scholarly journals Increased Tumor Penetration of Single-Domain Antibody–Drug Conjugates Improves In Vivo Efficacy in Prostate Cancer Models

2020 ◽  
Vol 80 (6) ◽  
pp. 1268-1278 ◽  
Author(s):  
Ian Nessler ◽  
Eshita Khera ◽  
Steven Vance ◽  
Anna Kopp ◽  
Qifeng Qiu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Single Domain Antibody ◽  
In Vivo Efficacy ◽  
Antibody Drug Conjugates ◽  
Tumor Penetration ◽  
Drug Conjugates ◽  
Domain Antibody ◽  
Cancer Models ◽  
Antibody Drug

scholarly journals Antibody Co-Administration Can Improve Systemic and Local Distribution of Antibody–Drug Conjugates to Increase In Vivo Efficacy

2020 ◽  
Vol 20 (1) ◽  
pp. 203-212 ◽  
Author(s):  
Jose F. Ponte ◽  
Leanne Lanieri ◽  
Eshita Khera ◽  
Rassol Laleau ◽  
Olga Ab ◽  
...  
Keyword(s):  
Local Distribution ◽  
In Vivo Efficacy ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Divinylpyrimidine reagents generate antibody-drug conjugates with excellent in vivo efficacy and tolerability

2022 ◽  
Author(s):  
Stephen J Walsh ◽  
Soleilmane Omarjee ◽  
Friederike M. Dannheim ◽  
Dominique-Laurent Couturier ◽  
Dorentina Bexheti ◽  
...  
Keyword(s):  
In Vivo Efficacy ◽  
Antibody Drug Conjugates ◽  
Structural Characterisation ◽  
Drug Conjugates ◽  
Antibody Drug

The development of divinylpyrimidine (DVP) reagents for the synthesis of antibody-drug conjugates (ADCs) with in vivo efficacy and tolerability is reported. Detailed structural characterisation of the synthesised ADCs was first...

scholarly journals 620 Tumor cell-intrinsic STING pathway is activated in the presence of cues from immune cells and contributes to the anti-tumor activity of tumor cell-targeted STING agonist antibody-drug conjugates

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A656-A656
Author(s):  
Naniye Malli Cetinbas ◽  
Travis Monnell ◽  
Winnie Lee ◽  
Kalli Catcott ◽  
Chen-Ni Chin ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cancer Cell ◽  
Immune Cells ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Primary Monocyte ◽  
Sting Pathway ◽  
Anti Tumor Activity ◽  
Antibody Drug

BackgroundSTING pathway agonism has emerged as a potential therapeutic mechanism to stimulate an innate anti-tumor immune response. While in principle systemic administration of a STING agonist would have many therapeutic benefits, including the delivery of STING to all tumor lesions, such an approach may be limited by toxicity. Antibody-drug conjugates (ADCs) constitute a proven therapeutic modality that is ideally suited to allow systemic administration while stimulating the innate immunity in a targeted manner. We have previously demonstrated that targeted delivery of a STING agonist with an ADC induces robust anti-tumor immune responses.MethodsHerein we investigated the mechanism of action of tumor cell-targeted STING agonist ADCs. We evaluated STING pathway activation and anti-tumor activity elicited by ADCs harboring either wild type (wt) or mutant Fc deficient in Fcγ receptor (FcγR) binding in wt or STING knockout (ko) cancer cell mono-cultures, immune cell co-cultures, and in in vivo tumor models.ResultsConsistent with previous reports, the majority of cancer cell lines tested failed to induce STING pathway following STING agonist payload treatment in mono-cultures. In cancer cell:THP1 monocytic cell co-cultures, tumor-targeted STING agonist ADCs with wt Fc exhibited robust STING activation, whereas Fc-mutant ADCs or non-targeted control ADCs had minimal activity. Similar results were obtained when THP1 cells were treated in plates coated with target antigen without cancer cells, demonstrating STING activation in THP1 cells following FcγR-mediated uptake of antigen-bound ADCs. Tumor-targeted Fc-wt ADCs led to marked induction of STING pathway and cancer cell-killing in cancer cell:PBMC or primary monocyte co-cultures, and complete tumor regressions in in vivo tumors. Surprisingly, while at reduced levels relative to the Fc-wt ADCs, Fc-mutant ADCs exhibited significant activity in these in vitro and in vivo models, suggesting that tumor cell-intrinsic STING pathway may be activated in the presence of cues from immune cells. Consistently, STING agonist payload treatment in the presence of conditioned media from PBMC and primary monocyte but not from THP1 cultures, led to STING activation in cancer cell mono-cultures. Moreover, Fc-mutant ADCs had diminished activity in STING ko cancer cell:PBMC or primary monocyte co-cultures, demonstrating the contribution of tumor cell-intrinsic STING activation to the anti-tumor activity elicited by tumor cell-targeted STING agonist ADCs.ConclusionsIn conclusion, we demonstrated that tumor cell-targeted STING agonist ADCs induce robust anti-tumor activity through mechanisms involving both FcγR and tumor antigen-mediated ADC internalization and subsequent induction of STING pathway in immune cells and tumor cells.

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 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 Monodisperse Polysarcosine-based Highly-loaded Antibody-Drug Conjugates

2018 ◽  
Author(s):  
Warren Viricel ◽  
Guy Fournet ◽  
Sabine Beaumel ◽  
Emeline Perrial ◽  
Sébastien Papot ◽  
...  
Keyword(s):  
Physicochemical Properties ◽  
Drug Loading ◽  
Antitumor Efficacy ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Hydrophilic Drug ◽  
Highly Loaded ◽  
Antibody Drug

<div> <div> <div> <p>We report the synthesis of monodisperse (i.e. discrete) polysarcosine compounds and their use as a hydrophobicity masking entity for the construction of highly-loaded homogeneous β- glucuronidase-responsive antibody-drug conjugates (ADCs). The highly hydrophilic drug-linker platform described herein improves drug-loading, physicochemical properties, pharmacokinetics and in vivo antitumor efficacy of the resulting conjugates. </p> </div> </div> </div>

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.

Monodisperse Polysarcosine-Based Antibody-Drug Conjugates

2018 ◽  
Author(s):  
Warren Viricel ◽  
Guy Fournet ◽  
Sabine Beaumel ◽  
Emeline Perrial ◽  
Sébastien Papot ◽  
...  
Keyword(s):  
Physicochemical Properties ◽  
Drug Loading ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Highly Loaded ◽  
Antibody Drug

We report the on-resin synthesis of monodisperse (<i>i.e.</i> discrete) polysarcosine compounds and their use as an hydrophobicity masking entity for the construction of highly-loaded homogeneous antibody-drug conjugates (ADC). The polysarcosine-based drug-linker platform described herein improves drug-loading, physicochemical properties, pharmacokinetics and shows excellent potency <i>in vivo</i>.

Sign in / Sign up

Export Citation Format

Share Document