ABSTRACT
Progress in cytokine engineering is driving therapeutic translation by overcoming the inherent limitations of these proteins as drugs. The interleukin-2 (IL-2) cytokine harbors great promise as an immune stimulant for cancer treatment. However, the cytokine's concurrent activation of both pro-inflammatory immune effector cells and anti-inflammatory regulatory T cells, its toxicity at high doses, and its short serum half-life have limited clinical application. One promising approach to improve the selectivity, safety, and longevity of IL-2 is complexation with anti-IL-2 antibodies that bias the cytokine towards the activation of immune effector cells (i.e., effector T cells and natural killer cells). Although this strategy shows therapeutic potential in preclinical cancer models, clinical translation of a cytokine/antibody complex is complicated by challenges in formulating a multi-protein drug and concerns about complex stability. Here, we introduce a versatile approach to designing intramolecularly assembled single-agent fusion proteins (immunocytokines, ICs) comprising IL-2 and a biasing anti-IL-2 antibody that directs the cytokine's activities towards immune effector cells. We establish the optimal IC construction and further engineer the cytokine/antibody affinity to improve immune biasing function. We demonstrate that our IC preferentially activates and expands immune effector cells, leading to superior antitumor activity compared to natural IL-2 without inducing toxicities associated with IL-2 administration. Collectively, this work presents a roadmap for the design and translation of immunomodulatory cytokine/antibody fusion proteins.
ABSTRACT
Recent studies of persons with spinal cord injury (SCI) report higher conversion rates of the American Spinal Injury Association (ASIA) Impairment Scale (AIS) grades, especially for complete injuries. We examined the rate of conversion over time after complete SCI, accounting for demographic and injury characteristics. Subjects were 16 years of age and older with a complete SCI injury between 1995 and 2015, enrolled in the National SCI Database as day-1 admissions. We grouped subjects into 3-year intervals and assessed trends in conversion for the total sample and by tetraplegia (Tetra), high paraplegia (levels T1-9, HPara), and low paraplegia (levels T10-12, LPara).We used logistic regression to identify factors related to conversion such as age, sex, etiology, and level of injury. Of 2036 subjects, 1876 subjects had a follow-up examination between 30 and 730 days post-injury. Average age at injury was 34.2 ± 14.6 years; 79.8% were male, 44.6% Tetra, 35.3% HPara, and 20.1% LPara. There was a strong trend toward increased rates of conversion over time (p < 0.01 for all groups), especially for Tetra (to incomplete from 17.6% in 1995-1997 to 50% in 2013-2015, and to motor incomplete from 9.4% to 28.1%). Conversion rates for Para were less dramatic. There were increased odds of converting to incomplete for year of injury, level of injury (Tetra >LPara >HPara), non-violent etiology, and age (older is better). We found similar factors for conversion to motor incomplete, except sex was significant and etiology was not. Conversion rates from complete to incomplete and motor incomplete injury have been increasing, particularly for persons with tetraplegia. This has implications for acute clinical trials and for prognostication early after SCI.
ABSTRACT
T-cell receptors (TCRs) recognize pathogens to ignite immune responses, making them attractive scaffolds for development as immunotherapeutics. However, manipulation of TCRs has been impeded by difficulties in their engineering and expression. Wagner and colleagues now establish new platforms to generate high-affinity TCR variants that potently activate T cells, and they also create soluble TCR fusion proteins that specifically recognize cognate peptides. This work provides specific tools to combat cytomegalovirus (CMV) infection and helps illuminate a general path to actuation of engineered TCR-based therapeutics.
