University of Southampton

Cancer Research Technology Limited

Genmab A+s

Martin John Glennie

Aymen Al-Shamkhani

Mark Steven Cragg

Ingrid Teige

Stephen Beers

Alison Louise Tutt

Sean Lim

Paul Parren

Peter David Johnson

Jessica Teeling

Ali Roghanian

Jane Elizabeth Willoughby

Ruth Rosemary French

Hak Tak Claude Chan

Sigrid Ruuls

Ole D Baadsgaard

Jorgen Petersen

Haichun Huang

Jan Van De Winkel

Ole Baadsgaard

Arnout F Gerritsen

Yvo Graus

Jørgen Petersen

Jan G J Van De Winkel

Björn Frendéus

Linda Mårtensson

Aymen Al-shamkhani

Juliet Gray

Ann White

Bjoern Frendeus

Ole D M Sc Baadsgaard

Björn Frendeus

Jan GJ Van De Winkel

Ole DM Sc Baadsgaard

Jessica Woodmill Cottage Teeling

The disclosure relates to a method of treatment or prevention of B-cell related disease in a subject comprising the administration of a binding molecule capable of binding to a B-cell and promoting killing of the B-cell; and an immunostimulatory agent arranged to stimulate effector lymphocytes, such as NK and/or T cells. Additionally, an anti-CD27 binding agent for use in a combination therapy with an anti-CD20 binding agent for the treatment or prevention of B-cell related disease in a subject. The disclosure also relates to a method of treatment or prevention of cancer in a subject comprising the administration of a cancer-cell-depleting binding agent capable of binding to the cancer cell and promoting killing of the cancer cell; and an immunostimulatory agent arranged to stimulate NK and/or T-cell activation. Additionally, an anti-CD27 binding agent for use in a combination therapy with a cancer-cell-depleting binding agent for the treatment or prevention of cancer in a subject.

Cancer and B-cell related disease therapy

The invention relates to antibodies specific for 4-1BB and OX40, as well as to methods for using such antibodies and therapeutic uses thereof.

Immunomodulatory antibodies

The invention provides a method of treating a patient having target cells that express Fc&#x3b3;RIIb, the method comprising administering (i) an antibody molecule that specifically binds a surface antigen of the target cell, which antibody molecule has an Fc domain capable of binding Fc&#x3b3;RIIb; in combination with (ii) an agent that prevents or reduces binding between the Fc domain of the antibody molecule and Fc&#x3b3;RIIb; characterized in that the patient is selected on the basis that their target cells express an elevated level of Fc&#x3b3;RIIb.

Combined use of Fc&#x3b3;RIIb (CD32B) and CD20 specific antibodies

Described is the sequential administration of first a Treg depleting antibody molecule selected from antibody molecules, such as an antibody molecule binding specifically to target belonging to the tumour necrosis factor receptor superfamily (TNFRSF), such as a Treg depleting anti-4-1 BB antibody or a Treg depleting OX-40 antibody, and then an immunostimulatory antibody molecule, such as an immunostimulatory anti-4-1 BB anti-body or an immunostimulatory OX-40 antibody, for use in the treatment of cancer. Described are also novel anti-4-1 BB antibodies and novel OX-40 antibodies that may be used in such sequential administration.

Combination of a Treg depleting anti-4-1BB antibody and anti-PD1 antibody

Through a combination of in vitro and in vivo approaches, the inventors show that human IgG2 (h2) delivers unique Fc&#x3b3;R-independent agonistic activity to anti-CD40 antibodies and to antibodies specific to other immunostimulatory receptors, including 4-1BB and CD28. Investigation of an anti-human CD40 mAb, LOB7.4, revealed that the unique activity of h2 was dependent upon the precise arrangement of hinge and CH1 disulfide bonds. Chemical 'shuffling' or mutagenesis to 'lock' LOB7.4 into either a more flexible &#x2018;h2A&#x2019; or more compact &#x2018;h2B&#x2019; conformation endowed antagonistic and agonistic properties, respectively. Engineering of h2 in this way allows development of reagents with either immunostimulatory or immunosuppressive characteristics, with direct implication for the design of therapeutic mAb agents and fusion proteins.

Modified antibodies containing modified IGG2 domains which elicit agonist or antagonistic properties and use thereof

The invention provides a method of treating a patient having target cells that express FcyRIIb, the method comprising administering (i) an antibody molecule that specifically binds a surface antigen of the target cell, which antibody molecule has an Fc domain capable of binding FcyRIIb; in combination with (ii) an agent that prevents or reduces binding between the Fc domain of the antibody molecule and FcyRIIb; characterized in that the patient is selected on the basis that their target cells express an elevated level of FcyRIIb.

Combined use of Fc gamma RIIb (CD32B) and CD20-specific antibodies

Methods of inducing T cell proliferation and expansion in vivo for treating conditions wherein antigen-specific T cell immune response are therapeutically desirable such as cancer, infection, inflammation, allergy and autoimmunity and for enhancing the efficacy of vaccines are provided. These methods comprise the administration of at least one CD27 agonist, preferably an agonistic CD27 antibody, alone or in association with another moiety such as immune stimulant or immune modulator such as an anti-CD40, OX-40, 4-1BB, or CTLA-4 antibody or an agent that depletes regulatory cells, or a cytokine. These mono and combination therapies may also optionally include the administration of a desired antigen such as a tumor antigen, an allergen, an autoantigen, or an antigen specific to an infectious agent or pathogen against which a T cell response (often CD8+) is desirably elicited.

Human immune therapies using a CD27 agonist in combination with another immune agonist to treat cancer

Human immune therapies using a CD27 agonist alone or in combination with other immune modulators

Isolated human monoclonal antibodies which bind to and inhibit human CD20, and related antibody-based compositions and molecules, are disclosed. The human antibodies can be produced by a transfectoma or in a non-human transgenic animal, e.g., a transgenic mouse, capable of producing multiple isotypes of human monoclonal antibodies by undergoing V-D-J recombination and isotype switching. Also disclosed are pharmaceutical compositions comprising the human antibodies, non-human transgenic animals and hybridomas which produce the human antibodies, and therapeutic and diagnostic methods for using the human antibodies.

Human monoclonal antibodies against CD20

Methods of inducing T cell proliferation and expansion in vivo for treating conditions wherein antigen-specific T cell immune response are therapeutically desirable such as cancer, infection, inflammation, allergy and autoimmunity and for enhancing the efficacy of vaccines are provided. These methods comprise the administration of at least one CD27 agonist, preferably an agonistic CD27 antibody, alone or in association with another moiety such as immune stimulant or immune modulator such as an anti-CD40, OX-40, 4-IBB, or CTLA-4 antibody or an agent that depletes regulatory cells, or a cytokine. These mono and combination therapies may also optionally include the administration of a desired antigen such as a tumor antigen, an allergen, an autoantigen, or an antigen specific to an infectious agent or pathogen against which a T cell response (often CD8+) is desirably elicited.

Isolated human monoclonal antibodies which bind to and inhibit human CD20, and related antibody-based compositions and molecules, are disclosed. Also disclosed are pharmaceutical compositions comprising the human antibodies, and therapeutic and diagnostic methods for using the human antibodies.

Growing community of inventors

Southampton, United Kingdom

Martin John Glennie