Therapeutic high affinity T cell receptor targeting a KRAS cancer neoantigen.

Neoantigens derived from somatic mutations are specific to cancer cells and are ideal targets for cancer immunotherapy. KRAS is the most frequently mutated oncogene and drives the pathogenesis of several cancers. Here we show the identification and development of an affinity-enhanced T cell receptor (TCR) that recognizes a peptide derived from the most common KRAS mutant, KRAS, presented in the context of HLA-A*11:01.

Bispecific Targeting of PD-1 and PD-L1 Enhances T-cell Activation and Antitumor Immunity.

The programmed cell death protein 1 receptor (PD-1) and programmed death ligand 1 (PD-L1) coinhibitory pathway suppresses T-cell-mediated immunity. We hypothesized that cotargeting of PD-1 and PD-L1 with a bispecific antibody molecule could provide an alternative therapeutic approach, with enhanced antitumor activity, compared with monospecific PD-1 and PD-L1 antibodies. Here, we describe LY3434172, a bispecific IgG1 mAb with ablated Fc immune effector function that targets both human PD-1 and PD-L1.

Characterization of 7A5: A Human CD137 (4-1BB) Receptor Binding Monoclonal Antibody with Differential Agonist Properties That Promotes Antitumor Immunity.

The CD137 receptor plays a key role in mediating immune response by promoting T cell proliferation, survival, and memory. Effective agonism of CD137 has the potential to reinvigorate potent antitumor immunity either alone or in combination with other immune-checkpoint therapies. In this study, we describe the discovery and characterization of a unique CD137 agonist, 7A5, a fully human IgG1 Fc effector-null monoclonal antibody.

Correction to: Discovery and preclinical characterization of the antagonist anti-PD-L1 monoclonal antibody LY3300054.

Unfortunately, after publication of this article [1], it was noticed that corrections to the legends of Figs. 1 and 2 were not correctly incorporated. The correct legends can be seen below.

Discovery and preclinical characterization of the antagonist anti-PD-L1 monoclonal antibody LY3300054.

Background: Modulation of the PD-1/PD-L1 axis through antagonist antibodies that block either receptor or ligand has been shown to reinvigorate the function of tumor-specific T cells and unleash potent anti-tumor immunity, leading to durable objective responses in a subset of patients across multiple tumor types.

Results: Here we describe the discovery and preclinical characterization of LY3300054, a fully human IgG1λ monoclonal antibody that binds to human PD-L1 with high affinity and inhibits interactions of PD-L1 with its two cognate receptors PD-1 and CD80. The functional activity of LY3300054 on primary human T cells is evaluated using a series of in vitro T cell functional assays and in vivo models using human-immune reconstituted mice.

Molecular Basis for Necitumumab Inhibition of EGFR Variants Associated with Acquired Cetuximab Resistance.

Acquired resistance to cetuximab, an antibody that targets the EGFR, impacts clinical benefit in head and neck, and colorectal cancers. One of the mechanisms of resistance to cetuximab is the acquisition of mutations that map to the cetuximab epitope on EGFR and prevent drug binding. We find that necitumumab, another FDA-approved EGFR antibody, can bind to EGFR that harbors the most common cetuximab-resistant substitution, S468R (or S492R, depending on the amino acid numbering system).

Comparison of predicted extinction coefficients of monoclonal antibodies with experimental values as measured by the Edelhoch method.

Pace et al. (1995) [1] recommended an equation used to predict extinction coefficient of a protein. However, no antibody data was included in the development of this equation.

Backbone flexibility of CDR3 and immune recognition of antigens.

Conformational entropy is an important component of protein-protein interactions; however, there is no reliable method for computing this parameter. We have developed a statistical measure of residual backbone entropy in folded proteins by using the ϕ-ψ distributions of the 20 amino acids in common secondary structures. The backbone entropy patterns of amino acids within helix, sheet or coil form clusters that recapitulate the branching and hydrogen bonding properties of the side chains in the secondary structure type.

A universal combinatorial design of antibody framework to graft distinct CDR sequences: a bioinformatics approach.

Antibody (Ab) humanization is crucial to generate clinically relevant biologics from hybridoma-derived monoclonal antibodies (mAbs). In this study, we integrated antibody structural information from the Protein Data Bank with known back-to-mouse mutational data to build a universal consensus of framework positions (10 heavy and 7 light) critical for the preservation of the functional conformation of the Complimentarity Determining Region of antibodies. On the basis of FR consensus, we describe here a universal combinatorial library suitable for humanizing exogenous antibodies by CDR-grafting.

Combinations of affinity-enhancing mutations in a T cell receptor reveal highly nonadditive effects within and between complementarity determining regions and chains.

Understanding the energetic and structural response to multiple mutations in a protein-protein interface is a key aspect of rational protein design. Here we investigate the cooperativity of combinations of point mutations of a T cell receptor (TCR) that binds in vivo to HLA-A2 MHC and a viral peptide. The mutations were obtained from two sources: a structure-based design study on the TCR alpha chain (nine mutations) and an in vitro selection study on the TCR beta chain (four mutations).

Structure-based design of a T-cell receptor leads to nearly 100-fold improvement in binding affinity for pepMHC.

T-cell receptors (TCRs) are proteins that recognize peptides from foreign proteins bound to the major histocompatibility complex (MHC) on the surface of an antigen-presenting cell. This interaction enables the T cells to initiate a cell-mediated immune response to terminate cells displaying the foreign peptide on their MHC. Naturally occurring TCRs have high specificity but low affinity toward the peptide-MHC (pepMHC) complex.

Overexpression of wild-type activin receptor alk4-1 restores activin antiproliferative effects in human pituitary tumor cells.

Activin is a member of the TGF beta family of cytokines involved in the control of cell proliferation. We have previously shown that the majority of clinically nonfunctioning pituitary tumors do not respond to activin-induced growth suppression. Human pituitary tumors specifically express alternatively spliced activin type I receptor Alk4 mRNAs, producing C-terminus truncated isoforms designated Alk4-2, 4-3, and 4-4.