scholarly journals Targeting and Efficacy of Novel mAb806-Antibody-Drug Conjugates in Malignant Mesothelioma

2020 ◽  
Vol 13 (10) ◽  
pp. 289
Author(s):  
Puey-Ling Chia ◽  
Sagun Parakh ◽  
Ming-Sound Tsao ◽  
Nhu-An Pham ◽  
Hui K. Gan ◽  
...  

Epidermal growth factor receptor (EGFR) is highly overexpressed in malignant mesothelioma (MM). MAb806 is a novel anti-EGFR antibody that selectively targets a tumor-selective epitope. MAb806-derived antibody drug conjugates (ADCs), ABT-414, ABBV-221 and ABBV-322, may represent a novel therapeutic strategy in MM. EGFR and mAb806 epitope expressions in mesothelioma cell lines were evaluated using an array of binding assays, and the in vitro cell effects of ABT-414 and ABBV-322 were determined. In vivo therapy studies were conducted in mesothelioma xenograft and patient-derived xenograft (PDX) tumor models. We also performed biodistribution and imaging studies to allow the quantitative targeting of MM by mAb806 using a 89Zr-labeled immunoconjugate—ch806. A high EGFR expression was present in all mesothelioma cell lines evaluated and mAb806 binding present in all cell lines, except NCIH-2452. ABT-414 and ABBV-322 resulted in significant tumor growth inhibition in MM models with high EGFR and mAb806 epitope expressions. In contrast, in an EGFR-expressing PDX model that was negative for the mAb806 epitope, no growth inhibition was observed. We demonstrated the specific targeting of the mAb806 epitope expressing MM tumors using 89Zr-based PET imaging. Our data suggest that targeting EGFR in MM using specific ADCs is a valid therapeutic strategy and supports further investigation of the mAb806 epitope expression as a predictive biomarker.

Synlett ◽  
2021 ◽  
Author(s):  
Kazuki Takahashi ◽  
Akira Sugiyama ◽  
Kei Ohkubo ◽  
Toshifumi Tatsumi ◽  
Tatsuhiko Kodama ◽  
...  

IR700, a silicon phthalocyanine (SiPc) photosensitizer, is an antibody-drug conjugate payload used clinically. It is, however, the sole SiPc payload to date, possibly due to the difficulty of its synthesis, resulting from its asymmetric phathalocyanine skeleton. Here we report a new axially-substituted SiPc payload with easier synthesis. Trastuzumab conjugated with the SiPc showed light- and antigen-dependent cytotoxicity in HER2-overexpressed cancer cell lines.


Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2223
Author(s):  
Aranzazu Manzano ◽  
Alberto Ocaña

Antibody-drug conjugates (ADCs) represent a novel and promising therapeutic strategy for the treatment of cancer patients. ADCs target antigens highly expressed on the membrane surface of tumor cells to selectively deliver a cytotoxic drug. Ovarian tumors differentially express tumor-specific antigens, which can be used to guide ADCs. This strategy allows for optimizing tumor targeting while minimizing systemic toxicity compared to classical chemotherapeutic agents. ADCs can be improved by using a cleavable linker allowing the delivery of the toxic payload in surrounding cells not expressing the target protein, therefore acting on heterogeneous tumors with different cell populations. Currently, more than 15 ADCs are under preclinical investigation in ovarian cancer, and some of them have already been tested in early-phase clinical trials with promising results. In this review, we summarize the mechanism of action and the toxicity profile of ADCs and discuss the latest preclinical discoveries and forthcoming applications in ovarian cancer.


2010 ◽  
Author(s):  
Sankar Mohan ◽  
Carol O'Brien ◽  
Heidi Savage ◽  
Gail Phillips ◽  
Mark Lackner ◽  
...  

2019 ◽  
Vol 14 (10) ◽  
pp. S759
Author(s):  
P.L. Chia ◽  
D. Cao ◽  
H. Gan ◽  
E. Reilly ◽  
A. Phillips ◽  
...  

2019 ◽  
Vol 20 (16) ◽  
pp. 3912 ◽  
Author(s):  
Ying Shen ◽  
Yi-Ming Li ◽  
Jing-Jing Zhou ◽  
Zhan Zhou ◽  
Ying-Chun Xu ◽  
...  

Wilms tumor 1 (WT1) oncoprotein is an intracellular oncogenic transcription factor which is barely expressed in normal adult tissues but over expressed in a variety of leukemias and solid cancers. WT1-derived HLA-A*02:01 T cell epitope, RMFPNAPYL (RMF), is a validated target for T cell-based immunotherapy. We generated two T cell receptor mimic antibody-drug conjugates (TCRm-ADCs), ESK-MMAE, and Q2L-MMAE, against WT1 RMF/HLA-A*02:01 complex with distinct affinities, which mediate specific antitumor activity. Although ESK-MMAE showed higher tumor growth inhibition ratio in vivo, the efficacy of them was not so promising, which might be due to low expression of peptide/HLA targets. Therefore, we explored a bispecific TCRm-ADC that exerted more potent tumor cytotoxicity compared with TCRm-ADCs. Hence, our findings validate the feasibility of the presenting intracellular peptides as the targets of ADCs, which broadens the antigen selection range of antibody-based drugs and provides new strategies for precision medicine in tumor therapy.


Blood ◽  
2007 ◽  
Vol 110 (2) ◽  
pp. 616-623 ◽  
Author(s):  
Andrew G. Polson ◽  
Shang-Fan Yu ◽  
Kristi Elkins ◽  
Bing Zheng ◽  
Suzanna Clark ◽  
...  

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.


2018 ◽  
Vol 13 (10) ◽  
pp. S745
Author(s):  
P.L. Chia ◽  
D. Cao ◽  
H. Gan ◽  
A. Rigopoulos ◽  
E. Riley ◽  
...  

1987 ◽  
Vol 56 (6) ◽  
pp. 722-726 ◽  
Author(s):  
LG Durrant ◽  
MC Garnett ◽  
J Gallego ◽  
NC Armitage ◽  
KC Ballantyne ◽  
...  

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