformate to chlorin e6 dissolved in anhydrous N,N'-dimethylformamide. TLC analysis using C18-bonded silica pla...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Antibody-targeted photolysis: selective photodestruction of human T-cell leukemia cells using monoclonal antibody-chlorin e6 conjugates.

Oseroff

Ohuoha

Hasan

et al. 1986

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

147

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“…The clinical utility of these immunotoxins has so far been limited. The fusion of antibody with a membrane active toxin could yield an immunotoxin with enhanced properties, but the chemical coupling of polyclonal antibody with the C. perfringens alpha-toxin has yielded disappointing results (109). Chovnick et al (26) have reported the generation of a hybrid anti-Tac-C. perfringensalpha-toxin antibody by fusing cpa with the 5' end of the segment encoding VHCHl from the anti-Tac heavy chain.…”

Section: Immunotoxinsmentioning

confidence: 99%

Bacterial phospholipases C.

Titball

1993

Microbiological Reviews

224

175

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“…They prepared protein conjugates with a structural analog of carcinogen, which in itself cannot induce a tumor. The pre-immunization of animals with this conjugate essentially decreased the probability of tumorigenesis caused by an actual carcinogen [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

A Novel Approach to the Development of Anticarcinogenic Vaccines

et al. 2010

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Human exposure to chemical carcinogens is an important etiological factor in cancer diseases. In this article, we will discuss a new approach to the development of anticarcinogenic vaccines. The main task in our research was to select a benzo[a]pyrene immunomimetic peptide considered as a hapten-specific component. For this purpose, we synthesized carcinogen-protein conjugates and prepared mono- and polyclonal antibodies to benzo[a]pyrene. Phage display technology was used to select the benzo[a]pyrene immunomimetic peptide, followed by an evaluation of the immunological properties of the obtained peptide. The obtained benzo[a]pyrene immunomimetic peptide could only simulate chemical carcinogens in the frame of the pIII protein. As a result, we prepared a recombinant protein composed of the benzo[a]pyrene immunomimetic peptide and pIII-encoding sequences. Using ELISA, we demonstrated that the recombinant protein specifically interacts with the anti-benzo[a]pyrene monoclonal antibody (mAB B2). Using molecular modeling, we predicted the 3-D structure of the mAB B2 active center and analyzed the characteristics of its interaction with different polycyclic aromatic hydrocarbons, as well as with the benzo[a]pyrene immunomimetic peptide. Thus, a comprehensive analysis of the results of the obtainment of hapten-specific components of anticarcinogenic vaccines allowed us to outline a strategy for future development in this direction.

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Antibodies Conjugated to Potent Cytotoxins as Specific Antitumor Agents

Cited by 16 publications

References 55 publications

Antibody-targeted photolysis: selective photodestruction of human T-cell leukemia cells using monoclonal antibody-chlorin e6 conjugates.

Antibody-targeted photolysis: selective photodestruction of human T-cell leukemia cells using monoclonal antibody-chlorin e6 conjugates.

Bacterial phospholipases C.

A Novel Approach to the Development of Anticarcinogenic Vaccines

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