Hoffmann-la Roche Inc.

Maurice Kent Gately

David Howard Presky

Ulrich Andreas Gubler

Jeffrey David Hulmes

Alvin Seth Stern

Richard Anthony Chizzonite

Yu-Ching Eugene Pan

Frank John Podlaski

Gary A Truitt

John Hakimi

Ping Ling

Chang-you Wu

Bruce H Devens

William R Benjamin

The present invention relates to novel p75 heterodimer specific anti-human IL-12 antibodies that are characterized by a higher potency and greater efficacy in neutralizing human IL-12 bioactivity than known heterodimer specific IL-12 monoclonal antibodies. The heterodimer specific antibodies recognize one or more epitopes of the human IL-12 p75 heterodimer, but do not bind to the p40 subunit alone. The heterodimer specific IL-12 antibodies neutralize rhesus monkey IL-12 bioactivity with a potency similar to their potency for neutralizing human IL-12 bioactivity making them useful IL-12 antagonists for in vivo studies in the rhesus monkey.

Methods of treating autoimmune diseases by administering monoclonal antibodies against human IL-12

Antibodies against human IL-12

The present invention is a novel cytokine protein called IL-12 or Cytotoxic Lymphocyte Maturation Factor (CLMF) which is produced and synthesized by human NC-37 B lymphoblastoid cells (American Type Culture Collection, Rockville, Md.). CLMF synergistically induces with low concentrations of IL-2 the cytolytic activity of Lymphokine Activated Killer (LAK) cells, and CLMF is capable of stimulating T-cell growth. Also claimed are the cloned gene for CLMF, its recombination in a suitable vector, the transformed cells containing said vector, the recombinant protein produced by the transformed cells and antibodies to CLMF.

Purification and characterization of cytotoxic lymphocyte maturation factor and monoclonal antibodies thereto

The present invention relates to a novel antibody against the IL-12 receptor and a novel combination of anibodies anainst the IL-12 receptor. The novel anti-IL-12 receptor anbody, designated as 2B10, provided in accordance with the present invention binds to the human IL-12 receptor but which is not capable of inhibiting the binding of human IL-12 to the high affinity human IL-12 receptor and is not capable of neutralizing human IL-12 bioactivity by binding to human IL-12 receptor.

Antibody to interleukin-12 receptor

The present invention relates to antibodies which bind to a novel cytotoxic lymphocyte maturation factor. When bound to the cytotoxic lymphocyte maturation factor, the antibodies can neutralize bioactivity of the factor.

Monoclonal antibodies to cytotoxic lymphocyte maturation factor

Analysis of the culture media of p40-transfected COS cells indicated the presence of 40 kDa monomers and 80 kDa disulfide-linked homodimers. Examination of partially purified p40 recombinant proteins demonstrated that only the homodimer but not the monomer binds to the IL-12 receptor. Partially purified 80 kDa homodimer inhibited [.sup.125 I]IL-12 binding to PHA-activated human lymphoblasts with an IC.sub.50 of 80 ng/ml, which is similar to the IC.sub.50 value (20 ng/ml) for the human IL-12 heterodimer. Although neither the 40 kDa monomer nor the 80 kDa dimer could stimulate human PHA-blast proliferation, the 80 kDa dimer inhibited IL-12-induced proliferation in a dose-dependent manner with an IC.sub.50 of 1 .mu.g/ml. The IL-12 p40 subunit contains the essential epitopes for receptor binding, but they are only active when p40 is covalently associated with a second protein such as p35 or p40. When p40 is associated with the p35 subunit, the heterodimer acts as an agonist mediating biologic activity. When p40 associates with itself, the homodimer behaves as an antagonist.

P-40 homodimer of interleukin-12

The invention relates to pharmaceutical compositions comprising at least one Vitamin D derivative and a method of using the pharmaceutical compositions in suppressing immune responses.

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Parsippany, NJ, United States of America

Maurice Kent Gately