Safety and Tolerability of Antibody-Drug Conjugates in Cancer

Wolska-Washer, Anna; Robak, Tadeusz

doi:10.1007/s40264-018-0775-7

Cited by 91 publications

(57 citation statements)

References 69 publications

(128 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Antibodies and small tyrosine kinase inhibitors (TKIs) have been largely used for cancer treatment [ 1 ]. Antibodies target proteins located outside the cellular membrane, thus they act mostly on proteins that are present in the tumoral cell membrane or in the interstitial space, which limits their effect on oncoproteins that act in the intracellular or nuclear compartment [ 2 , 3 ]. On the other hand, TKIs have a favorable permeability acting on proteins with enzymatic activity that are located within these compartments.…”

Section: Introductionmentioning

confidence: 99%

Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer

et al. 2020

View full text Add to dashboard Cite

Bromo and extraterminal domain (BET) inhibitors-PROteolysis TArgeting Chimera (BETi-PROTAC) is a new family of compounds that induce proteasomal degradation through the ubiquitination of the tagged to BET inhibitors Bromodomain proteins, BRD2 and BRD. The encapsulation and controlled release of BET-PROTACs through their vectorization with antibodies, like trastuzumab, could facilitate their pharmacokinetic and efficacy profile. Antibody conjugated nanoparticles (ACNPs) using PROTACs have not been designed and evaluated. In this pioneer approach, the commercial MZ1 PROTAC was encapsulated into the FDA-approved polymeric nanoparticles. The nanoparticles were conjugated with trastuzumab to guide the delivery of MZ1 to breast tumoral cells that overexpress HER2. These ACNPs were characterized by means of size, polydispersity index, and Z-potential. Morphology of the nanoparticles, along with stability and release studies, completed the characterization. MZ1-loaded ACNPs showed a significant cytotoxic effect maintaining its mechanism of action and improving its therapeutic properties.

show abstract

Section: Introductionmentioning

confidence: 99%

Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer

et al. 2020

View full text Add to dashboard Cite

show abstract

“…New ADCs have been recently approved by the Food and Drug Administration (FDA) for the treatment of a variety of lymphoid malignancies, such as ozogamicin conjugates to gemtuzumab (Mylotarg), inotuzumab (Besponsa), approved by the FDA in 2017, and the most recent ADC examples moxetumomab pasudotox (Lumoxiti) and polatuzumab vedotin (Polivy), approved in 2018 and 2019, respectively (see [18,19] for recent reviews). The successful cases of these ADCs have propelled efforts to discover and develop new conjugates as exemplified by the large number of clinical trials involving ADCs, exceeding 100 at the beginning of 2019 [20]. To expand the success of these four ADCs, it is imperative to identify novel antibody targets fulfilling the requirements needed for such a role: high expression on the tumor cell surface, differential expression in tumor versus normal cells, susceptibility to bind to a suitable antibody, and appropriate internalization rate as well as adequate intracellular trafficking [21].…”

Section: Introductionmentioning

confidence: 99%

CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110

et al. 2020

View full text Add to dashboard Cite

Background: In the search for novel antibody-drug conjugates (ADCs) with therapeutic potential, it is imperative to identify novel targets to direct the antibody moiety. CD13 seems an attractive ADC target as it shows a differential pattern of expression in a variety of tumors and cell lines and it is internalized upon engagement with a suitable monoclonal antibody. PM050489 is a marine cytotoxic compound tightly binding tubulin and impairing microtubule dynamics which is currently undergoing clinical trials for solid tumors. Methods: Anti-CD13 monoclonal antibody (mAb) TEA1/8 has been used to prepare a novel ADC, MI130110, by conjugation to the marine compound PM050489. In vitro and in vivo experiments have been carried out to demonstrate the activity and specificity of MI130110. Results: CD13 is readily internalized upon TEA1/8 mAb binding, and the conjugation with PM050489 did not have any effect on the binding or the internalization of the antibody. MI130110 showed remarkable activity and selectivity in vitro on CD13-expressing tumor cells causing the same effects than those described for PM050489, including cell cycle arrest at G2, mitosis with disarrayed and often multipolar spindles consistent with an arrest at metaphase, and induction of cell death. In contrast, none of these toxic effects were observed in CD13-null cell lines incubated with MI130110. Furthermore, in vivo studies showed that MI130110 exhibited excellent antitumor activity in a CD13-positive fibrosarcoma xenograft murine model, with total remissions in a significant number of the treated animals. Mitotic catastrophes, typical of the payload mechanism of action, were also observed in the tumor cells isolated from mice treated with MI130110. In contrast, MI130110 failed to show any activity in a xenograft mouse model of myeloma cells not expressing CD13, thereby corroborating the selectivity of the ADC to its target and its stability in circulation.

show abstract

“…The cytotoxic payload is released into target cancer cells only after internalization of the intact ADC, for example, via receptor-mediated endocytosis and trafficking to the lysosome, where the linker is subsequently cleaved by protein degradation [2,6]. The combination of drug specificity through the mAb component and the stability of the ADC in circulation prior to engagement with the target cell reduces the likelihood of systemic exposure, thus minimizing unwanted toxicity [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…Since the approval of the first ADC in 2000, the field has expanded considerably. There are now five different approved ADCs for malignant diseases, four for the treatment of solid tumors (ado-trastuzumab emtansine, enfortumab vedotin, famtrastuzumab deruxtecan-nxki, and sacituzumab govitecan-hziy), and more than 100 ADCs in the drug-development pipeline [3,9]. In this review, we compare ADCs approved for the treatment of hematologic malignancies, in terms of their primary components (antibody target, linker, and payload) and their clinical utility.…”

Section: Introductionmentioning

confidence: 99%

Antibody–drug conjugates for previously treated aggressive lymphomas: focus on polatuzumab vedotin

Burke

Morschhauser

Andorsky

et al. 2020

Expert Review of Clinical Pharmacology

View full text Add to dashboard Cite

Introduction: Antibody-drug conjugates (ADCs) are immunoconjugates and comprise a monoclonal antibody that is chemically attached to a cytotoxic drug (or payload) via a stable chemical linker. Since the approval of the first ADC in 2000, there are now nine different approved agents and over 100 ADCs in the drug-development pipeline. Areas covered: This review briefly describes the ADCs approved for treatment of lymphoma and their distinguishing factors in terms of target, linker and payload. The clinical implications of the use of ADCs are also considered. Here, we focus on polatuzumab vedotin, an ADC targeted to CD79b, which is approved for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) who have received at least one (EU approval) or two (US approval) prior therapies and are not eligible for bone marrow transplantation. The characteristics of polatuzumab vedotin are discussed and clinical data are presented. The future of polatuzumab vedotin clinical development, and ADCs in general, are also considered. Expert opinion: ADCs represent a significant advance in the treatment of lymphoma. Polatuzumab vedotin has shown clinical efficacy and a tolerable safety profile in both first-line and R/R DLBCL; future studies are planned to further investigate this ADC.

show abstract

Safety and Tolerability of Antibody-Drug Conjugates in Cancer

Cited by 91 publications

References 69 publications

Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer

Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer

CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110

Antibody–drug conjugates for previously treated aggressive lymphomas: focus on polatuzumab vedotin

Contact Info

Product

Resources

About