**will not be participating in the webinar
Antibody-Drug Conjugates: Oncology and Beyond
Tuesday, November 14, 2017, 9:00 AM - 5:00 PM EST
The New York Academy of Sciences, 7 World Trade Center, 250 Greenwich St Fl 40, New York, USA
Biochemical Pharmacology Discussion Group
The New York Academy of Sciences
Antibody–Drug Conjugates (ADCs) combine the selectivity of antibodies with the efficacy of small molecule drugs, allowing for more precise therapeutic approaches. This symposium will explore the opportunities and challenges of ADCs for cancer, and the need to resolve these open questions in order to fulfill the larger promise of this technology. We will also consider use of ADCs beyond cancer into other disease indications including autoimmune disease, difficult-to-treat bacterial infections, and atherosclerosis.
This event is proudly supported by:
The Biochemical Pharmacology Discussion Group is proudly supported by:
American Society of Clinical Oncology (ASCO)
November 14, 2017
Registration and Continental Breakfast
Opening Remarks and Conference Overview
Session I: Antibody Drug Conjugates for Oncology
Rovalpituzumab Tesirine, an anti-DLL3 ADC, for the Therapeutic Treatment of Tumors that Express DLL3
High-grade pulmonary neuroendocrine tumors remain among the most deadly malignancies. We developed patient-derived xenograft (PDX) models from small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) patients, characterized populations of tumor-initiating cells (TICs), and discovered elevated expression of DLL3. Since DLL3 is detected on the cell surface of primary SCLC and LCNEC tumors, while normal adult tissues do not express DLL3, we developed a DLL3-targeted ADC, rovalpituzumab tesirine (Rova-T; Saunders et al. 2015 Sci Transl Med). Treatment of mice bearing DLL3 positive SCLC PDX with Rova-T resulted in effective and durable responses, corresponding with a significant decrease in TIC frequency. In contrast, standard of care cisplatin/etoposide neither impacts TIC frequency nor results in durable responses in the clinic. Rova-T exerted clinically meaningful anti-tumor effects in a Phase I trial of recurrent/refractory SCLC (Rudin CM et al. 2017 Lancet Oncol). Current trials are evaluating Rova-T in front-line SCLC (NCT02819999). DLL3 is also expressed in neuroendocrine tumors of differing etiology (e.g. prostate, bladder, ovary, etc), metastatic melanoma, glioblastoma, and medullary thyroid cancer. In mice bearing DLL3-positive melanoma or small cell ovarian PDX, respectively, treatment with Rova-T resulted in effective and durable responses, correlating with a significant impact on TIC frequency. A “basket” trial enrolling patients with DLL3-positive solid tumors, including extra-pulmonary neuroendocrine tumors, melanoma and glioblastoma is now recruiting patients (NCT02709889). Collectively, our pre-clinical and clinic data shows that Rova-T offers a new targeted therapeutic strategy for patients with DLL3-positive solid tumors.
Preclinical Activity of the Novel Anti-Prolactin Receptor (PRLR) ADC in PRLR-Positive Breast Cancers **
The Prolactin Receptor (PRLR) is a type 1 cytokine receptor that is expressed in a subset of breast cancers and may contribute to its pathogenesis. It is relatively overexpressed in approximately 25% of human breast tumors while expressed at low levels in some normal human tissues including the mammary gland. We developed an anti-PRLR antibody-drug conjugate (ADC), to target PRLR-positive breast cancer. REGN2878-DM1 is comprised of a fully human high-affinity function-blocking anti-PRLR IgG1 antibody (REGN2878) conjugated via a noncleavable SMCC linker to the cytotoxic maytansine derivative DM1. Both unconjugated REGN2878 and conjugated REGN2878-DM1 block PRL-mediated activation in vitro and are rapidly internalized into lysosomes. REGN2878-DM1 induces potent cell-cycle arrest and cytotoxicity in PRLR-expressing tumor cell lines. In vivo, REGN2878-DM1 demonstrated significant antigen-specific antitumor activity against breast cancer xenograft models. In addition, REGN2878-DM1 showed additive activity when combined with the antiestrogen agent fulvestrant. Furthermore, in breast cancer cells that coexpress HER2 and PRLR, a HER2xPRLR bispecific ADC kills more effectively than HER2 ADC. These results illustrate promising antitumor activity against PRLR-positive breast cancer xenografts and support the evaluation of anti-PRLR ADCs as potential therapeutic agents in breast cancer.
MEDI4276: Biparatopic ADC Targeting HER2 Positive Cancers
Discovery of Novel Linker Payloads and Antibody Drug Conjugates for the Treatment of Cancer
With the approval of Adcetris and Kadcyla, antibody drug conjugates (ADCs) have established themselves as a new frontier in oncology drug discovery. These conjugates utilize microtubulin inhibitors as their payloads, which are also found in over 30 active clinical programs. Unfortunately, they are not universally successful across all programs with many resulting in termination due to poor efficacy or low therapeutic index (TI). The industry has recently turned its attention back to DNA damaging payloads as they tend to be more potent and effective in both proliferating and quiescent tumor cells. This approach has been previously validated with the clinical successes of Mylotarg® and Besponsa®, two calicheamicin based ADCs. However, to date, conjugates bearing that payload are not as effective in solid tumors that express MDR. Efforts to bring forth a new DNA-damaging payload that is active in MDR-expressing cells will be disclosed. Our medicinal chemistry strategy that began with a CBI dimer based payload and progressed to a CPI dimer with a specially designed spacer unit to impart increased plasma stability to the payload will be described. This strategy coupled with conjugation to the appropriate site on the antibody led to highly efficacious ADCs with acceptable therapeutic indices to advance to clinical development.
Networking Coffee Break
Session II: Tumor Microenvironment
Re-engineering the Tumor Microenvironment to Enhance Cancer Treatment: Bench to Bedside **
For nearly four decades, our research has focused on improving the delivery and efficacy of anti-cancer therapies. Working on the hypothesis that the abnormal tumor microenvironment fuels tumor progression and treatment resistance, we developed an array of novel imaging technologies and animal models to unravel the complex biology of tumors. Using these tools, we demonstrated that the blood and lymphatic vasculature, fibroblasts, immune cells and the extracellular matrix associated with tumors are abnormal, which together create a hostile tumor microenvironment (e.g., hypoxia, low pH, high interstitial fluid pressure, high solid stress) (Science 2005). We next hypothesized that if we could reengineer the tumor microenvironment, we should be able to improve the treatment outcome. Indeed, we demonstrated in mice and cancer patients that judicious use of antiangiogenic agents—originally designed to starve tumors—could transiently “normalize” tumor vasculature, alleviate hypoxia, increase delivery of drugs and anti-tumor immune cells, and improve the outcome of radiation, chemotherapy and immunotherapy (Cancer Cell 2014). Our clinical finding that the normalizing doses of bevacizumab can reverse hearing loss in NF2 patients led to its approval in UK (NEJM 2009). We also discovered that widely prescribed antihypertensive drugs are capable of “normalizing” the fibroblasts and extracellular matrix, opening compressed tumor vessels, and improving the delivery and efficacy of molecular and nanomedicine (Nature Communications 2013). This finding offers new hope for improving treatment of highly fibrotic tumors and has led to a successful clinical trial at MGH on losartan and chemo-radiation therapy in pancreatic ductal adenocarcinoma patients (NCT01821729).
Tumoral Distribution of Antibody Drug Conjugates – Impact on Efficacy and Strategies
Antibody drug conjugates (ADCs) continue to grow as a class of targeted therapeutics with multiple agents that are either FDA approved or in late stage clinical trials. However, the development of these drugs is complex due to the combination of antibody properties, linker stability, conjugation sites, and payload selection. An important but often less appreciated aspect of ADC development is the intratumoral distribution of the drugs and its impact on efficacy. The large size and rapid binding of antibodies quickly immobilizes the drug, resulting in poor penetration into the tumor tissue. Unlike unconjugated antibodies, ADCs cannot be given in large or frequent doses to overcome this binding site front due to their payload toxicity. This limited penetration, where many cells in the tumor are never exposed to the drug, can have a profound impact on efficacy. Poor distribution is further complicated by the fact that it is not exclusively the product of the ADC design but results from the interplay of the antibody, linker, and payload with the tumor physiology and target biology. Fortunately, there are multiple approaches to overcome this poor penetration, such as protein/antibody carrier design, dosing strategies, and use of payload bystander effects. Each of these has strengths and limitations that must be balanced with the particular target. Drug transport simulations in conjunction with experimental techniques can provide mechanistic insight into these strategies to help guide the next generation of ADCs to clinical success.
Networking Lunch Break
Session III: Other Indications for Antibody Drug Conjugates
Dolaflexin: A Polymer-based Approach to Create Improved ADCs
Targeting Glucocorticoids to Immune Cells as Antibody Drug Conjugates **
Glucocortiocids are excellent anti-inflammatories but use is limited by target-mediated toxicity. We sought to solve this problem using antibody targeting using site-specific incorporation, novel linker chemistry that delivered in vitro and in vivo stability, and existing and novel glucocorticoid receptor (GR) agonists as payloads. An anti-human CD74 antibody directed the payload to antigen-presenting immune cells. In vitro, the ADC caused CD74-dependent GR agonist activity in human cells. However, mechanism of action studies pointed to accumulation of free payload in the tissue culture supernatant as the dominant driver of activity and indeed administration of the ADC to human CD74 transgenic failed to activate GR target genes in splenic B cells. Suspecting dissipation of released payload, we designed an ADC bearing a novel GR agonist payload with reduced permeability to deliver target cell-specific activity. Our work shows that antibody-targeting offers significant potential for rescuing existing and new dose-limited drugs outside the field of oncology.
Anti-TNF- Glucocorticoid Antibody Drug Conjugate– A Disruptive Therapy for Rheumatic Diseases
Networking Coffee Break