The identification of immunosuppressive factors within human tumor microenvironments, and the ability to block these factors, would be expected to enhance patients’ anti-tumor immune responses. We previously established that an unidentified factor, or factors, present in ovarian tumor ascites fluids reversibly inhibited the activation of T cells by arresting the T cell signaling cascade. Ultracentrifugation of the tumor ascites fluid has now revealed a pellet that contains small extracellular vesicles (EV) with an average diameter of 80nm. The T cell arrest was determined to be causally linked to phosphatidylserine (PS) that is present on the outer leaflet of the vesicle bilayer, as a depletion of PS expressing EV or a blockade of PS with anti-PS antibody significantly inhibits the vesicle induced signaling arrest. The inhibitory EV were also isolated from solid tumor tissues. The presence of immune suppressive vesicles in the microenvironments of ovarian tumors and our ability to block their inhibition of T cell function represent a potential therapeutic target for patients with ovarian cancer.
Abstract. The administration of therapeutic proteins via the subcutaneous route (sc) is desired for compliance and convenience, but could be challenging due to perceived immunogenic potential or unwanted immune responses. There are clinical and preclinical data supporting as well as refuting the generalized notion that sc is more immunogenic. We provide a mechanistic perspective of immunogenicity of therapeutic proteins administered via the sc route and discuss strategies and opportunities for novel therapeutic approaches to mitigate immunogenicity.KEY WORDS: biotechnology; immunogenicity; mitigation of immunogenicity; protein therapeutics; subcutaneous administration. IMMUNOGENICITY OF PROTEINS GIVEN VIA SC ROUTEThe subcutaneous (sc) route of administration of therapeutic proteins is desired over the intravenous (iv) route due to patient comfort and compliance. In addition, it could also prolong half-life of the therapeutic in circulation (1,2). However, this route of administration could be problematic due to a perceived potential for unwanted immunogenicity (3). As most of the vaccines are given via the sc route, it is expected that the sc route is more immunogenic than the iv route. However, a recent comparative clinical study of sc vs iv administration of abatacept, a fusion protein of Fc of human IgG and extracellular domain of CTLA-4, showed that the efficacy and immunogenicity are comparable between the two routes of administration (4,5). However, the immunogenic potential of chronic administration and long-term effects are not often adequately addressed during clinical trials (6). Few preclinical studies have shown that the sc route of administration does not increase immunogenicity (7-9). For example, the relative immunogenicity of Betaseron, interferon beta, is less for sc administration compared to iv administration (9). Based on clinical experience of head-to-head comparison and a few preclinical studies, one could argue that the generalization that the sc route is more immunogenic than the iv route is not universally valid.A comparative immunogenicity study of three brands of insulin in type 1 diabetics showed an increase in incidence of anti-insulin titer development, across brands, in patients selfadministering via sc route as compared to iv administration in hospital in the same cohort (10). In the therapeutic use of erythropoietin-α, incidence of immunogenicity increased with the change from iv to sc. It is appropriate to mention here that elimination of human serum albumin from the formulation as well as stopper material change (11) coincided with changes in route of administration, and thus, the effect of the sc route of administration on immunogenicity is not unambiguous for erythropoietin. There are several examples from preclinical relative immunogenicity studies that show the sc route is more immunogenic than the iv route. The sc administration of FVIII showed significantly higher total antibody titers compared to hemophilia A mice that were given FVIII via the iv route (12). A similar ob...
Subcutaneous administration of biologics is highly desirable; however, incomplete bioavailability after sc administration remains a major challenge. In this work we investigated the effects of excipient dependent hyper-osmolarity on lymphatic uptake and plasma exposure of rituximab as a model protein. Using Swiss Webster (SW) mice as our animal model, we compared the effects of NaCl, mannitol and, O-Phospho-L-Serine (OPLS) on plasma concentration of rituximab over 5 days after sc administration. We observed an increase in plasma concentrations in animals administered rituximab in hypertonic buffer solutions, as compared to isotonic buffer. Bioavailability, as estimated by our pharmacokinetic model, increased from 29% in isotonic buffer to 54% in hypertonic buffer containing NaCl, to almost complete bioavailability in hypertonic buffers containing high dose OPLS or mannitol. This improvement in plasma exposure is due to improved lymphatic trafficking as evident from the increase in the fraction of dose trafficked through the lymph node in the presence of hypertonic buffers. The fraction of the dose trafficked through the lymphatic, as estimated by the model, increased from 0.05 % in isotonic buffer to 13% in hyper-tonic buffer containing NaCl to about 30% for hypertonic buffers containing high dose OPLS and mannitol. Our data suggests that hypertonic solutions may be a viable option to improve sc bioavailability.
Subcutaneous route of administration is highly desirable for protein therapeutics. It improves patient compliance and quality of life1,2, while reducing healthcare cost2. Recent evidence also suggests that sc administration of protein therapeutics can increase tolerability to some treatments such as intravenous immunoglobulin therapy (IVIG) by administering it subcutaneously (subcutaneous immunoglobulin therapy SCIG), which will reduce fluctuation in plasma drug concentration3. Furthermore, sc administration may reduce the risk of systemic infections associated with iv infusion1,2. This route, however, has its challenges especially for large multi-domain proteins. Poor bioavailability and poor scalability from preclinical models are often cited. This commentary will discuss barriers to sc absorption as well as physiological and experimental factors that could affect pharmacokinetics of subcutaneously administered large protein therapeutics in preclinical models. A mechanistic pharmacokinetic model is proposed as a potential tool to address the issue of scalability of sc pharmacokinetic from preclinical models to humans
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