Immunotoxins: hybrid molecules of monoclonal antibodies and a toxin subunit specifically kill tumour cells

Blythman, Hildur E.; Casellas, Pierre; Gros, Olivier; Gros, Pierre; Jansen, F. K.; Paolucci, F.; Pau, Bernard; Vidal, Hubert

doi:10.1038/290145a0

Cited by 224 publications

(55 citation statements)

References 7 publications

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“…There is considerable evidence suggesting that the primary role of transferrin as a growth factor in vitro is to provide iron (23,(38)(39)(40)(41)(42). Monoclonal antibodies against T-cell differentiation antigens also have been used in attempts to eliminate tumor cells by immunological effector mechanisms (43)(44)(45)(46) (1982) …”

Section: Discussionmentioning

confidence: 99%

Monoclonal antibody to transferrin receptor blocks transferrin binding and inhibits human tumor cell growth in vitro.

Trowbridge¹,

Lopez²

1982

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

295

143

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A murine hybridoma has been obtained that produces a monoclonal antibody against the human transferrin receptor. In contrast to previously characterized monoclonal antibodies that recognize the transferrin receptor, this antibody, designated 42/6, blocks the binding of transferrin to its receptor and inhibits the growth of the human T leukemic cell line, CCRF-CEM, in vitro. Inhibition of cell growth was dose dependent, and as little as 2.5 jtg of purified antibody per ml had a detectable effect, even though transferrin was present in the tissue culture medium in large molar excess. Cells grown in the presence of antibody for 7 days accumulated in S phase of the cell cycle. The addition of iron to antibody-treated cultures in the form of ferric complexes or ferrous sulfate did not overcome the growth inhibitory effects of the anti-transferrin-receptor antibodies. This result suggests that either transferrin is the only means by which CCRF-CEM leukemic cells can be provided with sufficient iron in vitro or that other factors in addition to iron starvation are involved in the antibody-mediated growth inhibition. The inhibition of cell growth by 42/6 monoclonal antibody suggests that monoclonal antibodies against proliferation-associated cell surface antigens, such as the transferrin receptor, may be useful pharmacological reagents to modify-cell growth in vitro.Iron plays an important role in cell growth and metabolism (1). Key reactions in energy metabolism and DNA synthesis are catalyzed by iron-containing enzymes, and it has been known for several years that transferrin, the major serum iron-transport protein, is an obligatory growth factor for cells growing in vitro (2-11). More recently, it has become apparent that cell surface receptors for transferrin are not only found in abundance on maturing erythroid cells and placental membranes but are expressed on proliferating cells in vitro and in vivo (12-16).We and others have obtained monoclonal antibodies that react with the human cell surface receptor for transferrin and confirmed that the expression of transferrin receptors is regulated by the growth state ofthe cells (17)(18)(19)(20)(21)(22). Although the antitransferrin-receptor monoclonal antibody, which we obtained and designated B3/25, inhibits the growth of a human melanoma cell line in nude mice (23), it does not interfere with either transferrin binding or cell growth in vitro. In this paper, we report the identification ofanother murine monoclonal antibody against-the human transferrin receptor that blocks transferrin binding and show that this antibody blocks the growth of a human T leukemic cell line in vitro.MATERIALS AND METHODS Cell Lines. CCRF-CEM, a human thymus-derived (T) leukemic cell line (24), was grown in RPMI 1640 medium supplemented with 10% horse serumn. BW5147, a murine T lymphoma cell line (25) was grown in Dulbecco's modified Eagle's medium supplemented with 10% horse serum.Monoclonal Antibodies. Monoclonal antibodies B3/25 and T56/14 directed against the human transferrin ...

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Section: Discussionmentioning

confidence: 99%

Monoclonal antibody to transferrin receptor blocks transferrin binding and inhibits human tumor cell growth in vitro.

Trowbridge¹,

Lopez²

1982

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

295

143

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“…The first successful in vivo use of an immunotoxin was described in Nature in 1981 [14]. The technology developed rapidly, and the first clinical trials in solid tumor patients followed [15,16].…”

Section: Overcoming Historical Obstacles To Clinical Use Of Immunotoxinsmentioning

confidence: 99%

Advances in Anticancer Immunotoxin Therapy

2015

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Immunotoxins are a novel class of antibody-conjugated therapeutics currently in clinical development for a variety of malignancies. They consist of an antibody-based targeting domain fused to a bacterial toxin payload for cell killing. Immunotoxins kill cells by inhibiting protein synthesis, a unique mechanism of action that is toxic to both dividing and nondividing cells. Recent advances in the design and administration of immunotoxins are overcoming historical challenges in the field, leading to renewed interest in these therapeutics.The Oncologist 2015;20:176-185Implications for Practice: Immunotoxins are a novel class of antibody-based therapeutics currently in clinical development. A review of the field will help physicians better inform patients about the potential benefits and toxicities of these experimental treatments.

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“…On the other side, immunotoxins were described in 1981 with a pretty advanced description of monoclonal antibodyricin A conjugates [3]. Research in this field was extremely active and many antibodies as well as many different vegetal and bacterial toxins were tested.…”

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confidence: 99%