Inhibitors that block the programmed cell death-1 (PD-1) pathway can potentiate endogenous antitumor immunity and have markedly improved cancer survival rates across a broad range of indications. However, these treatments work for only a minority of patients. The efficacy of anti-PD-1 inhibitors may be extended by cytokines, however, the incorporation of cytokines into therapeutic regimens has significant challenges. In their natural form when administered as recombinant proteins, cytokine treatments are often associated with low response rates. Most cytokines have a short half-life which limits their exposure and efficacy. In addition, cytokines can activate counterregulatory pathways, in the case of immune-potentiating cytokines this can lead to immune suppression and thereby diminish their potential efficacy. Improving the drug-like properties of natural cytokines using protein engineering can yield synthetic cytokines with improved bioavailability and tissue targeting, allowing for enhanced efficacy and reduced off-target effects. Using structure guided engineering we have designed a novel class of antibody-cytokine fusion proteins consisting of a PD-1 targeting antibody fused together with an interleukin-21 (IL-21) cytokine mutein. Our bifunctional fusion proteins can block PD-1/programmed death-ligand 1 (PD-L1) interaction whilst simultaneously delivering IL-21 cytokine to PD-1 expressing T cells. Targeted delivery of IL-21 can improve T cell function in a manner that is superior to anti-PD-1 monotherapy. Fusion of engineered IL-21 variants to anti-PD1 antibodies can improve the drug-like properties of IL-21 cytokine leading to improved cytokine serum half-life allowing for less frequent dosing. In addition, we show that targeted delivery of IL-21 can minimize any potential detrimental effect on local antigen-presenting cells. A highly attenuated IL-21 mutein variant (R9E:R76A) fused to a PD-1 antibody provides protection in a humanized mouse model of cancer that is refractory to anti-PD-1 monotherapy. Collectively, our preclinical data demonstrate that this approach may improve upon and extend the utility of anti-PD-1 therapeutics currently in the clinic.

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TlBa2Ca2Cu3O9±δ high Tc thin films were prepared on MgO 〈100〉 surfaces by a combination of laser ablation from a stoichiometric Ba2Ca2Cu3Ox target and the thermal evaporation of thallium oxide. X-ray diffraction measurements showed that the films consisted of predominantly c axis oriented TlBa2Ca2Cu3O9±δ, and scanning electron microscopy revealed that the surfaces had a flat, platelike morphology. The ac inductive measurements indicated that the onset of superconductivity occurred at 117 K with a transition width (10%–90%) of ∼3 K. Zero resistivity was reached at 120 K. The critical current density was ∼3×104 A/cm2 at 110 K.

Chloride impurities in titanium powders are extremely difficult to remove and present a longstanding problem in titanium powder metallurgy. We show that the detrimental effects of chlorides on the sintering of titanium can be mitigated with trace additions of yttrium oxide, which has a high affinity for the normally volatile species and forms highly stable oxychloride reaction products. Compacts that would otherwise exhibit gross swelling and excessive porosity due to chloride impurities can be now sintered to near full density by liquid phase sintering. The potency of yttrium oxide additions is observable at levels as low as 500 ppm. The scavenging of chlorine by Y 2 O 3 appears to be independent of alloy composition and sintering regime. It is effective when used with high-chloride powders such as Kroll sponge fines but ineffective when used with powders containing NaCl impurities or during solid-state sintering. The identification of highly potent chlorine scavengers may enable the future development of chloride-tolerant powder metallurgy (PM) alloys aimed at utilizing low-cost, high-chloride powder feedstocks.