Development and preclinical evaluation of a novel FGFR3-targeted antibody-drug conjugate in bladder cancer

Background: Nectin-4 is a tumor-associated antigen, which was observed in multiple cancer types, including bladder, breast, lung, pancreatic and ovarian cancer. Enfortumab Vedotin (EV) is the first approved nectin-4 antibody-drug conjugate (ADC) with MMAE as its payload for the treatment of urothelial carcinoma (UC). However, beyond UC, EV hasn’t been approved for other indications. In addition, severe skin adverse reactions were reported in EV-treated patients. There are several new nectin-4 ADCs in development but haven’t entered confirmative clinical studies so far. To overcome the limitations of efficacy and safety, we developed a novel mechanism nectin-4 ADC GLR1059, with a payload that was more effective for potential indications with nectin-4 expression and had lower toxicity, including skin adverse reactions. Methods: For in vitro studies, binding affinity and specificity, internalization, cancer cell killing, bystander effect and serum stability were performed. For in vivo studies, efficacy studies were conducted on cell line-derived xenografts (CDX) of multiple cancer types, e.g. breast cancer (including triple-negative breast cancer), and urothelial carcinoma. Pharmacokinetic (PK) properties were studied in BALB/c mice and tumor-bearing nude mice, and safety studies were conducted in humanized nectin-4 mice. Results: GLR1059 is a nectin-4 ADC composed of a novel humanized IgG1 monoclonal antibody, a cleavable linker and a microtubule targeting agent (not auristatin derivatives). Moreover, to generate DAR4 ADCs with higher homogeneity, the payload was site-specifically conjugated to the antibody via a disulfide bond bridge. In surface plasmon resonance (SPR) assays, GLR1059 had strong and specific binding to human nectin-4, and it did not bind to nectin-1, nectin-2, or nectin-3. Furthermore, GLR1059 exhibited efficient internalization and potent activity in nectin-4 expressing cell lines and effective bystander activity. In a panel of CDX models, GLR1059 demonstrated compelling anti-tumor activity across bladder cancer and breast cancer (including TNBC), with tumor growth inhibition rates (TGI) significantly higher than EV (approximately 2-4 times). In the tumor-bearing mice PK study, the Cmax of free payload in tumor tissue was approximately 100-fold higher than that in the blood (131±14ng/g vs 1.04±0.27ng/mL). GLR1059 demonstrated longer survival and less weight loss in the single- and repeated-dose toxicity studies in humanized nectin-4 mice. Notably, GLR1059 significantly reduced the incidence and severity of skin toxicity compared with EV (1/6 vs 6/6). Conclusion: Preclinical data show that GLR1059 has the potential to achieve better efficacy and safety, and the different drug mechanisms provide new options to overcome drug resistance of current nectin-4 ADCs. Citation Format: Jiao Jiao, Yingjie Sun, Jiaxing Wang, Liming Che, Menghan Cui, Wenjie Shao, Hairui Yuan, Yan Huang, Nannan Zhai, Yuling Tang, Xiaomei Zheng, Siyao Li. GLR1059, next-generation nectin-4-targeted ADC with a novel mechanism-of-action payload, demonstrated significantly potent anti-tumor efficacy and reduced toxicity in preclinical evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1567.

Bladder cancer (BLCA) is a prevalent urological malignancy that exhibits a high degree of tumor heterogeneity and morbidity. Tumor angiogenesis, a vital hallmark of cancer, greatly influences the tumor microenvironment (TME). The emergence of anti-angiogenic drugs has provided a new turning point in cancer treatment. An integrated machine learning system was constructed to build the angiogenesis-related gene signatures (ARGS). ARGS was used to assess TME status in BLCA. Pharmacophore construction was employed to construct pharmacophore features of highly cytotoxic drug payload combinations for antibody-drug conjugates (ADCs). In addition,we developed a natural compound using artificial intelligence-driven drug design technology.This compound exhibits anti-angiogenic effects in BLCA and serves as a highly cytotoxic drug payload for ADCs. Multi-dimensional machine learning was used to screen biomarkers for evaluating the post-treatment effects of drug therapy in BLCA. The ARGS consists of 12 angiogenesis-related genes associated with prognostic risk in BLCA. The ARGS divides BLCA patients into high-risk and low-risk groups. Significant TME remodeling was identified in the high-risk BLCA cohort and demonstrated a strong association with tumor angiogenesis. Expression levels of key immune checkpoint markers significantly differed between BLCA risk groups. Saikosaponin D (SSD) shows promising potential as a novel ADC drug for anti-angiogenic treatment in BLCA. Multi-dimensional machine learning results indicate that MYH11 is the most likely biomarker for evaluating the post-treatment effects of SSD therapy. SSD may potentially treat tumors by regulating angiogenesis in BLCA. The detection of MYH11 can be used to assess the therapeutic effectiveness of SSD in BLCA.

Introduction: Cancer cells over-express proteins on their cell surface that can be exploited as drug targets and has led to development of two successful Anti-body Drug Conjugates (ADCs), Brentuximab and Trastuzumab Emtansine. Because a strong correlation exists between mRNA levels and protein expression we analyzed RNAseq data from TCGA to look at known ADC targets as a proof-of-concept to discovering new therapeutic targets. Methods: We used mRNA expressions (transcripts per million, TPM) from publicly available RNA sequencing data from the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project to analyze the expression of ADC targets in tumor and normal tissues. We chose thirty-seven targets with known ADCs in clinical development. Graphs were generated to show distribution of each gene's expression across all tumor and normal tissue types in TCGA and GTEx. Potential targets were determined based on tumor expression of at least two times the highest expression in any normal tissue. Proteins known to be secreted in the blood stream at high levels were excluded as they are unlikely to make a good ADC target (eg. AFP, FOLH1). Results: Using ERBB2 as the prototype gene, we were able to detect over-expression in all tumors that have HER-2 ove-rexpression in the literature including breast, bladder, NSCLC, Gastroesophageal, endometrial, HNSCC, ovarian, and colon cancer. Other genes with overexpression in select tumors including BSG (RCC, Melanoma, ACC), CD70 (RCC, DLBCL, mesothelioma, cervical), ENPP3 (RCC, endometrial, breast, lung adeno), FGFR2 (breast, gastric), FOLR1 (ovarian, lung adeno), GPNMB (lung, melanoma, HNSCC, renal), MSLN (lung adeno, mesothelioma, ovarian), SLC39A6 (breast), TDGF1 (thymoma, testicular, adrenocortical) were discovered as well. Tumors exhibited a significantly higher expression compared to normal tissue for ERBB2: breast cancer vs normal breast: p < 0.001; bladder cancer vs normal bladder: p < 0.001; lung adenocarcinoma vs normal lung: p < 0.001; ovarian cancer vs normal ovary: p < 0.001. Conclusion: Overall, this large-scale analysis from TCGA reveals that RNA-seq can be used as an initial screen to identify novel targets for ADCs. Further analysis will identify previously unappreciated targets that can be exploited for drug development across diverse cancers. Further confirmation with protein expression is warranted. Citation Format: Roman Groisberg, Jason Rosznik, Funda Meric-Bernstam, Vivek Subbiah. Comprehensive evaluation of antibody-drug conjugate targets for drug development across tumor types: Analysis from TCGA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2343.

The cell surface antigen Lymphocyte antigen 75 (LY75, CD205, DEC-205) is over-expressed in several tumor histotypes. It is a type I C-type lectin receptor (CLR), normally expressed on various APC subsets, characterized by a cytoplasmic domain containing protein motifs crucial for endocytosis and internalization upon ligation. These features make the antigen ideal to be exploited as a target for a novel ADC. MEN1309 is a humanized IgG1 antibody directed against the cell surface antigen Ly75, conjugated through a cleavable linker to a potent maytansinoid microtubule disruptor, DM4. In this study, we evaluated the in vitro and in vivo (xenografts and PDX) efficacy of MEN1309 in different tumor histotypes. A PK/PD relationship was also investigated in tumor-bearing mice. IHC demonstrated high prevalence of Ly75 in human pancreatic, triple negative breast, and bladder cancers, as well as in diffuse large B-cell lymphoma. In vitro experiments showed that cytotoxic activity of MEN1309 was in nM/sub nM range against several lymphoma, pancreatic, bladder and triple-negative breast cancer (TNBC) cell lines. Moreover, MEN1309 exhibited high cell-killing ability against cells having either strong as well as low to moderate antigen expression. In vivo, MEN1309 at 2.5-5 mg/kg (schedule varying from single dose, q7dx3, or q21dx3) showed an impressive antitumor activity, resulting in complete and long lasting responses in most of the xenograft models representing lymphoma, TNBC, bladder and pancreatic cancers, expressing the antigen at high but also at low levels. No treatment related toxicity in terms of change of body weight and death events were detected. Moreover, the administration of (i) isotype control-DM4, (ii) the non-conjugate antibody IgG1 and (iii) the free toxin DM4 (at a dosage corresponding to the equimolar concentration linked at 10 mg/kg ADC) showed little to no therapeutic efficacy on tumor growth. In TNBC patient-derived xenograft (PDX) model (coming from a heavily pre-treated patient and expressing high level of the antigen Ly75), MEN1309 (5 mg/kg q21dx3) showed a complete tumor regression. Finally, in the pancreatic adenocarcinoma xenograft model HPAFII, the pharmacokinetics profile in serum of MEN1309 at 5 mg/kg was characterized and it was qualitatively correlated, using immunofluorescence, with the occurrence of phosphorylation of Serine 10 of H3 Histone in cancer cells, as a pharmacodynamic (PD) marker of DM4 activity on microtubules. Initial ADC exposure was noteworthy and was followed by a relatively fast decline. In parallel with the decay of the serum ADC concentrations there was a progressive increase in the number of positive cells showing the PD marker for mitotic arrest. Overall, our data suggest that MEN1309 is a selective and potent novel antitumoral ADC and it deserves to enter into aPhase I study for a variety of Ly75 positive tumor histotypes. Citation Format: Mario Bigioni, Giuseppe Merlino, Cristina Bernadó Morales, Rossana Bugianesi, Attilio Crea, Rosanna Manno, Joaquin Arribas, Rachel Dusek, Nickolas Attanasio, Keith Wilson, Christian Rohlff, Monica Binaschi. MEN1309, a novel antibody drug conjugate (ADC) targeting Ly75 antigen, induces complete responses in several xenografts of solid tumors [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 2630. doi:10.1158/1538-7445.AM2017-2630

C4.4A (LYPD3) is a cancer- and metastasis-associated transmembrane cell surface protein which is expressed at high frequency and density in multiple tumor types including squamous and non-squamous non-small cell lung carcinoma ((NSCLC), head & neck squamous cell carcinoma (HNSCC), esophageal squamous cell carcinoma (ESCC) and bladder cancer. C4.4A expression is restricted to a limited number of tissues (e.g. suprabasal layer of skin) making C4.4A an attractive target for the treatment of cancer with a C4.4A-targeted antibody-drug conjugate (ADC). BAY 1129980 (C4.4A-ADC), is an ADC consisting of a fully human C4.4A-targeting monoclonal antibody (technology licensed from BioInvent) conjugated via a novel, non-cleavable alkyl hydrazide linker to a novel, highly potent auristatin W, an antimitotic agent (technology licensed from Seattle Genetics, Inc.). This C4.4A-ADC has been previously shown to be efficacious in C4.4A positive cell line-derived and PDX models of NSCLC. Here we present new preclinical efficacy data of C4.4A-ADC in patient-derived xenograft (PDX) models of ESCC, HNSCC and bladder cancer. Models were selected based on tumor C4.4A levels as determined by mRNA levels and immunohistochemistry (IHC), the latter of which allowed ranking of models according to H-score, percentage of C4.4A positivity, and staining intensity (0 to 3+) in the cell membrane. Representative C4.4A-positive models were selected for in vivo efficacy studies (n=7 each): 4 HNSCC, 4 ESCC and 2 bladder cancers. C4.4A-ADC was administered as one cycle (Q4Dx3) at doses of 7.5 and 15 mg/kg, and efficacy was assessed up to 4 weeks post treatment for optimum tumor growth inhibition (TGI). In ESCC models a response to C4.4A ADC was seen in ES0190 (TGI of 77%; 15mg/kg) and in ES0195 (59%). In HNSCC models an ADC effect on tumor growth was observed in HN10847 (46%), HN9619 (34%), and HN10321 (22%). Finally, both bladder models tested were sensitive to treatment, with a transient response seen in BL0597 (41%) and a strong and complete tumor growth control in BL5001 (93%,) which was superior to cisplatin. The data show that C4.4A-positive PDX models of ESCC, HNSCC and bladder cancer can respond to C4.4A-ADC. C4.4A expression served as a marker for preselection of the models. Nevertheless, other factors may affect response and sensitivity of these tumor models, such as sensitivity to tubulin inhibition, ADC uptake and intracellular processing. In summary, these data support further exploration of the potential of BAY 1129980 in HNSCC, ESCC and bladder cancer in addition to NSCLC. A Phase 1 clinical trial of BAY 1129980 is ongoing (NCT02134197). Citation Format: Joerg Willuda, Carol Pena, Christoph Kneip, Patricia E. Carrigan, Hans-Georg Lerchen, Lars Linden, Bertolt D. Kreft. Response of C4.4A-positive patient-derived xenograft models of ESCC, HNSCC and bladder cancer to BAY1129980, a C4.4A-targeted antibody drug conjugate [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 3091. doi:10.1158/1538-7445.AM2017-3091

Bladder cancer is a significant global health challenge. Despite advances in surgery and platinum-based chemotherapy over the decades, limited improvements in clinical outcomes have been observed. However, recent years have witnessed the development of immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) that has transformed the therapeutic landscape of bladder cancer across different disease stages. ICIs block inhibitory pathways including PD-1/PD-L1 and CTLA-4 and reawake antitumor immunity, whereas ADCs, the combination of tumor-selective antibodies with potent cytotoxic payloads, ensure targeted cancer cell death with less systemic toxicity. Both therapies have exhibited clinical benefit in bladder cancer individually and in combination. Clinical trials including NIAGARA, CheckMate-274, and EV-302, have defined new perioperative and first-line standards based on ICIs and ADCs. Ongoing advancements in HER2-, Trop-2-, and Nectin-4-directed ADCs, bispecific and small-molecule conjugates, and combination with ICIs are revolutionizing the therapeutic options for bladder cancer. Of note, the combination of an ADC, enfortumab vedotin, with ICI, pembrolizumab, has improved survival in advanced disease scenarios in bladder cancer. Resistance against ICIs and ADCs remains a significant challenge, but identifying predictive biomarkers, integrating molecular profiling with these therapies, and developing effective combination strategies hold strong potential to achieve durable, precise, and personalized treatment outcomes for bladder cancer.

Bladder cancer is the 10th most common cancer type in the world. There were more than 573,000 new cases of bladder cancer in 2020. It is the 13th most common cause of cancer death with an estimated more than 212,000 deaths worldwide. Low-grade non-muscle-invasive bladder cancer (NMIBC) is usually successfully managed with transurethral resection (TUR) and overall survival for NMIBC reaches 90% according to some reports. However, long-term survival for muscle-invasive bladder cancer (MIBC) and metastatic bladder cancer remains low. Treatment options for bladder cancer have undergone a rapid change in recent years. Immune checkpoint inhibitors (ICI), targeted therapies, and antibody-drug conjugates are available now. As bladder cancer is genetically heterogeneous, the optimization of patient selection to identify those most likely to benefit from a specific therapy is an urgent issue in the treatment of patients with bladder cancer.

e16547 Background: Poliovirus receptor (PVR) is a ligand for TIGIT and plays a crucial role in tumor immune evasion. We have identified that PVR is highly expressed in bladder cancer (BC), particularly in cases that are resistant to immunotherapy. This study aims to investigate whether antibody-drug conjugate (ADC) targeting PVR can provide both antitumor activity and inhibition of immune escape in BC. Methods: Forty-one BC patients who received anti-PD1 neoadjuvant therapy were analyzed to identify proteins linked to immunotherapy resistance. Briefly, laser-capture microdissection was employed to isolate 3 urothelial and 3 stromal regions from each FFPE sample, enabling high-sensitivity mass spectrometry to spatially define the proteomic profiles in immunotherapy-responsive and unresponsive samples. Expression levels of PVR and common ADC targets were head-to-head compared by IHC in a cohort includes 347 BC samples. A fully humanized anti-PVR monoclonal antibody was conjugated to the toxin MMAE and the linker MC-VC-PAB to produce the potential therapeutic ADC, PVR-MMAE. The antitumor efficacy of PVR-MMAE was assessed in BC cell lines and organoids. Humanized NGS mice were engrafted with human peripheral blood mononuclear cells following by orthotopic xenografted with 5637 cells. Rats given 0.1% BBN in drinking water for 28 weeks produced bladder tumors. Animals were administered either isotype-MMAE, PVR-MMAE (2 mg/kg), or a combination of PVR-MMAE and anti-PD-1twice weekly for 4 weeks intravenously. Finally, the potential toxicity of PVR-MMAE was evaluated by dose escalation in normal rats. Results: PVR was found to be a significantly upregulated tumor-associated membrane antigen in immunotherapy-unresponsive patients. Objective response rates to immunotherapy were 19% in the PVR high group and 90% in the PVR low group. The positive expression rate of PVR in BC was 76%, comparable to HER-2 (74%), Trop-2 (69%), nectin-4 (82%) and EGFR (80%). High PVR expression correlated with advanced stage and poorer prognosis. Functional assays indicated that PVR is not only a tumor-associated antigen but also conferred strong oncogenic effects. PVR-MMAE showed significant antitumor effect in PVR-positive cells and organoids, with an IC50 of 5-10 µg/mL. Tumor growth was significantly inhibited by PVR-MMAE versus isotype-MMAE in the orthotopic xenograft model and BBN-induced BC model. Combined therapy with PVR-MMAE and anti-PD-1 showed superior efficacy over monotherapy. Additionally, intravenous administration of PVR-MMAE was safe within effective therapeutic dose ranges. Conclusions: A de novo anti-PVR monoclonal antibody conjugated with MMAE was developed. Preclinical data on bladder cancer cell lines, organoids and animal models showed the potent antitumor efficiency of anti-PVR antibody-drug conjugate as a single agent or in combination with ICIs in bladder cancer.

664 Background: Antibody-drug conjugates (ADCs) are a novel class of therapeutics that combine a tumor cell targeting antibody with a cytotoxic payload. Two ADCs are currently approved in the US for treatment of advanced bladder cancer: enfortumab vedotin (EV) and sacituzumab govitecan (SG). Radiation therapy (RT) plays a central role in trimodality therapy (TMT), a curative treatment approach for muscle-invasive bladder cancer (MIBC). However, the biological activity of ADCs combined with RT in preclinical MIBC models has not been reported. Methods: We use a molecularly annotated panel of human MIBC preclinical models to test the impact of RT on expression of ADC targets and define the combined activity of EV and SG with RT. We also test the in vivo activity of combining ADCs with image-guided, fractionated RT in bladder cancer flank xenograft mouse models. Results: Radiation has variable impact on expression levels of nectin-4 and trop-2, the targets of EV and SG, respectively, as determined by immunoblot, immunofluorescence microscopy, and immunohistochemistry (IHC). Whereas modest dose-dependent increases in nectin-4 and/or trop-2 levels were observed in some models, no significant changes were observed in other models. Importantly, RT did not lead to a significant decrease in nectin-4 or trop-2 expression in any of the models. EV and SG showed additive or synergistic cell killing when combined with RT across preclinical models in vitro. Combining EV or SG with fractionated RT in vivo was well-tolerated, showed improved tumor control, and prolonged survival in bladder cancer flank xenograft mouse models compared to either ADC or RT alone. Conclusions: ADCs demonstrate combination activity with RT across a panel of molecularly diverse bladder cancer preclinical models. These studies provide preclinical data supporting clinical trials to investigate the safety and efficacy of combining ADCs with RT as a bladder-preserving therapy for MIBC.

Integrin β4 drives immune evasion and therapeutic resistance to PD-1 blockade in bladder cancer via MEK/ERK signaling

Agensys (an affiliate of Astellas Pharma), Santa Monica, CA Abstract: SLITRK6 is a member of the SLITRK family of neuronal transmembrane proteins involved in neurite outgrowth. It was discovered by Agensys using suppressive subtractive hybridization on biopsies from bladder cancer patients. Expression in bladder cancer was confirmed by RNA and immunohistochemical analysis. These studies showed SLITRK6 to be highly expressed in bladder carcinoma in situ as well as in invasive and metastatic bladder cancer. In addition, SLITRK6 was shown to be expressed in a subset of lung cancer, breast cancer and glioblastoma specimens. Agensys has generated a novel antibody drug conjugate (ADC), targeting SLITRK6, which is being developed for the treatment of advanced bladder cancer. This Monomethyl Auristatin E based ADC binds to cell surface SLITRK6 with high affinity and cross reacts with the cynomolgus monkey orthologue. Selection and development of this ADC will be discussed including antibody choice, drug platform choice, conjugation development and other aspects of pre-clinical evaluation. Citation Format: Kendall Morrison. Development of AGS15E, a novel antibody drug conjugate targeting SLITRK6 for the treatment of bladder cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4332. doi:10.1158/1538-7445.AM2013-4332

Emerging strategies for the improvement of chemotherapy in bladder cancer: Current knowledge and future perspectives

Antibody drug conjugates (ADCs) consist of an antibody, a cytotoxic payload, and a linker between the two. ADCs are becoming increasingly used in metastatic bladder cancer. Enfortumab vedotin (EV) in combination with pembrolizumab recently demonstrated impressive improvements in survival and overall responses compared to chemotherapy in the frontline metastatic setting. Sacituzumab govitecan (SG) and single agent EV are also effective, later line options for patients who have progressed on prior chemotherapy and/or immunotherapy. New ADCs, including those targeting HER2, have also displayed promising results in bladder cancer patients. Trials are exploring the use of ADCs in combination with each other as well as with immunotherapy. Novel ADCs with dual targets, dual payloads, and other augmentations are being developed and may represent new options for patients moving forward. However, these advances raise many questions. How to best manage the differing toxicities seen with ADCs? What is best sequencing of ADCs? What are the common resistance mechanisms to ADCs? How do these resistance mechanisms affect subsequent use of ADCs? And how effective are these agents in bladder cancer variants and divergent histologies? This talk with cover the expanding role of ADCs in metastatic bladder cancer. Citation Format: Nicholas Simon. Metastatic bladder cancer: The expanding role of antibody drug conjugates [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA018.

<div>Abstract<p><i>SLITRK6</i> is a member of the SLITRK family of neuronal transmembrane proteins that was discovered as a bladder tumor antigen using suppressive subtractive hybridization. Extensive immunohistochemistry showed SLITRK6 to be expressed in multiple epithelial tumors, including bladder, lung, and breast cancer as well as in glioblastoma. To explore the possibility of using SLITRK6 as a target for an antibody–drug conjugate (ADC), we generated a panel of fully human mAbs specific for SLITRK6. ADCs showed potent <i>in vitro</i> and <i>in vivo</i> cytotoxic activity after conjugation to Monomethyl Auristatin E or Monomethyl Auristatin F. The most potent ADC, ASG-15ME, was selected as the development candidate and given the product name AGS15E. ASG-15ME is currently in phase I clinical trials for the treatment of metastatic urothelial cancer. This is the first report that SLITRK6 is a novel antigen in bladder cancer and also the first report of the development of ASG-15ME for the treatment of metastatic bladder cancer. <i>Mol Cancer Ther; 15(6); 1301–10. ©2016 AACR</i>.</p></div>

SLITRK6 is a member of the SLITRK family of neuronal transmembrane proteins that was discovered as a bladder tumor antigen using suppressive subtractive hybridization. Extensive immunohistochemistry showed SLITRK6 to be expressed in multiple epithelial tumors, including bladder, lung, and breast cancer as well as in glioblastoma. To explore the possibility of using SLITRK6 as a target for an antibody-drug conjugate (ADC), we generated a panel of fully human mAbs specific for SLITRK6. ADCs showed potent in vitro and in vivo cytotoxic activity after conjugation to Monomethyl Auristatin E or Monomethyl Auristatin F. The most potent ADC, ASG-15ME, was selected as the development candidate and given the product name AGS15E. ASG-15ME is currently in phase I clinical trials for the treatment of metastatic urothelial cancer. This is the first report that SLITRK6 is a novel antigen in bladder cancer and also the first report of the development of ASG-15ME for the treatment of metastatic bladder cancer. Mol Cancer Ther; 15(6); 1301-10. ©2016 AACR.