Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Patent
1996-05-16
1999-09-28
Feisee, Lila
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
5303881, 53038815, 53038823, 5303871, 536 2353, 43524027, 4352523, C07K 1600, C07H 2104
Patent
active
059590858
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to human monoclonal antibodies against human cytokines and methods of making, identifying and using such antibodies, preferably human monoclonal antibodies against human cytokines or lymphokines such as IL-1.alpha., IL-1.beta., IL-4, IL-5, IL-6, IL-8, IL-10, TNF-.alpha., etc.
BACKGROUND OF THE INVENTION
The applicability of human monoclonal antibodies (HuMAbs), especially HuMAbs to human cytokines, in therapy holds great promise; see, for example, Griffiths et al., EMBO J., 12:725-734 (1993) and the review in Larrick et al., J. Biol. Response Modif., 5:379 (1986). However, the production of useful HuMAbs against human cytokines has proved difficult.
Specifically, while the possible existence in human serum of autoantibodies Immunol., 145:2140-2146 (1990) (IL-1.alpha.); Hansen et al., Immunol. Letters, 30:133-140 (1991) (IL-1.alpha.); Bendtzen et al., Immunol. Today, 11:167-169 (1990) (IL-1.alpha. and TNF-.alpha.); Bendtzen et al., Immunol. Today, 10:222 (1989) (IL-1.alpha. and TNF-.alpha.); Saurat et al., J. Allergy Clin. Immunol., 88:244-256 (1991) (IL-1.alpha.); Suzuki et al., Clin. Exp. Immunol., 85:407-412 (1991) (IL-1.alpha.); Sunder-Plassmann et al., Kidney International, 40:787-791 (1991) (IL-1.alpha.); Gallay et al., Eur. Cytokine Netw., 2:329-338 (1991) (IL-1.alpha. and IL-1.beta.); Mae et al., Lymphokine Cytokine Res., 10:61-68 (1991) (IL-1.alpha.); Fomsgaard et al., Scand. J. Immunol., 30:219 (1989) (TNF-.alpha.); Hansen et al., Scand. J. Immunol., 33: 777-781 (1991) (IL-6); Crabtree et al., Scand. J. Immunol., 37:65-70 (1993) (IL-8); Bost et al., Immunology, 65:611-615 (1988) (IL-2); Ross et al., Clin. Exp. Immunol., 82:57-62 (1990) (IFN-.alpha.2b and IFN-.gamma.); and Caruso et al., J. Immunol., 144:685-690 (1990) (IFN-.gamma.)!, no one has been able to produce an isolated and purified HuMAb to a human cytokine, especially a HuMAb having high affinity, e.g., a K.sub.a of above about 10.sup.9 M.sup.-1. Some of the reasons are pointed out in the cited article by Griffiths et al. in EMBO. J.: are difficult to make by immortalizing B-lymphocytes. Furthermore, it is especially difficult to generate human mAbs directed against human antigens (anti-self antibodies), for example antibodies against soluble TNF to block septic shock, against membrane-bound carcinoembryonic antigen to image colorectal carcinoma, or against lymphocyte antigens to destroy tumour in lymphoma. This difficulty results from immunological tolerance mechanisms that prevent the antigen-driven expansion of B-cell clones with self specificities. After antibody gene rearrangement, virgin B-cells may display antibodies with self-reactivity, but tolerance mechanisms can lead to their deletion or to their anergy. It has been suggested that cells may be anergized if the antigen is soluble, but deleted if the antigen is membrane bound. B-cell tolerance does not seem to occur when concentrations of soluble antigen are low (in contrast to T-cell tolerance) and B-cells with poor affinities for antigen are not tolerized, even at higher antigen concentrations. Such non-tolerized B-cells are not usually expanded because they lack T-cell help, although proliferation can be induced artificially by using polyclonal B-cell activators. are engaged in making autoantibodies. However, the `natural autoantibodies` produced do not lend themselves to therapeutic use as they are often IgM, low affinity and polyreactive." (Citations omitted.)
Although the Griffiths et al. article speaks of "human self-antibodies with high specificity," only single-chain V.sub.H and V.sub.L fragments are actually disclosed. Moreover, there is no disclosure in the article that any of the heavy/light-chain combinations mentioned therein are actually from one human antibody. Moreover, the human antibody fragments disclosed all have relatively low affinities, i.e., K.sub.a s below 2.times.10.sup.7 M.sup.-1 and most below 10.sup.7 M-.sup.1.
SUMMARY OF THE INVENTION
The present invention is directed to human monoclonal a
REFERENCES:
patent: 4946778 (1990-08-01), Ladner et al.
Roitt, I.M. (ed.) Essential Immunology, 1991. (pp. 141-142).
Svenson, M et al. 1992. Cytokine 4:125-133.
Pascual. V. et al. 1990. J. Clin. Invest. 86:1320-1328.
Goding, J.W (ed.) 1986. Monoclonal Antibodies: Principles & Practice.
Banchereau Jacques
Djossou Odile
Fossiez Francois
Garrone Pierre
Davis Minh-Tam
Feisee Lila
Foulke Cynthia L.
Schering Corporation
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