scholarly journals Preclinical Characterization of the Distribution, Catabolism, and Elimination of a Polatuzumab Vedotin-Piiq (POLIVY®) Antibody–Drug Conjugate in Sprague Dawley Rats

2021 ◽  
Vol 10 (6) ◽  
pp. 1323
Author(s):  
Victor Yip ◽  
M. Violet Lee ◽  
Ola M. Saad ◽  
Shuguang Ma ◽  
S. Cyrus Khojasteh ◽  
...  
Keyword(s):  
B Cell Lymphoma ◽  
The United States ◽  
Clinical Development ◽  
Sprague Dawley ◽  
Antibody Drug Conjugate ◽  
Post Dose ◽  
Drug Conjugate ◽  
Sprague Dawley Rats ◽  
A Minor ◽  
Antibody Drug

Polatuzumab vedotin (or POLIVY®), an antibody–drug conjugate (ADC) composed of a polatuzumab monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a cleavable dipeptide linker, has been approved by the United States Food and Drug Administration (FDA) for the treatment of diffuse large B-cell lymphoma (DLBCL). To support the clinical development of polatuzumab vedotin, we characterized the distribution, catabolism/metabolism, and elimination properties of polatuzumab vedotin and its unconjugated MMAE payload in Sprague Dawley rats. Several radiolabeled probes were developed to track the fate of different components of the ADC, with 125I and 111In used to label the antibody component and 3H to label the MMAE payload of the ADC. Following a single intravenous administration of the radiolabeled probes into normal or bile-duct cannulated rats, blood, various tissues, and excreta samples were collected over 7–14 days post-dose and analyzed for radioactivity and to characterize the metabolites/catabolites. The plasma radioactivity of polatuzumab vedotin showed a biphasic elimination profile similar to that of unconjugated polatuzumab but different from unconjugated radiolabeled MMAE, which had a fast clearance. The vast majority of the radiolabeled MMAE in plasma remained associated with antibodies, with a minor fraction as free MMAE and MMAE-containing catabolites. Similar to unconjugated mAb, polatuzumab vedotin showed a nonspecific distribution to multiple highly perfused organs, including the lungs, heart, liver, spleen, and kidneys, where the ADC underwent catabolism to release MMAE and other MMAE-containing catabolites. Both polatuzumab vedotin and unconjugated MMAE were mainly eliminated through the biliary fecal route (>90%) and a small fraction (<10%) was eliminated through renal excretion in the form of catabolites/metabolites, among which, MMAE was identified as the major species, along with several other minor species. These studies provided significant insight into ADC’s absorption, distribution, metabolism, and elimination (ADME) properties, which supports the clinical development of POLIVY.

scholarly journals Targeting CD205 with the antibody drug conjugate MEN1309/OBT076 is an active new therapeutic strategy in lymphoma models

Haematologica ◽  
2020 ◽  
Vol 105 (11) ◽  
pp. 2584-2591 ◽  
Author(s):  
Eugenio Gaudio ◽  
Chiara Tarantelli ◽  
Filippo Spriano ◽  
Francesca Guidetti ◽  
Giulio Sartori ◽  
...  
Keyword(s):  
Cell Lines ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Antibody Drug Conjugate ◽  
In Vivo Models ◽  
Drug Conjugate ◽  
Anti Tumor Activity ◽  
Class Antibody ◽  
Antibody Drug

Antibody drug conjugates represent an important class of anti-cancer drugs in both solid tumors and hematological cancers. Here, we report preclinical data on the anti-tumor activity of the first-in-class antibody drug conjugate MEN1309/OBT076 targeting CD205. The study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination and validation experiments on in vivo models. CD205 was first shown frequently expressed in lymphomas, leukemias and multiple myeloma by immunohistochemistry on tissue microarrays. Anti-tumor activity of MEN1309/OBT076 as single agent was then shown across 42 B-cell lymphoma cell lines with a median IC50 of 200 pM and induction of apoptosis in 25/42 (59.5%) of the cases. The activity appeared highly correlated with its target expression. After in vivo validation as the single agent, the antibody drug conjugate synergized with the BCL2 inhibitor venetoclax, and the anti-CD20 monoclonal antibody rituximab. The first-in-class antibody drug targeting CD205, MEN1309/OBT076, demonstrated strong pre-clinical anti-tumor activity in lymphoma, warranting further investigations as a single agent and in combination.

Toward clinical development of SYD985, a novel HER2-targeting antibody-drug conjugate (ADC).

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 626-626 ◽  
Author(s):  
Gijs Verheijden ◽  
Patrick Beusker ◽  
Ruud Ubink ◽  
Miranda van der Lee ◽  
Patrick Groothuis ◽  
...  
Keyword(s):  
Clinical Development ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

scholarly journals A novel HER2-targeted antibody-drug conjugate offers the possibility of clinical dosing at trastuzumab-equivalent exposure levels

2020 ◽  
Author(s):  
Robyn M. Barfield ◽  
Yun Cheol Kim ◽  
Stepan Chuprakov ◽  
Fangjiu Zhang ◽  
Maxine Bauzon ◽  
...  
Keyword(s):  
Early Stage ◽  
Systemic Exposure ◽  
Sprague Dawley ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Her2 Breast Cancer ◽  
Treatment Indications ◽  
Exposure Levels ◽  
Antibody Drug

AbstractTrastuzumab and the related antibody-drug conjugate (ADC), ado-trastuzumab emtansine (T-DM1), both target HER2-overexpressing cells. Together, these drugs have treatment indications in both early-stage and metastatic settings for HER2+ breast cancer. T-DM1 retains the antibody functionalities of trastuzumab and adds the potency of a cytotoxic maytansine payload. Interestingly, in the clinic, T-DM1 cannot always replace the use of trastuzumab plus chemotherapy administered together as single agents. We hypothesize that this failure may be due in part to the limited systemic exposure achieved by T-DM1 relative to trastuzumab because of toxicity-related dosing constraints on the ADC. We have developed a trastuzumab-based ADC site-specifically conjugated to maytansine through a noncleavable linker. This construct, termed CAT-01-106, has a drug-to-antibody ratio (DAR) of 1.8, approximately half the average DAR of T-DM1, which comprises a mixture of antibodies variously conjugated with DARs ranging from 0-8. The high DAR species present in T-DM1 contribute to its toxicity and limit its clinical dose. CAT-01-106 showed superior in vivo efficacy compared to T-DM1 at equal payload dosing and was equally or better tolerated compared to T-DM1 at equal payload dosing up to 120 mg/kg in Sprague-Dawley rats and 60 mg/kg in cynomolgus monkeys. CAT-01-106 also showed improved pharmacokinetics in rats relative to T-DM1, with 40% higher ADC exposure levels. Together, the data suggest that CAT-01-106 may be sufficiently tolerable to enable clinical dosing at trastuzumab-equivalent exposure levels, combining the functions of both the antibody and the payload in one drug and potentially improving patient outcomes.

scholarly journals The ROR1 antibody-drug conjugate huXBR1-402-G5-PNU effectively targets ROR1+ leukemia

2021 ◽  
Vol 5 (16) ◽  
pp. 3152-3162
Author(s):  
Eileen Y. Hu ◽  
Priscilla Do ◽  
Swagata Goswami ◽  
Jessica Nunes ◽  
Chi-ling Chiang ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Acute Lymphocytic Leukemia ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Malignant Cells ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Mantle Cell ◽  
Antibody Drug

Abstract Antibody-drug conjugates directed against tumor-specific targets have allowed targeted delivery of highly potent chemotherapy to malignant cells while sparing normal cells. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein with limited expression on normal adult tissues and is overexpressed on the surface of malignant cells in mantle cell lymphoma, acute lymphocytic leukemia with t(1;19)(q23;p13) translocation, and chronic lymphocytic leukemia. This differential expression makes ROR1 an attractive target for antibody-drug conjugate therapy, especially in malignancies such as mantle cell lymphoma and acute lymphocytic leukemia, in which systemic chemotherapy remains the gold standard. Several preclinical and phase 1 clinical studies have established the safety and effectiveness of anti-ROR1 monoclonal antibody–based therapies. Herein we describe a humanized, first-in-class anti-ROR1 antibody-drug conjugate, huXBR1-402-G5-PNU, which links a novel anti-ROR1 antibody (huXBR1-402) to a highly potent anthracycline derivative (PNU). We found that huXBR1-402-G5-PNU is cytotoxic to proliferating ROR1+ malignant cells in vitro and suppressed leukemia proliferation and extended survival in multiple models of mice engrafted with human ROR1+ leukemia. Lastly, we show that the B-cell lymphoma 2 (BCL2)-dependent cytotoxicity of huXBR1-402-G5-PNU can be leveraged by combined treatment strategies with the BCL2 inhibitor venetoclax. Together, our data present compelling preclinical evidence for the efficacy of huXBR1-402-G5-PNU in treating ROR1+ hematologic malignancies.

scholarly journals A Novel c-MET-Targeting Antibody-Drug Conjugate for Pancreatic Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Yangbing Jin ◽  
Zehui Zhang ◽  
Siyi Zou ◽  
Fanlu Li ◽  
Hao Chen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cholesterol Biosynthesis ◽  
The United States ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Pancreatic Cancer Cells ◽  
Factor C ◽  
Antibody Drug

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated death in the United States and has a 5-year survival rate of &lt;4%. Although much effort has been invested in the research and development of pancreatic cancer drugs over the past 30 years, due to the lack of effective targetable carcinogenic drivers, no new targeted therapies that can improve patient prognosis have been approved for clinical use. SHR-A1403 is a new c-mesenchymal-epithelial transition factor (c-MET) antibody-drug conjugate that can be used for the targeted treatment of PDAC with high c-MET expression. This study reports for the first time the application prospects of SHR-A1403 in preclinical models of PDAC. SHR-A1403 significantly inhibited the proliferation, migration, and invasion of pancreatic cancer cells and induced cell cycle arrest and apoptosis. These changes were caused by inhibition of intracellular cholesterol biosynthesis by SHR-A1403. Therefore, targeting c-MET through SHR-A1403 showed strong preclinical anti-tumour efficacy in pancreatic cancer. Our work suggests the potential application of c-MET-targeted antibody-drug conjugate treatment for PDAC in clinical practise.

scholarly journals Design considerations of an IL13Rα2 antibody–drug conjugate for diffuse intrinsic pontine glioma

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Xiaolei Lian ◽  
Dina Kats ◽  
Samuel Rasmussen ◽  
Leah R. Martin ◽  
Anju Karki ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
The United States ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Normal Brain ◽  
Cell Models ◽  
Pontine Glioma ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

AbstractDiffuse intrinsic pontine glioma (DIPG), a rare pediatric brain tumor, afflicts approximately 350 new patients each year in the United States. DIPG is noted for its lethality, as fewer than 1% of patients survive to five years. Multiple clinical trials involving chemotherapy, radiotherapy, and/or targeted therapy have all failed to improve clinical outcomes. Recently, high-throughput sequencing of a cohort of DIPG samples identified potential therapeutic targets, including interleukin 13 receptor subunit alpha 2 (IL13Rα2) which was expressed in multiple tumor samples and comparably absent in normal brain tissue, identifying IL13Rα2 as a potential therapeutic target in DIPG. In this work, we investigated the role of IL13Rα2 signaling in progression and invasion of DIPG and viability of IL13Rα2 as a therapeutic target through the use of immunoconjugate agents. We discovered that IL13Rα2 stimulation via canonical ligands demonstrates minimal impact on both the cellular proliferation and cellular invasion of DIPG cells, suggesting IL13Rα2 signaling is non-essential for DIPG progression in vitro. However, exposure to an anti-IL13Rα2 antibody–drug conjugate demonstrated potent pharmacological response in DIPG cell models both in vitro and ex ovo in a manner strongly associated with IL13Rα2 expression, supporting the potential use of targeting IL13Rα2 as a DIPG therapy. However, the tested ADC was effective in most but not all cell models, thus selection of the optimal payload will be essential for clinical translation of an anti-IL13Rα2 ADC for DIPG.

scholarly journals Evaluation and use of an anti‐cynomolgus monkey CD79b surrogate antibody–drug conjugate to enable clinical development of polatuzumab vedotin

2019 ◽  
Vol 176 (19) ◽  
pp. 3805-3818 ◽  
Author(s):  
Dongwei Li ◽  
Donna Lee ◽  
Randall C. Dere ◽  
Bing Zheng ◽  
Shang‐Fan Yu ◽  
...  
Keyword(s):  
Cynomolgus Monkey ◽  
Clinical Development ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug
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