CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors.

PURPOSE: CD137 is a T- and NK-cell costimulatory receptor involved in consolidating immunologic responses. The potent CD137 agonist urelumab has shown clinical promise as a cancer immunotherapeutic but development has been hampered by on-target off-tumor toxicities. A CD137 agonist targeted to the prostate-specific membrane antigen (PSMA), frequently and highly expressed on castration-resistant metastatic prostate cancer (mCRPC) tumor cells, could bring effective immunotherapy to this immunologically challenging to address disease. EXPERIMENTAL DESIGN: We designed and manufactured CB307, a novel half-life extended bispecific costimulatory Humabody VH therapeutic to elicit CD137 agonism exclusively in a PSMA-high tumor microenvironment (TME). The functional activity of CB307 was assessed in cell-based assays and in syngeneic mouse antitumor pharmacology studies. Nonclinical toxicology and toxicokinetic properties of CB307 were assessed in a good laboratory practice (GLP) compliant study in cynomolgus macaques. RESULTS: CB307 provides effective CD137 agonism in a PSMA-dependent manner, with antitumor activity both in vitro and in vivo, and additional activity when combined with checkpoint inhibitors. A validated novel PSMA/CD137 IHC assay demonstrated a higher prevalence of CD137-positive cells in the PSMA-expressing human mCRPC TME with respect to primary lesions. CB307 did not show substantial toxicity in nonhuman primates and exhibited a plasma half-life supporting weekly clinical administration. CONCLUSIONS: CB307 is a first-in-class immunotherapeutic that triggers potent PSMA-dependent T-cell activation, thereby alleviating toxicologic concerns against unrestricted CD137 agonism.

TRYBE®: an Fc-free antibody format with three monovalent targeting arms engineered for long in vivo half-life.

TrYbe® is an Fc-free therapeutic antibody format, capable of engaging up to three targets simultaneously, with long in vivo half-life conferred by albumin binding. This format is shown by small-angle X-ray scattering to be conformationally flexible with favorable 'reach' properties. We demonstrate the format's broad functionality by co-targeting of soluble and cell surface antigens. The benefit of monovalent target binding is illustrated by the lack of formation of large immune complexes when co-targeting multivalent antigens. TrYbes® are manufactured using standard mammalian cell culture and protein A affinity capture processes. TrYbes® have been formulated at high concentrations and have favorable drug-like properties, including stability, solubility, and low viscosity. The unique functionality and inherent developability of the TrYbe® makes it a promising multi-specific antibody fragment format for antibody therapy.

Circular economy and the matter of integrated resources.

A circular economy offers solutions for global sustainability challenges through the transition from the linear take-make-use-dispose economy to a better organisation of resources. However, realising a circular economy has ran into various biophysical constraints. Circular economy implementation is shaped by the Ellen MacArthur Foundation's butterfly diagram that depicts 'biological' and 'technical' flows as separate cycles, subsequently interpreted as organic materials circulating in open loop systems via the environment and inorganic materials circulating in closed loop systems within society. Conversely, in our view, resource flows often contain tightly bound combinations of organic and inorganic materials either due to their natural composition or due to their technical design. Building on this observation, a new diagram is proposed that broadens the scope of the circular economy to cover extractive sectors and the return of materials from anthropogenic use to natural reserves, thereby reshaping the conceptual space within which solutions such as effective zero-waste-residue technologies, business models, and policies can be developed for the optimal management of integrated resources from a whole-system perspective. The diagram offers a realistic outlook on the biophysical limitations of circularity and endeavours to inspire discussion that supports the transition towards a sustainable circular economy.

Advances and bottlenecks in microbial hydrogen production.

Biological production of hydrogen is poised to become a significant player in the future energy mix. This review highlights recent advances and bottlenecks in various approaches to biohydrogen processes, often in concert with management of organic wastes or waste CO2 . Some key bottlenecks are highlighted in terms of the overall energy balance of the process and highlighting the need for economic and environmental life cycle analyses with regard also to socio-economic and geographical issues.

PI3K inhibitors as potential therapeutics for autoimmune disease.

Aberrant overactivation of the immune system can give rise to chronic and persistent self-attack, culminating in autoimmune disease. This is currently managed therapeutically using potent immunosuppressive and anti-inflammatory drugs. Class I phosphoinositide 3-kinases (PI3Ks) have been identified as ideal therapeutic targets for autoimmune diseases given their wide-ranging roles in immunological processes. Recent studies into the function of selective PI3K inhibitors in vitro and in vivo have yielded encouraging results, allowing progression into the clinic. Here, we review their recent progress across a range of autoimmune diseases.