Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.

Antibodies directed to polysaccharide (PS) antigens of bacteria are crucial to host immunity to infection. The isotypes of antibodies made to PS, however, are restricted primarily to IgM and IgG1 and IgG2 in man and to IgM and IgG3 in mice. Using sequential sublining and sib selection, an IgG1 murine monoclonal antibody that has variable regions identical to those of a parent IgG3 monoclonal antibody directed to the high-molecular-weight component of the O-specific side chain of Pseudomonas aeruginosa immunotype 1 lipopolysaccharide was derived. These antibodies differed markedly in their antigen binding and effector functions. IgG3 was superior in binding to multivalent PS both in purified and whole bacterial form, fixation of the third component of complement to the bacterial surface, and opsonization of P. aeruginosa for uptake by both murine and human phagocytes. These data suggest that the IgG subclass of these murine anti-LPS antibodies is an important determinant of both avidity for multivalent antigen and biologic function.

The lack of a robust small-animal model for hepatitis C virus (HCV) has hindered the discovery and development of novel drug treatments for HCV infections. We developed a reproducible and easily accessible xenograft mouse efficacy model in which HCV RNA replication is accurately monitored in vivo by real-time, noninvasive whole-body imaging of gamma-irradiated SCID mice implanted with a mouse-adapted luciferase replicon-containing Huh-7 cell line (T7-11). The model was validated by demonstrating that both a smallmolecule NS3/4A protease inhibitor (BILN 2061) and human alpha interferon (IFN-␣) decreased HCV RNA replication and that treatment withdrawal resulted in a rebound in replication, which paralleled clinical outcomes in humans. We further showed that protease inhibitor and IFN-␣ combination therapy was more effective in reducing HCV RNA replication than treatment with each compound alone and supports testing in humans. This robust mouse efficacy model provides a powerful tool for rapid evaluation of potential anti-HCV compounds in vivo as part of aggressive drug discovery efforts.Human liver disease caused by hepatitis C virus (HCV) has emerged as a major challenge to public health, affecting an estimated 175 million people worldwide (2). Greater than 50% of infections lead to chronic liver disease with a risk of developing liver cirrhosis and hepatocellular carcinoma (1). Infection with HCV has also been identified as the most common indication for liver transplantation in the United States and Europe (9). Treatment options for chronic HCV infection are limited to a combination of pegylated alpha interferon (IFN-␣) and ribavirin (RB) (11), which is only partially effective and is often associated with troublesome side effects. Patients with genotype 1 HCV, the predominant genotype worldwide, are the most resistant to . Thus, development of novel therapies for HCV is greatly needed, yet has progressed slowly.HCV is an enveloped, positive-strand RNA virus and a member of the family Flaviviridae (10). Efficient replication of an HCV subgenomic replicon in in vitro cell culture has provided a valuable tool for molecular characterization of HCV, investigating virus host interactions, screening antiviral compounds, and developing new drug targets (4,26,29). Recently, an in vitro cell culture system capable of producing an infectious genotype 2a HCV has also been described (25,39,41). While the cell-based assays have provided a useful tool for screening compounds, they have not proved sufficient to predict the activity of compounds in vivo (21,35,38). The limited pipeline of new HCV antivirals may, in part, be attributed to the absence of robust small-animal models, which are typically used for simultaneously assessing drug action, efficacy, and toxicity. Difficulty in developing animal models is largely a result of the narrow host range of HCV, which infects only humans and chimpanzees. Over the past few years, several small-animal models such as the HCV-Trimera and chimeric scid-Alb/uPA Hepatech mouse models h...

Mucoid strains of Pseudomonas aeruginosa are the major pulmonary pathogens for cystic fibrosis patients. Opsonizing antibodies to the mucoid exopolysaccharide (MEP) antigen may protect animals and some cystic fibrosis patients from infection. However, MEP does not readily elicit opsonic antibodies either during chronic infection or after vaccination. To evaluate alternative means to induce opsonic antibodies, a murine monoclonal anti-idiotypic antibody directed to an opsonic monoclonal antibody specific to MEP was produced. The anti-idiotypic antibody bound to F(ab')2 fragments of the opsonic antibody, blocked binding to MEP, bound to cross-reactive idiotopes on human opsonic antibodies to MEP, and elicited MEP-specific antibodies in syngeneic and allogeneic mice. These anti-idiotype-induced, MEP-specific antibodies fixed complement to mucoid P. aeruginosa cells and opsonized them for phagocytic killing by human leukocytes. These studies demonstrate the potential utility of anti-idiotypic monoclonal antibody for generating protective immunity against bacterial polysaccharides.