49 research outputs found
Abstract 2186: Peptide-cleavable maytansinoid (ADCs) induce high bystander killing leading to improved anti-tumor activity <i>in vivo</i>
No full textAbstract
Antibodies targeting surface antigens on cancer cells typically have progressively lower access to tumor cells that are further removed from blood vessels. Also, the antibody will not bind to cells in the tumor mass that do not express antigen, including stromal cells of the tumor, many of which reportedly aid in the survival or metastasis of cancer cells.
ADCs can bind to antigen positive cancer cells, after which they are internalized and catabolized to release one or more cytotoxic metabolite(s) that can kill the targeted cell. Metabolites that are membrane permeable may also diffuse into and kill neighboring cells, often called bystander cells, that would normally be less accessible.
The goal of this work was to design ADCs that would have increased bystander activity, which could result in greater killing of cancer cells and stromal cells in the tumor environment. We have prepared a new type of peptide-cleavable immolative ADC (PCI-ADC) that efficiently releases membrane permeable cytotoxic maytansinoid metabolites upon cleavage of the peptide linker, followed by immolation. Several PCI-ADCs were prepared that release metabolites having different degrees of hydrophobicity. As the hydrophobicity of the metabolite increased, the PCI-ADCs’ bystander activity also increased. The lead PCI-ADC generally displayed a similar degree of in vitro cytotoxicity as maytansinoid ADCs that utilize disulfide linkers, however the PCI-ADC induced significantly more bystander killing. In mice bearing large tumor xenografts (250 mm3) or tumor xenografts that express the target antigen heterogeneously, PCI-ADCs were found to be more efficacious than maytansinoid ADCs that use disulfide linkers, as well as our recently reported peptide-para-anilino maytansinoid ADCs. The nature of the amino acid residues in the peptide linker of the PCI-ADC was also altered so that the tolerability of the ADCs in mice could be increased without impeding efficacy.
In conclusion, we have developed a promising new type of maytansinoid ADC, one that provides a high degree of bystander killing, improved activity in homogeneous and heterogeneous tumor models in vivo, and has a different mechanism of metabolite release than current maytansinoid based ADCs.
Citation Format: Wayne C. Widdison, Juliet A. Costoplus, Jose F. Ponte, Leanne Lanieri, Yulius Setiady, Ling Dong, Anna Skaletskaya, Rui Wu, Qifeng Qiu, Yelena Kovtun, Ravi V. Chari. Peptide-cleavable maytansinoid (ADCs) induce high bystander killing leading to improved anti-tumor activity in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2186. doi:10.1158/1538-7445.AM2017-2186</jats:p
Novel Mechanisms of Autoantibody Induction and Pathogenesis in Experimental Autoimmunity
No full textAbstract 71: Bystander activity and <i>in vivo</i> efficacy of a folate receptor α (FRα)-targeting antibody-drug conjugate with a novel peptide linker
No full textAbstract
Folate receptor α (FRα) is an antigen that is overexpressed on the cell surface of solid tumors including ovarian cancer. The differential expression on cancer cells makes FRα an attractive target for antibody-drug conjugates (ADCs), and an ADC targeting FRα, Mirvetuximab soravtansine, has demonstrated promising activity and safety profiles in the clinic. Here, we employed a new linker (NL) to enhance the bystander activity of ADCs, which is the ability of ADCs to generate cell-permeable catabolites that can diffuse into and kill proximal cancer cells with little or no target expression. With the goal of improving the potency of anti-FRα ADC in solid tumors with heterogeneous FRα expression, we constructed the M9346A-NL-DM. M9346A-NL-DM is a conjugate of the tubulin-disrupting maytansinoid (DM), linked via a novel linker to M9346A, a humanized antibody that binds FRα with high affinity. After cellular uptake and catabolism of the ADC, the new linker undergoes lysosomal cleavage followed by self-immolation to generate free DM that can readily penetrate neighboring cancer cells. Correspondingly, M9346A-NL-DM showed enhanced bystander cytotoxic activity against proximal antigen-negative cells in vitro. In the xenograft tumor models in vivo, M9346A-NL-DM demonstrated enhanced efficacy against tumors with heterogeneous expression of FRα. Interestingly, M9346A-NL-DM also showed improved antitumor activity against a tumor model with homogeneous expression of FRα, possibly due to better tumor penetration of the cell-permeable catabolite. In summary, M9346A-NL-DM is a novel ADC with enhanced bystander activity and antitumor activity that can target tumors with heterogeneous expression of FRα.
Citation Format: Qifeng Qiu, Rui Wu, Leanne Lanieri, Erin Maloney, Anna Skaletskaya, Shan Jin, Lintao Wang, Olga Ab, Joe Ponte, Yulius Setiady, Wayne Widdison, Thomas Keating, Ravi Chari, Richard Gregory, Erica Hong. Bystander activity and in vivo efficacy of a folate receptor α (FRα)-targeting antibody-drug conjugate with a novel peptide linker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 71. doi:10.1158/1538-7445.AM2017-71</jats:p
Cutting Edge: Ly49C/I− Neonatal NK Cells Predispose Newborns to Autoimmune Ovarian Disease Induced by Maternal Autoantibody
No full textAbstract B130: Correlation of in vitro cytotoxicity and catabolism of antibody-drug conjugates (ADCs) in target cancer cells
No full textAnalysis of Joint Property Disputes Undergoing Mediation: A Case Study of the Pasir Pangaraian Religious Court
No full textMarriage is an inner relationship between a man and a woman whose aim is to form an eternal family based on the Almighty Godhead. Joint assets are assets that are acquired throughout the marriage from the time the marriage takes place until the marriage ends or the dissolution of the marriage due to divorce, death or a court decision. Mediation is an effort to resolve conflict by involving a neutral third party, who does not have the authority to make decisions that helps the disputing parties reach a resolution (solution) that is acceptable to both parties. This research aims to analyze joint assets from the perspective of statutory regulations, customary law and Islamic law, as well as dispute resolution through mediation. In this research, the author uses case study data from the Pasir Pengaraian religious court to find out the problems of joint property disputes which were resolved through mediation. The results of this research show that even though there are problems that arise because one party feels that the distribution is unfair, they can find a middle point through mediation. Therefore, mediation has become an important mechanism in law and mediation provides an effective solution to resolve disputes between the parties involved without having to go through formal justice channels. By holding mediation, the disputing parties hand over the resolution of their dispute to one or more independent arbitrators who are considered experts in the matte
Addressing and Improving Legal Development in the Economy Through a Case Study of the Increase in Hajj Pilgrimage Costs in Indonesia
No full textThe Hajj pilgrimage is an important religious journey and must be carried out by all Muslims in the world and Indonesia has the largest Muslim population in the world. This research aims to analyze the development of the number of Hajj pilgrims in Indonesia in recent years and analyze the significant increase in Hajj costs after the Hajj pilgrimage was closed during the Covid-19 pandemic. In this research, the author uses statistical data to determine the development of Hajj pilgrims, the factors increasing the cost of the Hajj pilgrimage and the social and economic impact. The results of this research show that despite the increase in the cost of the Hajj pilgrimage, pilgrims still continue to increase compared to the previous year. One of the factors for the increase in Hajj pilgrims is due to the closure of access to the Hajj pilgrimage in 2020 to 2021, this is due to the Covid-19 pandemic. The impact of the pandemic has affected all countries' economies, one of the countries affected is Indonesia, because this significant change in the Indonesian economy has resulted in an increase in the cost of the Hajj. With the proposed increase in the cost of the Hajj pilgrimage every year, it is a form of understanding regarding legal and economic development in Indonesia. It can be said that if the law is unable to play an effective role, it will certainly have a negative impact on economic development
