Sharlene Adams

PT-100, a Small Molecule Dipeptidyl Peptidase Inhibitor, Has Potent Antitumor Effects and Augments Antibody-Mediated Cytotoxicity via a Novel Immune Mechanism

The amino boronic dipeptide, PT-100 (Val-boro-Pro), a dipeptidyl peptidase (DPP) inhibitor, has been shown to up-regulate gene expression of certain cytokines in hematopoietic tissue via a high-affinity interaction, which appears to involve fibroblast activation protein. Because fibroblast activation protein is also expressed in stroma of lymphoid tissue and tumors, the effect of PT-100 on tumor growth was studied in mice in vivo. PT-100 has no direct cytotoxic effect on tumors in vitro. Oral administration of PT-100 to mice slowed growth of syngeneic tumors derived from fibrosarcoma, lymphoma, melanoma, and mastocytoma cell lines. In WEHI 164 fibrosarcoma and EL4 and A20/2J lymphoma models, PT-100 caused regression and rejection of tumors. The antitumor effect appeared to involve tumor-specific CTL and protective immunological memory. PT-100 treatment of WEHI 164-inoculated mice increased mRNA expression of cytokines and chemokines known to promote T-cell priming and chemoattraction of T cells and innate effector cells. The role of innate activity was further implicated by observation of significant, although reduced, inhibition of WEHI 164 and A20/2J tumors in immunodeficient mice. PT-100 also demonstrated ability to augment antitumor activity of rituximab and trastuzumab in xenograft models of human CD20+ B-cell lymphoma and HER-2+ colon carcinoma where antibody-dependent cytotoxicity can be mediated by innate effector cells responsive to the cytokines and chemokines up-regulated by PT-100. Although CD26/DPP-IV is a potential target for PT-100 in the immune system, it appeared not to be involved because antitumor activity and stimulation of cytokine and chemokine production was undiminished in CD26−/− mice.

Abstract 3485: MM-111, an ErbB2/ErbB3 bispecific antibody with potent activity in ErbB2-overexpressing cells, positively combines with trastuzumab to inhibit growth of breast cancer cells driven by the ErbB2/ErbB3 oncogenic unit

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC MM-111 is a novel bispecific antibody fusion protein which targets the ErbB2/ErbB3 oncogenic unit, blocking activation of the phosphatidylinositol 3-kinase (PI3K) pro-survival pathway. The anti-ErbB2 arm of MM-111 binds with high affinity to the ErbB2 receptor, which localizes the bispecific molecule to ErbB2 over-expressing tumor cells and promotes binding of the anti-ErbB3 arm to the ErbB3 receptor. MM-111 binding to ErbB3 results in inhibition of ErbB3 signaling by blocking the binding of the ErbB3 physiological ligand heregulin. MM-111 treatment of ErbB2 overexpressing cancer cells inhibits activation of the PI3K pathway with sub-nanomolar potency, blocks cell cycle progression and attenuates tumor cell growth in multiple xenograft models. ErbB2 over-expressing tumor cells are addicted to growth signals provided by the ligand-activated ErbB2/ErbB3 heterodimer. Activation of downstream PI3K pathway signaling also occurs through ligand-independent ErbB2/ErbB2 homodimers and ErbB2/ErbB3 heterodimers. Recently the ErbB2-targeted therapeutic antibody trastuzumab was shown to inhibit basal ErbB3 signaling in the absence of ligand stimulation, purportedly by interrupting ligand-independent ErbB2/ErbB3 heterodimers formed through overexpression of ErbB2. However, in these studies trastuzumab did not effectively block ligand-induced activation of the ErbB2/ErbB3 oncogenic unit. Indeed, there is emerging evidence that ligand-induced ErbB3 activation may have an important role in resistance to trastuzumab. As MM-111 and trastuzumab have distinct and potentially complimentary effects on signaling in cells overexpressing ErbB2, we hypothesized that their combination may synergistically effect inhibition of tumor cell growth driven by the ErbB2/3 signaling network. Our data demonstrate that MM-111 and trastuzumab positively combine to inhibit breast cancer growth in multiple in vitro breast cancer models expressing ErbB2 and ErbB3. Further, in the BT-474 breast cancer xenograft model the combination of MM-111 and trastuzumab results in greater inhibition of tumor growth and an increased number of completely regressed tumors compared to the monotherapy treatment groups. Pharmacodynamic analysis of samples from these studies show that repeated administration of the combined therapeutic agents results in strong inhibition of the ErbB3/PI3K pathway. In conclusion, we show that MM-111 and trastuzumab inhibit the growth of ErbB2 over-expressing breast tumors with distinct mechanisms that act synergistically in combination. Concurrent treatment with MM-111 and trastuzumab may provide a potent therapeutic regimen for ErbB2-overexpressing breast cancer patients and potentially deter acquired resistance to trastuzumab through ErbB3 activation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3485.

Abstract CT237: Preclinical characterization and first-in-human study of MM-141, a dual antibody inhibitor of IGF-1R and ErbB3

Background: MM-141 is a tetravalent bi-specific monoclonal antibody that binds IGF-1R and ErbB3, oncogenic receptors commonly co-expressed in solid tumors. In preclinical models, MM-141 blocks both ligand-dependent and -independent PI3K/AKT/mTOR signaling initiated through IGF-1R and ErbB3 complexes and potentiates the activity of gemcitabine, paclitaxel, nab-paclitaxel, docetaxel, irinotecan, tamoxifen, and everolimus. A multi-arm phase I study is ongoing, with continuing patient enrollment in Arm B (MM-141 in combination with everolimus). Monotherapy Arm A and combination Arm C (MM-141 with nab-paclitaxel and gemcitabine) are completed. Methods: Tumor expression of IGF-1R and ErbB3 was measured by immunohistochemistry. In vitro expression and degradation of IGF-1R and ErbB3 in pancreatic cell line models post-treatment were measured by immunoblotting and ubiquitination, respectively. The phase I dose-escalation study evaluated safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) properties of MM-141 as monotherapy (Arm A, n = 15) and in combination with everolimus (Arm B) or with nab-paclitaxel and gemcitabine (Arm C, n = 11). Pre- and post-treatment biopsies were acquired where mandated. Patients in the monotherapy Arm A received MM-141 at 6, 12, 20 mg/kg weekly or 40 mg/kg biweekly. Patients in the dose-escalation portion of Arm C received MM-141 at a weekly dose of 12 or 20 mg/kg in combination with weekly nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) on a schedule of 3 weeks on, 1 week off. Enrollment in Arm B (MM-141 in combination with everolimus) is ongoing. Patient serum free IGF-1 levels were detected using an in-house developed CLIA validated ELISA-based assay. Results: Here we report common co-expression of IGF-1R and ErbB3 in solid tumors. In stage IV metastatic pancreatic cancer, co-expression of IGF-1R and ErbB3 was associated with decreased patient survival. In preclinical models, increased expression of IGF-1R and ErbB3 desensitized tumors to gemcitabine and paclitaxel. However, co-treatment with MM-141 reversed this acquired resistance through blockade of growth factor binding and induction of IGF-1R and ErbB3 degradation. In the monotherapy arm of a phase I study, no dose-limiting toxicities were observed at any of the studied dose levels. The safety, tolerability, PK and PD profile of MM-141 support 2.8g bi-weekly MM-141 phase II recommended dose. The analysis of pre- and post-treatment biopsies confirmed that levels of IGF-1R and ErbB3 were decreased following MM-141 administration. In Arm C, the observed safety profile of MM-141 in combination with nab-paclitaxel and gemcitabine was comparable to expected toxicities reported with the chemotherapy combination when used alone. Retrospective analysis of serum free IGF-1 levels in breast cancer patients (Arm B) demonstrated that patients with elevated levels of this potential biomarker remained on study longer and received a greater number of doses of MM-141. Conclusion: These data support continued development of MM-141 in biomarker-selected patient populations and the upcoming phase II study of MM-141 in combination with nab-paclitaxel and gemcitabine in front-line metastatic pancreatic cancer patients with detectable free IGF-1 serum levels. Citation Format: Alexey A. Lugovskoy, Michel Curley, Jason Baum, Sharlene Adams, Sergio Iadevaia, Victoria Rimkunas, Adam Camblin, Lin Nie, Gege Tan, Bryan Johnson, Sara Mathews, Kerry Horgan, Chrystal U. Louis, Akos G. Czibere, Monica Arnedos, Jean-Charles Soria, Rastilav Bahleda, Anthony Shields, Patricia M. LoRusso, Mansoor Saleh, Steven J. Isakoff. Preclinical characterization and first-in-human study of MM-141, a dual antibody inhibitor of IGF-1R and ErbB3. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT237. doi:10.1158/1538-7445.AM2015-CT237

Abstract 655: Combination of MM-111, an ErbB2/ErbB3 bispecific antibody, with endocrine therapies as an effective strategy for treatment of ER+/HER2+ breast cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Approximately 75% of breast cancers are estrogen receptor (ER) positive. Although endocrine therapies such as tamoxifen, fulvestrant, and letrozole have demonstrated significant efficacy in treating ER+ breast cancer patients, intrinsic or acquired resistance has limited their success. Recent studies suggest that crosstalk between ErbB receptor signaling and ER signaling may contribute to resistance to endocrine therapy. Overexpression of human epidermal growth factor receptor 2 (HER2, synonymous with ErbB2) and upregulation of the ErbB3 ligand heregulin are associated with poor prognosis and reduced overall survival. MM-111 is a novel bispecific antibody fusion protein that specifically targets the ErbB2/ErbB3 heterodimer and blocks heregulin binding to ErbB3. MM-111 inhibits ligand-induced ErbB3 phosphorylation, tumor cell cycle progression, and tumor growth when ErbB2 is overexpressed. We hypothesized that combination of endocrine therapies with MM-111 may improve anti-tumor efficacy. In an estrogen-stimulated BT474-M3 ER-positive breast cancer cell three-dimensional spheroid assay, MM-111, when used as a single agent, showed growth inhibitory effects similar to the anti-estrogen drugs tamoxifen and fulvestrant. Combination of MM-111 with anti-estrogen therapy showed superior activity to either drug alone. In the presence of heregulin, MM-111 maintained its growth inhibitory activity, whereas the inhibitory effect of tamoxifen and fulvestrant was diminished. This suggests that activation of ErbB3 confers tumor cell resistance to anti-estrogen therapies. When both estrogen and heregulin were present, the combination of MM-111 and the anti-estrogen drugs demonstrated a significantly greater inhibitory effect than either drug alone. Western blot analysis showed that treatment of BT-474-M3 cells with the combination of MM-111 and the anti-estrogen drugs significantly increased apoptosis markers such as cytochrome C and BAX. Furthermore, an in vivo BT474-M3 xenograft model showed resistance to tamoxifen treatment (5 mg/pellet, 60-day release). In this xenograft model MM-111 sensitized tumor response to tamoxifen and the combination treatment dramatically inhibited tumor growth. In conclusion, the combination of MM-111 and endocrine therapies may provide a potent regimen that overcomes acquired resistance to endocrine therapies in ER+, ErbB2-overexpressing breast cancer 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 655. doi:10.1158/1538-7445.AM2011-655

Abstract 654: MM-111, an ErbB2/ErbB3 bispecific antibody, effectively combines with lapatinib to inhibit growth of ErbB2-overexpressing tumor cells

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The oncogenic receptor ErbB2 (HER2) is frequently overexpressed in a variety of cancer indications, including breast, gastric, bladder, and lung. ErbB3 (HER3), the preferred dimerization partner of ErbB2, is critical for the survival and growth of ErbB2-overexpressing tumors, but is poorly inhibited by current ErbB2-targeted therapies. MM-111 is a novel bispecific antibody designed to specifically inhibit function of the ErbB2/ErbB3 heterodimer in ErbB2-overexpressing tumors. MM-111 binds simultaneously to ErbB2 and ErbB3 and blocks the interaction of ErbB3 with its ligand, heregulin. Inhibiting the ErbB2/ErbB3 heterodimer prevents ligand-induced activation of the phosphotidylinositol 3-kinase (PI3K) pro-survival pathway, altering cell cycle progression and inhibiting tumor growth. Upregulation of both heregulin and ErbB3 has been observed in tumors that have acquired resistance to the ErbB2-targeted therapies trastuzumab and lapatinib. In addition, ErbB2 and ErbB3 are frequently upregulated in estrogen receptor positive breast cancers that have developed resistance to anti-estrogen therapies. These data indicate that the ErbB2/ErbB3 receptor heterodimer potently activates growth of tumors characterized by ErbB2 overexpression and implicate ErbB3 as a mechanism of resistance to current therapies. Because of its ability to inhibit ErbB3 activity, MM-111 could be effective in combination with ErbB2-targeted therapies by overcoming ErbB3-mediated resistance. Previous data demonstrating that MM-111 acts in concert with trastuzumab to inhibit growth of ErbB2-overexpressing human tumor models support this hypothesis. We now show that MM-111 effectively combines with lapatinib to inhibit growth of tumors driven by the ErbB2/ErbB3 heterodimer. MM-111, as a single agent, is more effective than lapatinib at inhibiting heregulin-driven activation of ErbB3 and AKT in ErbB2-overexpressing cancer cell lines. In these same cell lines, the combination of MM-111 and lapatinib results in greater AKT inhibition than either treatment alone. In addition, we have demonstrated in ErbB2-overexpressing 3D spheroid cancer models that treatment with the MM-111/ lapatinib combination increases the number of cells in early phase apoptosis as compared to single-drug treatments. Finally, in an ErbB2-overexpressing cancer xenograft model, the combination of MM-111 and lapatinib results in greater inhibition of tumor growth than either therapy alone. In conclusion, we show that MM-111 and lapatinib positively combine to inhibit the growth of ErbB2-overexpressing tumors. Our results suggest that concurrent treatment with MM-111 and lapatinib may provide a potent therapeutic regimen for cancer patients whose tumors overexpress ErbB2 by deterring ErbB3-mediated resistance to lapatinib. 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 654. doi:10.1158/1538-7445.AM2011-654

Dual Inhibition of IGF-1R and ErbB3 Enhances the Activity of Gemcitabine and Nab-Paclitaxel in Preclinical Models of Pancreatic Cancer

Purpose: Insulin-like growth factor receptor 1 (IGF-1R) is critically involved in pancreatic cancer pathophysiology, promoting cancer cell survival and therapeutic resistance. Assessment of IGF-1R inhibitors in combination with standard-of-care chemotherapy, however, failed to demonstrate significant clinical benefit. The aim of this work is to unravel mechanisms of resistance to IGF-1R inhibition in pancreatic cancer and develop novel strategies to improve the activity of standard-of-care therapies. Experimental Design: Growth factor screening in pancreatic cancer cell lines was performed to identify activators of prosurvival PI3K/AKT signaling. The prevalence of activating growth factors and their receptors was assessed in pancreatic cancer patient samples. Effects of a bispecific IGF-1R and ErbB3 targeting antibody on receptor expression, signaling, cancer cell viability and apoptosis, spheroid growth, and in vivo chemotherapy activity in pancreatic cancer xenograft models were determined. Results: Growth factor screening in pancreatic cancer cells revealed insulin-like growth factor 1 (IGF-1) and heregulin (HRG) as the most potent AKT activators. Both growth factors reduced pancreatic cancer cell sensitivity to gemcitabine or paclitaxel in spheroid growth assays. Istiratumab (MM-141), a novel bispecific antibody that blocks IGF-1R and ErbB3, restored the activity of paclitaxel and gemcitabine in the presence of IGF-1 and HRG in vitro. Dual IGF-1R/ErbB3 blocking enhanced chemosensitivity through inhibition of AKT phosphorylation and promotion of IGF-1R and ErbB3 degradation. Addition of istiratumab to gemcitabine and nab-paclitaxel improved chemotherapy activity in vivo. Conclusions: Our findings suggest a critical role for the HRG/ErbB3 axis and support the clinical exploration of dual IGF-1R/ErbB3 blocking in pancreatic cancer. Clin Cancer Res; 24(12); 2873–85. ©2018 AACR.

Abstract LB-243: The ErbB3-targeting antibody MM-121 (seribantumab) reverses heregulin-driven resistance to multiple chemotherapies on tumor cell growth

Purpose: Heregulin-mediated activation of the human epidermal growth factor receptor 3 (HER3/ErbB3) is required for the growth and survival of many epithelial cancers. This signaling pathway is also emerging as a mechanism of resistance to targeted agents and chemotherapies. MM-121 (seribantumab) is an investigational human monoclonal anti-ErbB3 antibody that has previously been shown to effectively block ligand-dependent activation of ErbB3 in a range of tumors, and has demonstrated clinical activity in biomarker positive patients in several Phase II trials. The purpose of this study was to examine in three indications of interest, the ability of heregulin to induce resistance to standard chemotherapies and the reversal of this effect by MM-121. Such systematic evaluation of different combinations can serve as a guide for the future clinical development of MM-121. Methods: To assess the effect of heregulin and MM-121 on chemotherapies in cancer cells, we conducted a high throughput proliferation screen in 3D cultures. A panel of 60 cell lines of relevant clinical indications (ovarian, breast and lung cancer) was selected and tested for the sensitivity to respective standard-of-care chemotherapies in the absence or presence of exogenously added heregulin. Using these data, we analyzed the rescuing capacity of heregulin and the MM-121 combination9s sensitivity, and selected representative combinations for in vivo models. Results: We show that in a large panel of cancer cell lines the presence of heregulin can induce resistance to multiple chemotherapies with very different mechanisms of action. The combination of MM-121 with any one of these chemotherapies can reverse the heregulin-meditated rescue and provide an additive treatment effect at therapeutically relevant doses achieved in the clinic. These results were further validated in xenograft mouse models of all three indications, using representative chemotherapies and doses. In addition, biomarker analysis revealed that ErbB3 receptor levels largely determine responsiveness to heregulin and MM-121. Conclusions: MM-121 is an anti-ErbB3 antibody designed to block ligand-mediated signaling, and currently in clinical development. The results presented here demonstrate the role of heregulin in reducing the sensitivity of tumors to standard-of-care chemotherapies, and the effect of ErbB3 pathway inhibition across indications. Citation Format: Kristina Masson, Viara Grantcharova, Olga Burenkova, Marisa Wainszelbaum, Sergio Iadevaia, Sharlene Adams, Andreas Raue, Akos Czibere, Birgit Schoeberl, Gavin MacBeath. The ErbB3-targeting antibody MM-121 (seribantumab) reverses heregulin-driven resistance to multiple chemotherapies on tumor cell growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-243. doi:10.1158/1538-7445.AM2015-LB-243

Abstract C169: MM-141, a bispecific antibody inhibitor of PI3K/AKT/mTOR, attenuates tumor growth and potentiates everolimus in mouse models of anti-hormonal therapy-resistant ER/PR+ breast cancer.

Purpose: PI3K/AKT/mTOR network adaptation through the upregulation of receptor tyrosine kinases signaling and subsequent re-activation of AKT is a common resistance mechanism to chemotherapies and small molecule inhibitors of mammalian target of rapamycin (mTOR). In order to block this feedback loop, MM-141, a tetravalent bispecific antibody directed at IGF-1R and ErbB3, was co-administered in combination with everolimus in various preclinical models of cancer. As everolimus is an approved therapy for women with advanced hormone receptor-positive breast cancer after failure of treatment with aromatase inhibitor, we have specifically focused on the analysis of a MM-141/everolimus combination in a hormone refractory breast cancer mouse model. Experimental Procedures: Estrogen-supplemented mice bearing BT-474-M3 ER+/PR+ breast cancer xenografts were implanted with tamoxifen-releasing pellets. Following the development of resistance to tamoxifen, these mice were randomized into pharmacodynamics and efficacy assessment sub-groups, and treated with everolimus, MM-141 or the combination. In pharmacodynamics assessment subgroups, the tumors were harvested 24 hours following the last MM-141 dose and profiled for a panel of molecular markers of activation of PI3K/AKT/mTOR pathway. In addition we have assessed the activity of MM-141, everolimus or the combination in cell culture on a broad panel of breast cancer cell lines using CellTiter-Glo® Luminescent Cell Viability Assay. Data Summary: We have demonstrated that MM-141 has significant anti-tumor activity in the ER+/PR+ BT-474-M3 breast cancer xenograft model and strongly potentiates the activity of everolimus in a tamoxifen-resistant setting. Pharmacodynamic profiling illustrates that the combination treatment achieves sustained inhibition of PI3K/AKT/mTOR signaling. MM-141 mediates the resistance to everolimus by inhibiting IGF-1R, ErbB3, and IRS-1 and controlling the re-activation of AKT. Further, MM-141 is able to inhibit the proliferation of a panel of breast cancer cell lines in vitro. This inhibition is increased upon co-treatment of the cells with MM-141 and everolimus. Conclusions: Our in vivo preclinical studies show that MM-141 combines synergistically with the mTOR inhibitor everolimus and this combination is active in reversing acquired resistance to the anti-hormonal therapy tamoxifen. This potentiation of everolimus by MM-141 is tied to its ability to reverse the re-activation of AKT signaling induced by this mTOR blocker. We demonstrate that this potentiation phenomenon is common in a wide panel of breast cancer cell lines. Overall, our results suggest that MM-141 could be a potentially valuable addition to the breast cancer treatment regimens comprising an mTOR inhibitor and an anti-hormonal therapy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C169. Citation Format: Sharlene Adams, Jason Baum, Breanne Sparta, Victoria Rimkunas, Jian Tang, Emily Pace, Shoshana Rosenthal, Adam Camblin, Sergio Iadevaia, Akos Czibere, Ulrik Nielsen, Alexey Lugovskoy. MM-141, a bispecific antibody inhibitor of PI3K/AKT/mTOR, attenuates tumor growth and potentiates everolimus in mouse models of anti-hormonal therapy-resistant ER/PR+ breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C169.

Abstract A38: MM-141, a novel tetravalent bispecific antibody directed at IGF-1R and ErbB3 that inhibits pancreatic tumor cell growth and potentiates the effects of gemcitabine.

Purpose: Overall 5-year survival rates for patients diagnosed with pancreatic cancer is approximately 5.5% and most patients do not show durable responses to therapy. While monoclonal antibodies have significantly advanced our ability to treat cancer, their potential in pancreatic cancer is yet to be realized. We believe that targeted therapeutic strategies focused on the identification and blockade of redundant growth factor signaling pathways critical for tumor cell survival will result in the discovery of novel antibody therapies for treatment of patients with pancreatic cancer. Methods and Summary: Cancer cell lines frequently rely on insulin-like growth factor 1 (IGF-1) and heregulin (HRG) signaling to support their survival and proliferation. Using a Network Biology approach, we have designed, constructed and optimized a novel tetravalent bispecific antibody, MM-141, for co-targeting of IGF-1R and ErbB3. MM141 blocks IGF-1, IGF-2, and HRG-induced signaling through IGF-1R and ErbB3, and causes downregulation of these receptors. MM-141 also downregulates IGF-1R-InsR hybrid receptors as well as ErbB1:ErbB3 and ErbB2:ErbB3 heterodimers. MM-141 does not bind other ErbB family receptors or homodimers of insulin receptor, thus reducing the risk of side effects. MM-141 inhibits phosphorylation of IGF-1R and ErbB3 receptors as well as downstream activation of the PI3K/Akt/mTOR pathway. In our preclinical tests, MM-141 displays inhibitory activity in the presence of single or multiple ligands, over a broad range of receptor profiles. Inhibition of cell growth by MM-141 has been observed in vitro as well as in vivo in multiple xenograft models including human pancreatic cancer (BxPC-3). Importantly, we show stronger activity of MM-141 compared to combinations of monospecific antibodies targeting IGF-1R and/or ErbB3. This appears to be due to the ability of MM-141 to block additional feedback loops through autocrine HRG signaling, FoxO-mediated upregulation of RTKs, or feedback activation of Akt by ribosomal S6 kinase (S6K) and insulin receptor substrate 1 (IRS-1). Additionally, we have performed pharmacodynamic and efficacy studies with MM-141 and gemcitabine in both monotherapy and combination therapy preclinical settings. We find that MM-141 potentiates the response to gemcitabine with respect to both downstream signaling effects on the PI3K/Akt/mTOR axis in short-term studies, as well as activity in long-term studies. Conclusions: Our in vitro and in vivo preclinical studies show that MM-141 has favorable pharmaceutical properties and pharmacokinetic profiles and shows activity in xenograft models of pancreatic cancer. These results suggest that MM-141 has the potential to be an effective therapeutic for treatment of patients with solid tumors including, but not limited to, pancreatic cancer. Citation Format: Bryan Johnson, Yang Jiao, Birgit Schoeberl, Ulrik Nielsen, Jonathan Fitzgerald, Alexey Lugovskoy, Sharlene Adams, Jason Baum, Jian Tang, Sergio Iadevaia, Neeraj Kohli, Rachel Rennard, Pragalath Sundararajan, Lihui Xu. MM-141, a novel tetravalent bispecific antibody directed at IGF-1R and ErbB3 that inhibits pancreatic tumor cell growth and potentiates the effects of gemcitabine. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A38.

Abstract 3756: Prediction of xenograft response to MM-121, an anti-ErbB3 inhibitor, using computational modeling and measurements of five biomarkers

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC One of the challenges faced by targeted therapeutics currently in the clinic is the relatively small population of patients who derive significant benefit from their use. We report the development of a preclinical classifier which can correctly predict xenograft response to MM-121, an anti-ErbB3 antibody, based on the measurement of a few key biomarkers in cell lysates. Deregulation of the ErbB family receptors is common in many cancers. Using a combination of computational modeling and quantitative experiments we identified ErbB3 as a key mediator of mitogenic signaling downstream of the ErbB receptors. Based on these results, we developed MM-121, a first in class anti-ErbB3 monoclonal antibody that blocks heregulin-induced signaling and inhibits tumor growth in multiple xenograft models of human cancer. Here we present our efforts to derive a predictive biomarker signature that identifies tumors that are responsive to MM-121. Using our computational model of the ErbB signaling pathway we identified the five most critical proteins for predicting activation of phospho-AKT - a key mediator of cell survival and apoptosis. These proteins include MM-121s target, ErbB3, and its ligand, heregulin. We profiled these biomarkers in a large panel of cancer cell lines, and using the measured effect of MM-121 on inhibiting tumor growth in eight xenograft tumor models, we determined a classification rule for predicting xenograft response. We subsequently used this classification rule to correctly predict a priori MM-121 response in 11 xenograft models. These results suggest that our computationally-derived biomarker signature is sufficient for predicting response to MM-121 in xenografts, and could offer significant clinical benefit by helping select patients for MM-121 treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3756.