Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy.

Antibodies that target cell-surface molecules on T cells can enhance anti-tumor immune responses, resulting in sustained immune-mediated control of cancer. We set out to find new cancer immunotherapy targets by phenotypic screening on human regulatory T (Treg) cells and report the discovery of novel activators of tumor necrosis factor receptor 2 (TNFR2) and a potential role for this target in immunotherapy. A diverse phage display library was screened to find antibody mimetics with preferential binding to Treg cells, the most Treg-selective of which were all, without exception, found to bind specifically to TNFR2. A subset of these TNFR2 binders were found to agonise the receptor, inducing iκ-B degradation and NF-κB pathway signalling in vitro. TNFR2 was found to be expressed by tumor-infiltrating Treg cells, and to a lesser extent Teff cells, from three lung cancer patients, and a similar pattern was also observed in mice implanted with CT26 syngeneic tumors. In such animals, TNFR2-specific agonists inhibited tumor growth, enhanced tumor infiltration by CD8+ T cells and increased CD8+ T cell IFN-γ synthesis. Together, these data indicate a novel mechanism for TNF-α-independent TNFR2 agonism in cancer immunotherapy, and demonstrate the utility of target-agnostic screening in highlighting important targets during drug discovery.GW, BM, SG, JC-U, AS, AG-M, CB, JJ, RL, AJL, SR, RS, LJ, VV-A, RM and RWW were funded by MedImmune; JP and VB were funded by AstraZeneca PLC; JW, RSA-L and JB were funded by NIHR Cambridge Biomedical Research Centre and Kidney Research UK; JS and JF were funded by Retrogenix Ltd

VRDN-001, a Novel IGF-1R Monoclonal Antibody for the Treatment of Thyroid Eye Disease (TED): a Proposed Adaptive Design for Exploratory Proof of Concept

Adaptive design of clinical trials allows for more efficiency and less subject burden than conventional trials in the exploration of effectiveness and safety of drugs. An adaptive strategy is a scheme that allows for prospectively planned modifications to one or more aspects of the design based on accumulated data from subjects within the trial as it is ongoing. Adaptation is planned before comparative analyses of trial data are conducted, allowing opportunities for modifications to the trial itself. VRDN-001 is a humanized IgG1κ monoclonal antibody that binds specifically and with high affinity to human insulin-like growth factor-1 receptor (IGF-1R) and inhibits receptor activation.VRDN-001 is a humanized IgG1κ monoclonal antibody that binds specifically and with high affinity to human insulin-like growth factor-1 receptor (IGF- 1R) and inhibits receptor activation

VRDN-002, a Second-Generation Insulin Like Growth Factor-1 Receptor (IGF-1R) Antagonist Antibody for Thyroid Eye Disease: Preclinical Pharmacokinetic Profile and Clinical Promise

VRDN-002 is a novel anti-IGF-1R antibody incorporating half-life extension modifications in its Fc region for treatment of Thyroid Eye Disease (TED), a condition driven by Thyroid Stimulating Hormone Receptor (TSHR) agonistic autoantibodies and crosstalk between TSHR and IGF-1R. We compared the pharmacokinetic (PK) parameters of VRDN-002 in cynomolgus monkeys to the marketed IGF-1R antibody, teprotumumab, to project potential human dosing regimens

Structure–Cytotoxicity Relationships of Analogues of <i>N</i>¹⁴-Desacetoxytubulysin H

Herein we report structure–cytotoxicity relationships for analogues of <i>N</i>¹⁴-desacetoxytubulyisn H <b>1</b>. A novel synthetic approach toward <b>1</b> enabled the discovery of compounds with a range of activity. Calculated basicity of the <i>N</i>-terminus of tubulysins was shown to be a good predictor of cytotoxicity. The impact of structural modifications at the C-terminus of <b>1</b> upon cytotoxicity is also described. These findings will facilitate the development of new tubulysin analogues for the treatment of cancer