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

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.

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 ADCT-402, a PBD dimer–containing antibody drug conjugate targeting CD19-expressing malignancies

Blood ◽  
2018 ◽  
Vol 131 (10) ◽  
pp. 1094-1105 ◽  
Author(s):  
Francesca Zammarchi ◽  
Simon Corbett ◽  
Lauren Adams ◽  
Peter C. Tyrer ◽  
Konstantinos Kiakos ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Hematological Malignancies ◽  
Minor Groove ◽  
Clinical Development ◽  
Antibody Drug Conjugate ◽  
Dna Minor Groove ◽  
Drug Conjugate ◽  
Key Points ◽  
Interstrand Crosslinking ◽  
Antibody Drug

Key Points ADCT-402 is a CD19-targeted ADC delivering SG3199, a cytotoxic DNA minor groove interstrand crosslinking PDB dimer warhead. ADCT-402 has potent and selective antitumor activity against CD19-expressing hematological malignancies warranting clinical development.

Computational Approaches in Antibody-drug Conjugate Optimization for Targeted Cancer Therapy

2018 ◽  
Vol 18 (13) ◽  
pp. 1091-1109 ◽  
Author(s):  
Rita Melo ◽  
Agostinho Lemos ◽  
Antonio J. Preto ◽  
Jose G. Almeida ◽  
Joao D.G. Correia ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Coarse Grained ◽  
Cytotoxic Agent ◽  
Target Cells ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Cross Correlation Analysis ◽  
Traditional Therapies ◽  
Modular Structures ◽  
Antibody Drug

Cancer has become one of the main leading causes of morbidity and mortality worldwide. One of the critical drawbacks of current cancer therapeutics has been the lack of the target-selectivity, as these drugs should have an effect exclusively on cancer cells while not perturbing healthy ones. In addition, their mechanism of action should be sufficiently fast to avoid the invasion of neighbouring healthy tissues by cancer cells. The use of conventional chemotherapeutic agents and other traditional therapies, such as surgery and radiotherapy, leads to off-target interactions with serious side effects. In this respect, recently developed target-selective Antibody-Drug Conjugates (ADCs) are more effective than traditional therapies, presumably due to their modular structures that combine many chemical properties simultaneously. In particular, ADCs are made up of three different units: a highly selective Monoclonal antibody (Mab) which is developed against a tumour-associated antigen, the payload (cytotoxic agent), and the linker. The latter should be stable in circulation while allowing the release of the cytotoxic agent in target cells. The modular nature of these drugs provides a platform to manipulate and improve selectivity and the toxicity of these molecules independently from each other. This in turn leads to generation of second- and third-generation ADCs, which have been more effective than the previous ones in terms of either selectivity or toxicity or both. Development of ADCs with improved efficacy requires knowledge at the atomic level regarding the structure and dynamics of the molecule. As such, we reviewed all the most recent computational methods used to attain all-atom description of the structure, energetics and dynamics of these systems. In particular, this includes homology modelling, molecular docking and refinement, atomistic and coarse-grained molecular dynamics simulations, principal component and cross-correlation analysis. The full characterization of the structure-activity relationship devoted to ADCs is critical for antibody-drug conjugate research and development.

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