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CXCR5 is a seven transmembrane protein coupled to protein G(i) expressed mainly on mature, resting B cells, follicular helper T cells (TFH), tonsillar B cells, and B cell lymphoma cells. CXCR5 is activated by its ligand CXCL13 and involved in cell migration. Dysregulated CXCL13 and/or CXCR5 expression and signaling have been associated with cancer promotion, as well as autoimmune and chronic inflammatory disorders. Overexpression of CXCL13 in autoimmune and lymphoproliferative disorders has been shown to correlate with disease progression. We therefore hypothesized that an antibody that selectively depletes CXCR5+ malignant B cells through antibody dependent cell-mediated cytotoxicity (ADCC) could be developed to treat B cell lymphomas. Here, we present preclinical data supporting the rationale for indication selection, biomarker identification, dose selection, and phase I clinical trial design. Using our single-cell screening platform technology, CelliGo™, we identified a panel of monoclonal antibodies against human CXCR5. We selected HFB2-4, which binds to CXCR5 expressing cells, blocks CXCL13-induced intracellular signaling and B cell migration, and induces ADCC of Raji B cell lymphoma cells at sub-nM concentrations. HFB2-4 demonstrates good PK behavior in mice and exhibits potent anti-tumor activity in a Raji xenograft murine model. HFB2-4 efficacy in this model is comparable to that of rituximab, despite a lower number of huCXCR5 receptors compared to CD20 on the surface of Raji cells. Our data shows that HFB2-4 holds promise as a therapeutic agent for B cell lymphoproliferative diseases by depleting CXCR5+ tumor B cells in refractory B cell lymphoma and lymphomas derived from severe Sjogren syndrome. Compared to the emerging treatments for refractory B cell lymphomas such as Antibody-Drug-Conjugates, bi-specific antibodies or cell therapies, HFB2-4 may represent a well-tolerated, efficacious, cost-efficient and easy to manufacture alternative. Citation Format: Ayrin Kok, Germain Margallducos, Stephanie Beq, Clarisse Monchecourt, Hombline Poullain, Muriel David, Carine George, Sami Ellouze, Mingjie Chen, Yun-Yueh Lu, Juying Li, Qian Zhang, Jean Wang, Francisco Adrian, Liang Schweizer, Nicola Beltraminelli. Dicovery and characterization of a novel anti-human CXCR5 antibody for the treatment of B cell lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1843.

Background: Epidemiologic studies suggest that insulin resistance may be associated with breast cancer risk. We conducted Mendelian randomization (MR) analyses to reduce the biases associated with previous studies and provide evidence for causal inference. Materials and Methods: We used genetic variants identified in genome-wide association studies for circulating fasting insulin (15 variants), early insulin secretion (16 variants), fasting proinsulin (8 variants), fasting glucose (35 variants), and 2-hour glucose (8 variants) as instruments in MR analyses. To reduce possible pleiotropic effects, variants associated with obesity were removed from the instruments. We first evaluated the association of these instruments with type 2 diabetes risk in 110,452 subjects to assess instrument validity. We then investigated the association of these instruments with breast cancer risk using data obtained from 122,977 cases and 105,974 controls of European descent included in the Breast Cancer Association Consortium (BCAC). Odds ratios (OR) were calculated to measure the associations of instrumental variables with risk of overall breast cancer and its subtypes defined by estrogen-receptor [ER] status. Results: All instrumental variables constructed for this study were strongly associated with type 2 diabetes risk with ORs of 3.01 (p=7.86x10-5), 0.22 (p=3.54x10-14), 1.90 (p=8.28x10-4), 6.11 (p=3.59x10-19), and 1.91 (p=6.8x10-16) for per unit increase of fasting insulin, early insulin secretion, fasting proinsulin, fasting glucose, and 2-hour glucose levels, respectively. Statistically significant associations with overall breast cancer risk were found for fasting insulin (OR=1.36 for per unit increase, 95% CI=1.09-1.70, p=0.011) and fasting proinsulin (OR=1.21, 95% CI=1.06- 1.38, p=0.011). These associations were observed only for ER-positive breast cancer. No statistically significant association at p Conclusions: Our study provides strong support that certain insulin resistance traits may be causally associated with risk of breast cancer, particularly ER-positive breast cancer. Citation Format: Xiang Shu, Lang Wu, Nikhil K. Khankari, Kyriaki Michailidou, Manjeet K. Bolla, Jean Wang, Joe Dennis, Xiao-ou Shu, Jacques Simard, Douglas F. Easton, Wei Zheng. Association between insulin resistance and breast cancer risk: A Mendelian randomization analysis of data from 228,000 women of European descent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1309. doi:10.1158/1538-7445.AM2017-1309

Background: Basal-like breast cancer (BLBC) is a rare aggressive subtype that is less likely to be detected through mammographic screening. Identification of circulating markers associated with BLBC could have promise in detecting and managing this deadly disease. Methods: Using samples from the Polish Breast Cancer study, a high-quality population-based case-control study of breast cancer, we screened 10,000 antigens on protein arrays using 45 BLBC patients and 45 controls, and identified 748 promising plasma autoantibodies (AAbs) associated with BLBC. ELISA assays of promising markers were performed on a total of 145 BLBC cases and 145 age-matched controls. Sensitivities at 98% specificity were calculated and a BLBC classifier was constructed. Results: We identified a 13-AAbs (CTAG1B, CTAG2, TP53, RNF216, PPHLN1, PIP4K2C, ZBTB16, TAS2R8, WBP2NL, DOK2, PSRC1, MN1, TRIM21) that distinguished BLBC from controls with 33% sensitivity and 98% specificity. We also discovered a strong association of TP53 AAb with its protein expression (p=0.009) in BLBC patients. In addition, MN1 and TP53 AAbs were associated with worse survival (MN1 AAb marker HR=2.25 95%CI= 1.03-4.91 p=0.04; TP53, HR=2.02, 95%CI 1.06-3.85, p=0.03). We found limited evidence that AAb levels differed by demographic characteristics. Conclusions: These AAbs warrant further investigation in clinical studies to determine their value for further understanding the biology of BLBC and possible detection. Currently, they are also being tested in a large national blind validation trial using a well characterized independent sample set. Citation Format: Wang (Student) J, Figueroa JD, Wallstrom G, Barker K, Park JG, Demirkan G, Lissowska J, Anderson K, Qiu J, LaBaer J. Plasma autoantibodies associated with basal-like breast cancers. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-02-04.

Background: Androgen receptor (AR) is a ligand-activated transcription factor that plays critical roles in lethal and incurable castration-resistant prostate cancer (CRPC). EPI-002 is a novel small molecule that specifically targets the AR N-terminal domain (NTD), while conventional therapies target the ligand-binding domain (LBD). Our previous work suggests that EPI-002 may have clinical potential to treat CRPC. Here, the objective was to evaluate EPI-002 against several clinically relevant conditions such as elevated expression of AR co-activators, variable lengths of the poly-glutamine tract (CAG-repeats) within AR NTD, and constitutively active AR splice variants lacking the LBD. Methods: To evaluate the effect of EPI-002 on AR transcriptional activity against overexpressed co-activators such as SRC1-3 and p300, luciferase reporter assays were performed using LNCaP cells transfected with an AR-driven reporter and various amounts of the co-activators. AR-negative COS1 cells were employed for reporter assays to examine if the length of CAG-repeats (varying from 0 to 49) affects EPI-002 inhibition. The effect of EPI-002 on constitutively active AR splice variants was studied in LNCaP95 cells, which express endogenous AR-V7 variant. The expression of several genes regulated by AR-V7 was analyzed by QPCR in LNCaP95 cells treated with antiandrogen enzalutamide or EPI-002. The proliferation of LNCaP95 cells treated with EPI-002 was measured using BrdU incorporation. The efficacy of EPI-002 on LNCaP95 xenografts was studied in castrated male mice by oral delivery and compared to control and enzalutamide. Results: EPI-002 effectively inhibited AR transcriptional activity in spite of overexpressed co-activators SRC1, SRC2, SRC3, or p300. The variable lengths of CAG-repeats within the NTD had no effect on the inhibition of AR by EPI-002. In LNCaP95 cells, EPI-002 significantly blocked the transcriptional activity of AR-V7 indicated by decreased levels of mRNA of AR-V7 regulated genes such as UBE2C. In contrast, enzalutamide had no effect on expression of these genes. EPI-002 significantly inhibited the androgen-independent and antiandrogen-resistant proliferation of LNCaP95 cells. In castrated male mice, EPI-002 attenuated the growth of LNCaP95 xenografts, whereas enzalutamide had no significant effect. By the end of the 28-day study, animals treated with EPI-002 had xenografts that were half of the size of those from the control arm. Conclusions: AR NTD inhibitor EPI-002 was effective against several clinically relevant conditions, including overexpressed co-activators, variable lengths of CAG-repeats, and constitutively active AR-V7. These findings support EPI-002 as a promising therapeutic agent to treat CRPC, particularly against castration-resistant tumors driven by constitutively active AR splice variants that are resistant to LBD-targeting therapies. Citation Format: Yu Chi (Kevin) Yang, Nasrin (Rina) Mawji, Jean Wang, Marianne Sadar. Preclinical evaluation of novel androgen receptor N-terminal domain inhibitor EPI-002 for the treatment of castration-resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 610. doi:10.1158/1538-7445.AM2014-610

Effect of PF-03475952, a potent and neutralizing CD44 antibody, on cancer cell apoptosis in vitro and metastasis in two orthotopic models Yuli Wang, Jean wang, Gary Li, Amy Jackson-Fisher, Brett Simmons, Eugenia Kraynov, Christy Ji, Baiyong Li, and David Pocalyko Pfizer Global Research & Development, San Diego, CA 92121 CD44 is a cell surface glycoprotein that has multiple functions. It can act as a receptor for ligands such as hyaluronic acid and osteopontin. Additionally, it can function as co-receptor to modulate the activation of growth factor receptors such as c-met & ERBB. CD44 can also influence cell signaling through interaction with components of the actin cytoskeleton such as the ERM protein. CD44 expression is increased in many types of human cancer. It is also a cell surface marker for cancer stem cells in breast cancer and HCC. In HCC, CD44 overexpression is a frequent event (∼30% based on several reports) and CD44 up regulation is associated with metastasis and poor patient survival. Down regulation of CD44 with RNAi knockdown or neutralizing antibody has been reported to reduce tumor metastasis, recurrence, and growth in different models. PF-03475952 is a fully human IgG2 anti-CD44 monoclonal antibody that was initially developed as a potential therapeutic agent for rheumatoid arthritis. It was shown previously that the PF-03475952 can disrupt the interaction of CD44 with its ligand, hyaluronic acid. The antibody binding induces loss of CD44 from the cell surface, and inhibits LPS-induced cytokine release from various leukocytes. In this report, we evaluated the potential of PF-03475952 as a cancer adjuvant therapy for HCC. HCC is the third most deadly forms of cancer world-wide with frequent early recurrence due to inter and extra hepatic metastasis. The effect of PF-03475952 on cancer metastasis was first demonstrated in an M24met melanoma model. The expression of CD44 and the effects of PF-03475952 on HCC cell lines were then characterized. In vitro, PF-03475952 was able to reduce cell adhesion and promote apoptosis in a CD44-dependent manner. More importantly, PF-03475952 can reduce lung metastasis in a CD44-positive HCC orthotopic model. The study suggested that the CD44 neutralizing antibody, PF-03475952, could be an efficacious agent as adjuvant therapy to prevent cancer metastasis. 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 1446.