Background ABBV-181 is a humanized anti-PD1 monoclonal antibody; dose finding and early safety, PK and pharmacodynamic data have been reported (ESMO18). This report summarizes data from the head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) expansion cohorts in the Ph1 FIH study (NCT03000257). Methods Patients (pts) with previously treated, advanced HNSCC and NSCLC received ABBV-181 IV, 250 mg Q2W or 500 mg Q4W to progression. Response was assessed by RECIST v1.1 and iRECIST. Results As of April 2019, 81 pts were dosed. Table . 1288P n (%) HNSCC n = 41 NSCLC n = 40 Median days on treatment, range 72, 1–407 71, 1–421 Dose: 250 mg/500 mg 31/10 19/21 AE any grade 40 (98) 40 (100) Grade (G) ≥3 AE 23 (56) 27 (67) ABBV-181 related G ≥ 3 AE 4 (10) 3 (7) Immune-mediated AE 15 (37) 15 (37) AE resulting in discontinuation of ABBV-181 Malignant neoplasm progresion General physical health Confusion Pneumonitis a Acute kidney injury a Hypothyroidism a Immune-mediated hepatitis a Disturbance in attention Dysponea Intracranial hemorrhage Neoplasm progression Acute respiratory distress syndrome Upper respiratory tract infection 5 (12) 2 (5) 1 (2) 0 0 0 1 (2) 0 0 0 0 1 (2) 1 (2) 0 9 (22) 3 (7) 0 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 0 0 1(2) G 5 AEs b Malignant neoplasm progression Acute respiratory distress syndrome Dyspnea Neoplasm progression Upper respiratory tract infection General physical condition abnormal 7 (17) 4 (10) 1 (2) 0 1 (2) 0 1 (2) 7 (18) 6(15) 0 1 (2) 0 1 (2) 0 a ABBV-181 related. b none considered related to ABBV-181. Most frequent G ≥ 1 AE (n): anemia (20), asthenia (20) and fatigue (16). ABBV-181 PK is approximately dose proportional, with comparable dose-normalized exposures at both doses; trough levels resulted in sustained PD-1 saturation on circulating CD4 T cells. Transient decreases in circulating T cells and increased Ki67+ CD8 T cells and serum CXCL9/CXCL10 were observed at both doses. In pts with ≥ 1 post baseline assessment, responses by investigator: 7/40 HNSCC pts (7 partial response, 6 by RECISTv.1.1, 1 by iRECIST), 6/36 NSCLC (5 PR, 1 complete response, all by RECIST v.1.1). 3 HNSCC and 2 NSCLC responders had PD-L1+ tumors. Conclusions Safety, PK and PD data support dosing ABBV-181 at 250 mg Q2W or 500 mg Q4W with expected biological and pharmacodynamic activity for an anti-PD-1 agent. Efficacy data demonstrate clinical activity per RECISTv.1.1 and iRECIST supporting continued development of ABBV-181. Clinical trial identification NCT03000257. Editorial acknowledgement Fatemeh Atashi (AbbVie employee). Legal entity responsible for the study AbbVie Inc. Funding AbbVie Inc. Disclosure A. Italiano: Advisory / Consultancy: Roche, Daiichi Sankyo, ImmuneDesign, Epizyme, Bayer, Lilly; Honoraria (self): Bayer, Daiichi Sankyo, Lilly, Epizyme, Novartis, Roche; Research grant / Funding (self): Roche, Bayer, AstraZeneca/MedImmune, PharmaMar, MSD Oncology, Merck Serono. P. Cassier: Honoraria (self): Novartis, Roche/Genentech, Blueprint Medicines, Amgen; Research grant / Funding (institution): Novartis, Roche/Genentech, Lilly, Blueprint Medicines, Bayer, AstraZeneca, Celgene, Plexxikon, AbbVie, Bristol-Myers Squibb, Merck Serono, Merck, Sharp and Dohme. C. Lin: Advisory / Consultancy: Novartis, Boehringer Ingelheim, Blueprint Medicines; Travel / Accommodation / Expenses: Lilly, Daiichi Sankyo, BeiGene, Novartis; Honoraria (self): Novartis, Roche, Daiichi Sankyo. K. Peltola: Advisory / Consultancy: Orion Pharma, BMS, MSD, Pfizer, Ipsen and Roche; Shareholder / Stockholder / Stock options: Faron Pharmaceuticals; Speaker Bureau / Expert testimony: BMS, Pfizer, MSD; Speaker Bureau / Expert testimony: Ipsen; Travel / Accommodation / Expenses: Roche and BMS. A. Gazzah: Travel / Accommodation / Expenses: Boehringer, Novartis, Pfizer, Roche. E. Calvo: Advisory / Consultancy: Novartis, Nanobiotix, Janssen-Cilag, PsiOxus, Seattle Genetics, EUSA Pharma, AbbVie, Celgene, AstraZeneca, Guidepoint Global, Roche/Genentech, GLG, Pfizer, Servier, Amcure; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (self): AstraZeneca, BeiGene, Novartis, START, Oncoart Associated, ; Leadership role: President and Founder of Foundation Intheos. D. Tosi: Advisory / Consultancy: Biomarin ; Research grant / Funding (self): Novartis, Astellas, Janssen; Travel / Accommodation / Expenses: Janssen, Pfizer, and Astellas Pharma, Nutricia and Amicus. B. Gao: Advisory / Consultancy: MSD. L. warburton: Travel / Accommodation / Expenses: MSD, Merck. M. Tanner: Advisory / Consultancy: Roche, Novartis and Pfizer; Speaker Bureau / Expert testimony: Roche, Novartis, Pfizer and Amgen. S. Englert: Full / Part-time employment: AbbVie Inc.; Shareholder / Stockholder / Stock options: AbbVie Inc. S. Lambert: Full / Part-time employment: AbbVie Inc.; Shareholder / Stockholder / Stock options: AbbVie Inc. A. Parikh: Shareholder / Stockholder / Stock options: AbbVie Inc.; Full / Part-time employment: AbbVie Inc. D. Afar: Shareholder / Stockholder / Stock options: AbbVie Inc.; Full / Part-time employment: AbbVie Inc. G. Vosganian: Shareholder / Stockholder / Stock options: AbbVie Inc.; Full / Part-time employment: AbbVie Inc. V. Moreno: Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Regeneron/Sanofi; Research grant / Funding (self): Medscape/Bayer. All other authors have declared no conflicts of interest.

Background: ABBV-181 is a humanized, recombinant, IgG1 monoclonal antibody targeting programmed cell death 1 (PD-1), incorporating an Fc mutation to limit FcgR-mediated effector function. Here we present preliminary ABBV-181 monotherapy data. Methods: Patients (pts) with previously treated advanced solid tumors received ABBV-181 to progression at 1, 3, or 10 mg/kg IV Q2W (3 + 3 dose finding phase). Following dose finding, multi-histology, non-small cell lung cancer (NSCLC) and head and neck squamous cell cancer (HNSCC) cohorts were opened. Dose limiting toxicities (DLTs) were assessed on days 1-28 of dose finding focused on immune mediated (IM) events, hemolysis, and cytopenia. Response is assessed Q8W per response evaluation criteria in solid tumors (RECIST v.1.1) and immune RECIST. Results: As of January 15, 2018, 53 pts were treated with ABBV-181: 25 in dose finding, 17, 6, and 5 in multi-histology, HNSCC and NSCLC cohorts, respectively. Median age was 61 (range 27-84) years, 41% male, most frequent diagnoses in dose finding and multi-histology: cholangio, ovarian, breast and cervical carcinoma. Median days on study were 43 (range 1-379), 42 (79%) pts had ≥ 1 adverse event (AE), 22 pts (42%) had grade ≥ 3 AEs and 8 (15%) pts had IM AEs. The most frequent AEs of any grade were: fatigue (18 pts), constipation and vomiting (9 pts each). No DLTs were reported. ABBV-181 was discontinued in 33 (62%) pts, 27 for progression and 1 each for AEs of diabetic ketoacidosis, progression and small intestinal obstruction. PD-L1 was expressed on 7/21 (33%) available pretreatment samples (Dako 28-8 assay with 1% threshold). By investigator assessment, 4/34 (12%) pts with post baseline assessment responded (all in dose finding, all partial responses). Sustained PD-1 saturation on circulating CD4 T cells was observed at all doses. ABBV-181 pharmacokinetics (PK) were approximately dose-proportional in dose finding. Conclusions: ABBV-181 monotherapy demonstrates target engagement and encouraging efficacy without unexpected safety signals. PK and pharmacodynamic data from dose finding support flat doses of 250 mg Q2W, 375 mg Q3W or 500 mg Q4W for expansion. Enrollment in the expansion cohorts continues. Clinical trial identification: NCT03000257. Legal entity responsible for the study: AbbVie Inc. Funding: AbbVie Inc. Disclosure: P.A. Cassier: Honoraria: Novartis, Roche-Genentech, Blueprint Medicines, Amgen; Institution research funding: Novartis, Roche/Genentech, Lilly, Blueprint Medicines, Bayer, AstraZeneca, Celgene, Plexxikon, AbbVie, Bristol-Myers Squibb, Merck Serono, Merck, Sharp and Dohme. K. Peltola: Advisory fees: Orion Pharma, BMS, MSD, Pfizer, Ipsen and Roche; Stock holder: Faron Pharmaceuticals. A.I. Spira: Consultant and institutional research support: AbbVie. M.M.E. Tanner: Finnish advisory board: Roche, Novartis, Pfizer; Speakers bureau: Roche, Novartis, Pfizer, Amgen. D. Afar, S. Englert, A. Parikh, A. Reddy, G. Vosganian: Employee and may own stock: AbbVie. A.W. Tolcher: Consultant: AbbVie. All other authors have declared no conflicts of interest.

Background: ABBV-368 is a novel humanized IgG1 agonist monoclonal antibody specific for human OX40, a TNF receptor superfamily member expressed on activated and memory T-cell subsets, as well as T regulatory cells. The proposed ABBV-368 therapeutic mechanism of action includes activation of T effector cells and inhibition of the suppressive capacity of T regulatory cells. This ongoing first-in-human, phase 1, two-part study (NCT03071757) is investigating the safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary antitumor activity of ABBV-368 in patients (pts) with advanced solid tumors. Methods: Eligible pts include adults (≥18 years) with advanced or metastatic solid tumors. ABBV-368 was administered intravenously in a 3 + 3 dose-escalation design at doses ranging from 0.01 to 3.0 mg/kg every 2 weeks (4 cohorts). PK was assessed in cycle 1 and cycle 3. OX40 receptor saturation, Ki67 proliferation marker expression in peripheral blood immune cell subsets, and additional PD biomarkers were evaluated. Results: As of Feb 12, 2018, 38 pts with advanced or metastatic tumors were enrolled in dose-escalation cohorts. Median age was 65 years (range, 38–78). No dose-limiting toxicities were reported during dose escalation. Overall, 15 (39.5%) pts reported grade (Gr) ≥3 treatment-emergent adverse events (TEAEs). Three (7.9%) pts reported Gr ≥ 3 TEAEs related to ABBV-368. Two investigator-reported immune-related AEs were documented, including hypothyroidism; neither were serious. ABBV-368 PK was approximately dose-proportional from 0.1- to 3-mg/kg doses during cycle 1, with dose-dependent target saturation. Initial antitumor activity has been observed. Updated safety, PK, PD, and efficacy data will be reported. Conclusions: ABBV-368 was well tolerated; a maximum tolerated dose was not reached. Antitumor activity was observed at doses predicted to be biologically active. Further evaluation of ABBV-368 is ongoing in pts with advanced solid tumors. Clinical trial identification: NCT03071757. Editorial acknowledgement: Medical writing support was provided by Mary L. Smith, PhD, CMPP, from TRM Oncology, Atlanta, GA, and funded by AbbVie. Legal entity responsible for the study: AbbVie Inc. Funding: AbbVie Inc. Disclosure: A. Spira: Consultant and Institutional research support: AbbVie. A. Patnaik: Research grants to institution: Merck & Co., Inc. LG; Advisory board member: Merck & Co., Inc., AstraZeneca, AbbVie, Pfizer, Genentech/Roche; Research grant: Bristol-Myers Squibb. A.W. Tolcher: Consultant: AbbVie. M.E. Blaney, A. Parikh, A. Reddy, W. Henner, M. McDevitt, D. Afar: Employee and may own stock: AbbVie. J. Powderly: Employee and leadership role: Carolina BioOncology Institute PLLC; Stock/ownership: Iovance, Juno, Bluebird Bio, Kite Pharma, ZioPharm; Speaker bureau: Genentech, Bristol-Myers Squibb, Merck; Research funding: AstraZeneca, Genentech, Clovis, Corvus, Incyte, AbbVie, Bristol-Myers Squibb, MacroGenics; Patent or intellectual property: Founder of BioCytics, developing T-cell immunotherapies. All other authors have declared no conflicts of interest.

The c-Met receptor is overexpressed in ∼50% of patients (pts) with non-small cell lung cancer (NSCLC). ABBV-399 is a first-in-class antibody-drug conjugate composed of ABT-700, an anti–c-Met antibody, conjugated to monomethyl auristatin E (a microtubule inhibitor). Preclinical data demonstrate that ABBV-399 can deliver a potent cytotoxin directly to c-Met+ tumor cells. ABBV-399 was administered at doses ranging from 2.4 to 3.0 mg/kg (dose expansion and combination cohorts at 2.7 mg/kg) once every 21 days to 29 pts with advanced c-Met+ (immunohistochemistry [IHC] H-score ≥150) NSCLC both as monotherapy (ABBV-399/monotherapy; 16 pts) and in combination with oral erlotinib 150 mg daily (ABBV-399/ERL; 13 pts) (NCT02099058). c-Met expression was assessed by IHC utilizing the SP44 antibody (Ventana; Tucson, AZ, USA). As of April 26, 2017, 16 pts with c-Met+ NSCLC received ≥1 dose of ABBV-399/monotherapy. Monotherapy treatment-related adverse events (TRAEs) occurring in ≥10% of pts (all dose levels and all grades) were fatigue (43.8%), nausea (37.5%), neuropathy (25.0%), vomiting (18.8%), anemia, constipation, and diarrhea (12.5% each). Three of 16 (19%) ABBV-399–treated c-Met+ NSCLC pts had a confirmed partial response (PR) with duration of response (DOR) 3.1, 4.8, and 11.1 months. At week 12, 9 of 16 pts (56.3%) had disease control. TRAEs in ABBV-399/ERL occurring in ≥10% of pts (all grades) were neuropathy (46.2%), nausea (23.1%), fatigue, acneiform rash, dry skin, and diarrhea (15.4% each). Four of 13 (31%) evaluable ABBV-399/ERL–treated c-Met+ pts had a PR (3 confirmed, 1 unconfirmed) with DOR 2.8, 5.3, 4.2+, and 9.1+ months. Three of the 4 pts with PR had EGFR-mutated tumor and recently progressed on TKI. At week 12, 10 of 13 pts (76.9%) had disease control. There were no treatment-related deaths as monotherapy or in combination with erlotinib. Responses were seen in both squamous and non-squamous histology. ABBV-399 is well tolerated at 2.7 mg/kg once every 21 days and has demonstrated antitumor activity in pts with c-Met+ NSCLC both as monotherapy and in combination with erlotinib. Early evidence suggests that ABBV-399 represents a novel treatment paradigm effective against multiple c-Met+ NSCLC molecular subtypes and histologies. Updated efficacy/safety data and c-Met IHC status will be presented. Safety and efficacy data from Q2week dosing of ABBV-399 will also be presented.

The c-Met receptor is overexpressed in multiple tumors. ABBV-399 is a first-in-class ADC composed of ABT-700, a previously described anti–c-Met antibody, conjugated to monomethyl auristatin E (a microtubule inhibitor). Preclinical data support ADC ABBV-399 as a unique strategy to deliver a potent cytotoxin directly to c-Met+ tumor cells (∼30-50% of tumors overexpress c-Met).

Abstract Background: PDL192 is a humanized IgG1 monoclonal antibody that binds the human TWEAK receptor (TweakR). TweakR, a member of the TNFR (Tumor Necrosis Factor Receptor) superfamily, is overexpressed in several human cancers including breast cancer (BC). In BC, it may also play a role in the invasive and metastatic potential of the disease (Willis et al, Mol Cancer Res 2008). In TweakR-expressing cancer cell lines or mouse xenograft models, PDL192 has a potent antitumor effect (Culp et al., CCR 2010). All these data therefore suggest that anti-TweakR targeting could be a promising new therapeutic approach for human BC patients. Material and methods: TweakR expression was assessed by IHC (immunohistochemistry) on 3 Tissue-Micro-Array (TMA) banks of BC samples (basal-like, ERBB2, and luminal A/B), and 25 primary human BC xenografts (HBCx). The cut-off of positivity was defined as at least 25% cells with membraneous or cytoplasmic staining or by a combined score of percentage of positive staining cells x intensity > 50. The in vivo antitumor effect of PDL192 was then assessed on 7 TweakR-positive models (10 mg/kg thrice a week for 3 weeks by intraperitoneal route) in which one in combination with chemotherapy as maintenance therapy, as previsouly reported (Marangoni et al., BJC 2009). Results: TMA analyses showed that TweakR was expressed in 16/37 basal like BC (43%), 23/37 ERBB2-positive BC (62%), and 38/71 luminal BC (54%). A high TweakR expression was correlated with double estrogen receptor- and Her2-positive tumors. Moreover, 13/25 xenografts have been found to be TweakR-positive (52%). Nine human BC models have been treated with PDL192, with 4 models (44%) showing a tumor growth inhibition (TGI) ranging between 59% and 91%. No correlation has been observed between TweakR expression and in vivo TGI. Moreover, when PDL192 was administered in complete remission after chemotherapy (doxorubicin + cyclophosphamide), we observed a highly significant delay of relapse greater than 2 months. Conclusions: TweakR is expressed in 77/145 human BC samples (53%). In in vivo experiments, PDL192 showed potent TGI in 4/9 models, and significantly delayed tumor relapses after chemotherapy-induced complete remission. All these data therefore support the use of anti-TWEAK receptor monoclonal antibodies in the treatment of TweakR-positive BC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1772. doi:10.1158/1538-7445.AM2011-1772

CS1 (CD319) is a member of the signaling lymphocytic activation molecule (SLAM) family of cell-surface proteins. It is expressed on natural killer cells and subsets of T and B cells. As part of a screening program to identify cell-surface proteins expressed in plasma cells, CS1 was identified as a candidate molecule. In this manuscript, we briefly review the cellular biology of CS1 and recent preclinical data that supported the development of elotuzumab, a humanized monoclonal antibody to CS1, as a potential therapeutic antibody for multiple myeloma. This antibody is currently in early-phase clinical trials.

Ewing family tumors (EFTs) are small round blue cell tumors that show features of neuroectodermal differentiation. However, the histogenetic origin of EFTs is still a matter of debate. We used high-density DNA microarrays for the identification of EFT-specific gene expression profiles in comparison with normal tissues of diverse origin. We identified 37 genes that are up-regulated in EFTs compared with normal tissues and validated expression of these genes in EFTs by both conventional and quantitative reverse transcription-polymerase chain reaction. The expression pattern of EFT-associated genes in normal tissues indicated a high similarity between EFTs and fetal and neuronal as well as endothelial tissues and supports the concept that a primitive neural crest-derived progenitor at the transition to mesenchymal and endothelial differentiation is transformed in EFTs. EFT-associated genes could be used for molecular discrimination between EFTs and other small round blue cell tumors and clearly identified a cell line (SK-N-MC) that was initially established as neuroblastoma as being an EFT. Ectopic expression of the EFT-specific EWS-FLI1 fusion protein in human embryonic kidney (HEK293) cells was not sufficient to induce the complete EFT-specific gene expression signature, suggesting that the EFT-specific gene expression profile is not just a consequence of EWS-FLI1 expression but depends on the histogenetic background of the EFT stem cell.

2557 Background: Current treatments for advanced stage prostate cancer are largely ineffectual, resulting in high mortality and morbidity. Experimental strategies to fulfill this unmet medical need include the use of toxin-based antibody-drug conjugates (ADCs) to specifically target cancer cells in vivo. Using gene expression profiling, TMEFF2 was identified as being selective to prostate cancer and was validated as a target suitable for an ADC approach using pre-clinical xenograft models in vivo. Methods: A panel of antibodies specific to TMEFF2 protein was generated. One antibody was selected on the basis of affinity and in vitro functionality as an ADC to undergo further analysis in vivo. Results: TMEFF2, a gene encoding a plasma membrane protein with 2 follistatin-like domains and one EGF-like domain, was found to exhibit a restricted normal tissue expression profile and was determined to be highly over-expressed in prostate cancer. A monoclonal antibody (mAb) raised against TMEFF2 was used in immunohistochemistry (IHC) of clinical specimens confirming significant TMEFF2 protein expression in 73% of primary prostate tumors. The exquisite tissue specificity of TMEFF2 followed by the over expression in prostate cancer, allowed for the use of an ADC based therapeutic strategy. We used an Auristatin-E conjugated anti-TMEFF2 mAb, Pr1-vcMMAE, to evaluate the effect on human prostate cancer xenograft tumors grown in male severe combined immunodeficient (SCID) mice. Treatment of SCID mice bearing LNCaP and CWR22 tumors, both of which express TMEFF2, with doses of 3 to 10 mg/kg of ADC resulted in significant and sustained tumor growth inhibition. No overt in vivo toxicity was observed with either murine or humanized ADC, despite significant cross-reactivity of anti-TMEFF2 mAb with murine TMEFF2 protein, indicating a high safety profile. Conclusions: The TMEFF2 protein exhibits the desired expression profile for an ADC target. Our data on significant tumor growth inhibition in the in vivo treatment models support humanized Pr1-vcMMAE as a novel therapeutic for the treatment of prostate cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Protein Design Labs, Inc. Protein Design Labs, Inc. Protein Design Labs, Inc.

We examined the potential of generating an immune response against Philadelphia chromosome-positive acute lymphoblastic leukemia. The immunostimulatory molecules chosen for this study were the cytokines IL-2 and GM-CSF and the costimulatory ligand CD80 (B7.1). We used a murine model based on a BALB/c pre-B cell line, BM185wt, in which leukemia is induced by the p185 BCR-ABL oncogenic product, which reproduces Philadelphia chromosome-positive ALL. BM185wt cells were transduced with retroviral vectors and the transduced clones expressing mIL-2, mGM-CSF, or mCD80 were used for challenge. Expression of the immunomodulators by BM185 cells was correlated with delay in leukemia development in immunocompetent mice, but not in immunodeficient mice, indicating an immune response against the modified leukemia cells. Expression of CD80 caused leukemia rejection in 50% of the cohort, which was associated with the CD4+ and CD8+ T cell-dependent development of anti-leukemia cytotoxic T lymphocytes. Furthermore, mice surviving the BM185/CD80 challenge or preimmunized with irradiated BM185/CD80 cells developed an immune response against subsequent challenge with the parental leukemia. These studies provide evidence that immunotherapeutic approaches can be developed for the treatment of ALL.

Human RIN1 was first characterized as a RAS binding protein based on the properties of its carboxyl-terminal domain. We now show that full-length RIN1 interacts with activated RAS in mammalian cells and defines a minimum region of 434 aa required for efficient RAS binding. RIN1 interacts with the "effector domain" of RAS and employs some RAS determinants that are common to, and others that are distinct from, those required for the binding of RAF1, a known RAS effector. The same domain of RIN1 that binds RAS also interacts with 14-3-3 proteins, extending the similarity between RIN1 and other RAS effectors. When expressed in mammalian cells, the RAS binding domain of RIN1 can act as a dominant negative signal transduction blocker. The amino-terminal domain of RIN1 contains a proline-rich sequence similar to consensus Src homology 3 (SH3) binding regions. This RIN1 sequence shows preferential binding to the ABL-SH3 domain in vitro. Moreover, the amino-terminal domain of RIN1 directly associates with, and is tyrosine phosphorylated by, c-ABL. In addition, RIN1 encodes a functional SH2 domain that has the potential to activate downstream signals. These data suggest that RIN1 is able to mediate multiple signals. A differential pattern of expression and alternate splicing indicate several levels of RIN1 regulation.