Multispecific antibodies binding to human CD40 and human CD137, methods for preparing such multispecific antibodies, and methods of using such multispecific antibodies for therapeutic or other purposes.

The present invention relates to novel binding agents and their use in medicine. In particular, the invention relates to binding agents such as bispecific antibodies binding human PD-L1 and binding human CD137. The invention furthermore relates to uses of the antibodies of the invention and to methods, nucleic acid constructs and host cells for producing antibodies of the invention.

The present disclosure provides antibody sequences found in antibodies that bind to human CD38. In particular, the present disclosure provides sequences of anti-human CD38 antibodies. Antibodies and antigen-binding portions thereof including such sequences present features compatible with pharmaceutical manufacturing and development can be provided as fully human antibodies (e.g., fully human monoclonal antibodies or antigen-binding fragments) that can be useful for medical methods and compositions, in particular for treating cancer.

The present invention relates to a method for reducing or preventing progression of a tumor or treating cancer. The method comprises administering to a subject, a binding agent comprising a first binding region binding to human CD137 and a second binding region binding to human PD-L1. The amount of binding agent administered in each treatment cycle is preferably about 0.3-5 mg/kg body weight or about 25-400 mg in total.

The invention provides methods for the treatment of cancer. The invention also provides a method for identifying a subject whose cancer is likely to respond to combination ICOS agonist and PD1 antagonist therapy, the method comprising determining the RNA signature (Table 1) score of a sample of the cancer of the subject.

The present disclosure provides a cytokine-based bioactivatable drug construct (“VitoKine”) platform that aims to reduce systemic mechanism-based toxicities and lead to broader therapeutic utility for proteins and cytokines such as IL-15 and IL-2 for the treatment of cancer, autoimmune diseases, inflammatory diseases, viral infection, transplantation and various other disorders. The novel VitoKine constructs of the present invention comprise: 1) a tissue or disease site targeting moiety D1 domain (“D1”), 2) a bioactivatable moiety D2 domain (“D2”), and a concealing moiety D3 domain (“D3”). Importantly, because the “active moiety” of the VitoKine construct will remain inert until activated locally by proteases that are upregulated in diseased tissues, this will limit binding of the active moiety to the receptors or to the targets in the peripheral or on the cell-surface of non-diseased cells and tissue to prevent over-activation of the pathway and reduce undesirable “on-target” “off tissue” toxicities. Additionally, the inertness of the VitoKine active moiety prior to protease activation will significantly decrease the potential antigen or target sink, and thus, prolong the in vivo half-life and result in improved biodistribution, bioavailability and therapeutic efficacy.

Isolated or recombinant monoclonal antibodies that bind to 4-1BB are provided. In son cases, antibodies of the embodiments can be used for the detection, diagnosis and/or therapeutic treatment of human diseases, such as cancer.

Implantable scaffolds that treat solid tumors and escape variants and that provide effective vaccinations against cancer recurrence are described. The scaffolds include genetically-reprogrammed lymphocytes and a lymphocyte-activating moiety.

The present disclosure is directed to a method of treating or preventing diabetes, prediabetes, and/or glucose intolerance using TNF Receptor Superfamily Member 25 (TNFRSF25) agonistic antibody or antigen binding fragment thereof. The disclosure is also directed to methods for increasing graft survival and for treating or preventing graft-versus-host disease (GVHD) using TNFRSF25 agonistic antibody.

Methods are provided for targeting cells for depletion, including without limitation tumor cells, in a regimen comprising contacting the targeted cells with a combination of agents that modulate immunoregulatory signaling. Immunoregulatory modulating agents include (i) an agent that blockades CD47 activity; and (ii) an agent that agonizes an immune costimulatory molecule, e.g. CD137. The regimen may further comprise an agent that specifically binds to the target cell, e.g. an antibody or biologically active fragment or derivative thereof. The level of depletion of the targeted cell is enhanced relative to a regimen in which a single immunoregulatory modulating agent is used; and the effect may be synergistic relative to a regimen in which a single immunoregulatory modulating agent is used.