scholarly journals In Vitro and In Vivo Evaluation of Cysteine and Site Specific Conjugated Herceptin Antibody-Drug Conjugates

PLoS ONE ◽  
2014 ◽  
Vol 9 (1) ◽  
pp. e83865 ◽  
Author(s):  
Dowdy Jackson ◽  
John Atkinson ◽  
Claudia I. Guevara ◽  
Chunying Zhang ◽  
Vladimir Kery ◽  
...  
Keyword(s):  
In Vivo Evaluation ◽  
Site Specific ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

In Vitro and In Vivo Evaluation of Cysteine Rebridged Trastuzumab–MMAE Antibody Drug Conjugates with Defined Drug-to-Antibody Ratios

2015 ◽  
Vol 12 (6) ◽  
pp. 1872-1879 ◽  
Author(s):  
Penny Bryant ◽  
Martin Pabst ◽  
George Badescu ◽  
Matthew Bird ◽  
William McDowell ◽  
...  
Keyword(s):  
In Vivo Evaluation ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

scholarly journals Synthesis of site-specific antibody-drug conjugates by ADP-ribosyl cyclases

2020 ◽  
Vol 6 (23) ◽  
pp. eaba6752 ◽  
Author(s):  
Zhefu Dai ◽  
Xiao-Nan Zhang ◽  
Fariborz Nasertorabi ◽  
Qinqin Cheng ◽  
Jiawei Li ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Reaction Times ◽  
Single Step ◽  
Her2 Positive ◽  
Site Specific ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Most of the current antibody-drug conjugates (ADCs) in clinic are heterogeneous mixtures. To produce homogeneous ADCs, established procedures often require multiple steps or long reaction times. The introduced mutations or foreign sequences may cause high immunogenicity. Here, we explore a new concept of transforming CD38 enzymatic activity into a facile approach for generating site-specific ADCs. This was achieved through coupling bifunctional antibody-CD38 fusion proteins with designer dinucleotide-based covalent inhibitors with stably attached payloads. The resulting adenosine diphosphate–ribosyl cyclase–enabled ADC (ARC-ADC) with a drug-to-antibody ratio of 2 could be rapidly generated through single-step conjugation. The generated ARC-ADC targeting human epidermal growth factor receptor 2 (HER2) displays excellent stability and potency against HER2-positive breast cancer both in vitro and in vivo. This proof-of-concept study demonstrates a new strategy for production of site-specific ADCs. It may provide a general approach for the development of a novel class of ADCs with potentially enhanced properties.

scholarly journals Site-Specific Antibody–Drug Conjugates in Triple Variable Domain Fab Format

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 764 ◽  
Author(s):  
Dobeen Hwang ◽  
Christoph Rader
Keyword(s):  
Tumor Tissue ◽  
In Vitro Cytotoxicity ◽  
Variable Domain ◽  
Site Specific ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Solid Malignancies ◽  
Antibody Drug

The interest in replacing the conventional immunoglobulin G (IgG) format of monoclonal antibodies (mAbs) and antibody–drug conjugates (ADCs) with alternative antibody and antibody-like scaffolds reflects a need to expand their therapeutic utility and potency while retaining their exquisite specificity, affinity, and low intrinsic toxicity. For example, in the therapy of solid malignancies, the limited tumor tissue penetration and distribution of ADCs in IgG format mitigates a uniform distribution of the cytotoxic payload. Here, we report triple variable domain Fab (TVD–Fab) as a new format that affords the site-specific and stable generation of monovalent ADCs without the Fc domain and a drug-to-antibody ratio (DAR) of 2. TVD–Fabs harbor three variable fragment (Fv) domains: one for tumor targeting and two for the fast, efficient, precise, and stable conjugation of two cargos via uniquely reactive lysine residues. The biochemical and in vitro cytotoxicity properties of a HER2-targeting TVD–Fab before and after conjugation to a tubulin inhibitor were validated. In vivo, the TVD–Fab antibody carrier revealed a circulatory half-life of 13.3 ± 2.5 h and deeper tumor tissue distribution compared to our previously reported dual variable domain (DVD)–IgG1 format. Taken together, the TVD–Fab format merits further investigations as an antibody carrier of site-specific ADCs targeting solid malignancies.

scholarly journals Sortase Enzyme-Mediated Generation of Site-Specifically Conjugated Antibody Drug Conjugates with High In Vitro and In Vivo Potency

PLoS ONE ◽  
2015 ◽  
Vol 10 (7) ◽  
pp. e0131177 ◽  
Author(s):  
Roger R. Beerli ◽  
Tamara Hell ◽  
Anna S. Merkel ◽  
Ulf Grawunder
Keyword(s):  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

scholarly journals Pharmacokinetic and Metabolism Studies of Monomethyl Auristatin F via Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2754
Author(s):  
Park ◽  
Lee ◽  
Byeon ◽  
Shin ◽  
Choi ◽  
...  
Keyword(s):  
Liquid Chromatography ◽  
Matrix Effects ◽  
Time Of Flight ◽  
Simple Liquid ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug ◽  
Tof Ms

A simple liquid chromatography–quadrupole-time-of-flight–mass spectrometric assay (LC-TOF-MS/MS) has been developed for the evaluation of metabolism and pharmacokinetic (PK) characteristics of monomethyl auristatin F (MMAF) in rat, which is being used as a payload for antibody-drug conjugates. LC-TOF-MS/MS method was qualified for the quantification of MMAF in rat plasma. The calibration curves were acceptable over the concentration range from 3.02 to 2200 ng/mL using quadratic regression. MMAF was stable in various conditions. There were no significant matrix effects between rat and other preclinical species. The PK studies showed that the bioavailability of MMAF was 0% with high clearance. Additionally, the metabolite profiling studies, in vitro/in vivo, were performed. Seven metabolites for MMAF were tentatively identified in liver microsome. The major metabolic pathway was demethylation, which was one of the metabolic pathways predicted by MedChem Designer. Therefore, these results will be helpful to understand the PK, catabolism, and metabolism behavior of MMAF comprehensively when developing antibody-drug conjugates (ADCs) in the future.

scholarly journals Antibody-Oligonucleotide Conjugates: A Twist to Antibody-Drug Conjugates

2021 ◽  
Vol 10 (4) ◽  
pp. 838
Author(s):  
Julien Dugal-Tessier ◽  
Srinath Thirumalairajan ◽  
Nareshkumar Jain
Keyword(s):  
Antibody Fragments ◽  
Lessons Learned ◽  
In Vivo Studies ◽  
Antibody Drug Conjugates ◽  
Advantages And Disadvantages ◽  
Drug Conjugates ◽  
Oligonucleotide Conjugates ◽  
Antibody Drug

A summary of the key technological advancements in the preparation of antibody–oligonucleotide conjugates (AOCs) and the distinct advantages and disadvantages of AOCs as novel therapeutics are presented. The merits and demerits of the different approaches to conjugating oligonucleotides to antibodies, antibody fragments or other proteins, mainly from the perspective of AOC purification and analytical characterizations, are assessed. The lessons learned from in vitro and in vivo studies, especially the findings related to silencing, trafficking, and cytotoxicity of the conjugates, are also summarized.

Antibody-drug conjugates targeted to CD79 for the treatment of non-Hodgkin lymphoma

Blood ◽  
2007 ◽  
Vol 110 (2) ◽  
pp. 616-623 ◽  
Author(s):  
Andrew G. Polson ◽  
Shang-Fan Yu ◽  
Kristi Elkins ◽  
Bing Zheng ◽  
Suzanna Clark ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Non Hodgkin Lymphoma ◽  
Antibody Drug

Abstract Targeting cytotoxic drugs to cancer cells using antibody–drug conjugates (ADCs), particularly those with stable linkers between the drug and the antibody, could be an effective cancer treatment with low toxicity. However, for stable-linker ADCs to be effective, they must be internalized and degraded, limiting potential targets to surface antigens that are trafficked to lysosomes. CD79a and CD79b comprise the hetrodimeric signaling component of the B-cell receptor, and are attractive targets for the use of ADCs because they are B-cell–specific, expressed in non-Hodgkin lymphomas (NHL), and are trafficked to a lysosomal-like compartment as part of antigen presentation. We show here that the stable-linker ADCs anti-CD79b-MCC-DM1 and anti-CD79b-MC-MMAF are capable of target-dependent killing of nonHodgkin lymphoma cell lines in vitro. Further, these 2 ADCs are equally effective as low doses in xenograft models of follicular, mantle cell, and Burkitt lymphomas, even though several of these cell lines express relatively low levels of CD79b in vivo. In addition, we demonstrate that anti-CD79b ADCs were more effective than anti-CD79a ADCs and that, as hypothesized, anti-CD79b antibodies downregulated surface B-cell receptor and were trafficked to the lysosomal-like major histocompatibility complex class II–positive compartment MIIC. These results suggest that anti-CD79b-MCC-DM1 and anti-CD79b-MC-MMAF are promising therapeutics for the treatment of NHL.

scholarly journals Uncialamycin-based antibody–drug conjugates: Unique enediyne ADCs exhibiting bystander killing effect

2021 ◽  
Vol 118 (25) ◽  
pp. e2107042118
Author(s):  
K. C. Nicolaou ◽  
Stephan Rigol ◽  
Emmanuel N. Pitsinos ◽  
Dipendu Das ◽  
Yong Lu ◽  
...  
Keyword(s):  
Antitumor Agents ◽  
Killing Effect ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Track Record ◽  
Synthetic Accessibility ◽  
Bystander Killing ◽  
Antibody Drug

Antibody–drug conjugates (ADCs) have emerged as valuable targeted anticancer therapeutics with at least 11 approved therapies and over 80 advancing through clinical trials. Enediyne DNA-damaging payloads represented by the flagship of this family of antitumor agents, N-acetyl calicheamicin γ1I, have a proven success track record. However, they pose a significant synthetic challenge in the development and optimization of linker drugs. We have recently reported a streamlined total synthesis of uncialamycin, another representative of the enediyne class of compounds, with compelling synthetic accessibility. Here we report the synthesis and evaluation of uncialamycin ADCs featuring a variety of cleavable and noncleavable linkers. We have discovered that uncialamycin ADCs display a strong bystander killing effect and are highly selective and cytotoxic in vitro and in vivo.

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