A5020791417- HER2/EGFR in Cancer Research
- Monoclonal and Polyclonal Antibodies Research
- Synthesis and Biological Evaluation
- Radiopharmaceutical Chemistry and Applications
- Cancer Treatment and Pharmacology
- Peptidase Inhibition and Analysis
- Advanced Biosensing Techniques and Applications
- interferon and immune responses
- CAR-T cell therapy research
- Virus-based gene therapy research
- Cancer Research and Treatments
- Glycosylation and Glycoproteins Research
- Nanoparticle-Based Drug Delivery
- Pharmacogenetics and Drug Metabolism
- Metabolomics and Mass Spectrometry Studies
- Lung Cancer Treatments and Mutations
- Protein Kinase Regulation and GTPase Signaling
- Drug Transport and Resistance Mechanisms
- Click Chemistry and Applications
- Microtubule and mitosis dynamics
- Neuroblastoma Research and Treatments
Mersana Therapeutics (United States)
2012-2024
Antibody-drug conjugates (ADC) are an emerging drug class that uses antibodies to improve cytotoxic targeting for cancer treatment. ADCs in current clinical trials achieve a compromise between potency and physicochemical/pharmacokinetic properties by conjugating potent cytotoxins directly antibody at 4:1 or less stoichiometric ratio. Herein, we report novel, polyacetal polymer-based platform creating ADC use poly-1-hydroxymethylethylene hydroxymethyl-formal (PHF), also known as Fleximer. The...
After significant effort over the last 30 years, antibody-drug conjugates (ADC) have recently gained momentum as a therapeutic modality, and nine ADCs been approved by FDA to date, with additional in late stages of development. Here, we introduce dolaflexin, novel ADC technology that overcomes key limitations most common platforms two features: higher drug-to-antibody ratio auristatin controlled bystander effect. The novel, cell permeable payload, F-hydroxypropylamide, undergoes metabolic...
While STING agonists have proven to be effective preclinically as anti-tumor agents, these promising results yet translated in the clinic. A agonist antibody–drug conjugate (ADC) could overcome current limitations by improving tumor accessibility, allowing for systemic administration well tumor-localized activation of greater activity and better tolerability. In line with this effort, a ADC platform was identified through systematic optimization payload, linker, scaffold based on multiple...
Antibody-drug conjugates (ADC) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many types. The activity safety profile of an ADC depends on its construction: antibody, payload, linker, conjugation method, as well the number payload drugs per antibody [drug-to-antibody ratio (DAR)]. To allow for optimization given target antigen, we developed Dolasynthen (DS), novel platform based auristatin hydroxypropylamide, that enables precise DAR-ranging site-specific...
Abstract Target selection for antibody–drug conjugates (ADC) frequently focuses on identifying antigens with differential expression in tumor and normal tissue, to mitigate the risk of on-target toxicity. However, this strategy restricts possible target space. SLC34A2/NaPi2b is a sodium phosphate transporter expressed variety human tumors including lung ovarian carcinoma, as well tissues from which these arise. Previous clinical trials NaPi2b targeting MMAE-ADCs have shown objective durable...
Abstract We present here a novel therapeutic agent, XMT-2056, that results in robust anti-tumor activity mediated by an immune response through targeted delivery of STING agonist to the tumor microenvironment. By leveraging antibody-drug conjugate (ADC) strategy, systemic administration with tumor-targeted can be achieved, potentially overcoming limitations either intratumoral or intravenous administrations unconjugated, small molecule agonists. XMT-2056 was generated conjugation...
Abstract STING pathway agonism has emerged as a potential therapeutic mechanism to stimulate an innate anti-tumor immune response. While in principle systemic administration of agonist would have many benefits, including the delivery all tumor lesions, such approach may be limited by toxicity. Antibody-drug conjugates (ADCs) constitute proven modality that is ideally suited enable without associated toxicity concerns via targeted strategy. Herein, we demonstrate systemically administered...
Abstract STING pathway agonism has emerged as a potential therapeutic mechanism to stimulate an innate anti-tumor immune response. However, the systemic administration of free agonist may be limited by toxicity, and broad biodistribution not ideal. Antibody-drug conjugates (ADCs) constitute proven modality that enables tumor-targeted delivery thus is ideally suited with reduced toxicity. To develop optimized STING-agonist ADC platform, we designed novel specifically tailored for use in ADC....
Abstract XMT-1522 is an anti-HER2 antibody-drug conjugate (ADC) comprised of a novel antibody (HT-19) and the Dolaflexin ADC platform, which allows for conjugation 12-15 proprietary auristatin drug payload molecules per without aggregation or detrimental impact on pharmacokinetics. The HT-19 binds to HER2 extracellular domain epitope does not compete binding with trastuzumab pertuzumab. In vitro, has sub-nanomolar potency in cell lines expressing as few 25,000 antigens cell, ∼100X more...
Abstract Antibody-drug conjugates are effective in the treatment of HER2-amplified breast cancer and Hodgkin's lymphoma, but current ADC technologies have faced limitations expanding addressable patient population target space. Ado-trastuzumab emtansine (T-DM1) is an with 3-4 cytotoxic drugs per antibody that was recently approved for HER2 IHC 3+ or cancer. Even within this high HER2-expressing population, several studies now shown greater T-DM1 benefit patients mRNA expression above median....
Abstract The ADC XMT-1522 consists of a novel human IgG1 anti-HER2 monoclonal antibody and novel, auristatin-based cytotoxic payload (Auristatin F-hydroxypropylamide, AF-HPA). An average DAR 12 AF-HPA molecules is achieved via biodegradable polymer conjugation platform. non-clinical DMPK properties have been characterized in vitro plasma microsomal stability studies, vivo tissue disposition excretion studies. Sample analysis for total drug released (free) its metabolites was performed by...
Abstract Antibody-drug conjugates (ADCs) are designed to bind tumor-associated antigens and deliver conjugated cytotoxic payloads antigen-positive cells. Some ADCs also kill neighboring cells (including antigen-negative cells) by a mechanism referred as the bystander effect. This effect can be beneficial when antigen has heterogeneous expression among in solid tumor, but it increase off-target toxicity of ADCs. Herein, we report on unique pharmacologic property Dolaflexin platform, which...
Abstract The type II sodium-dependent potassium transporter NaPi2b (SLC34A2) is highly expressed in non-squamous NSCLC and non-mucinous ovarian cancer (OC) with restricted normal tissue expression, suggesting it may be a suitable ADC target for these indications. XMT-1536 novel, potent anti-NaPi2b comprised of an average 15 auristatin molecules conjugated to XMT-1535, novel humanized antibody, via the Dolaflexin platform. payload enzymatically cleaved upon trafficking endosome/lysosome...
A key liability in transitioning a new chemical entity (NCE) to development candidate is NCE-related inhibition (or induction) of cytochrome P450 enzymes, superfamily heme-containing oxygenases that are the major route first-pass metabolism for majority marketed drugs. The drawback drug/NCE modulates CYP450 enzyme activity occurs when compound co-administered with another drug relies on same its metabolism. This could result overdose second case inhibition, or more rapid one both drugs...
Abstract ASN004 is an Antibody Drug Conjugate (ADC) that targets the 5T4 oncofetal antigen (trophoblast glycoprotein), which highly expressed in a wide range of malignant tumors, while having very limited expression normal tissues. incorporates novel single-chain homo-dimer antibody, Fleximer® linker technology (Mersana Therapeutics), and several cytotoxic dolastatin (auristatin) analog warheads per ADC molecule (drug/antibody ratio ∼15). shows high affinity for 5T4-expressing tumor cells....
Abstract Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody–drug conjugates (ADC), some cancers do not respond to MTI-based ADCs. Efforts fill this therapeutic gap have led recent expansion of the ADC “toolbox” include payloads with novel mechanisms action such as topoisomerase inhibition and DNA cross-linking. We present here development mono-alkylator platform that exhibits sustained tumor growth suppression at single doses in MTI-resistant...
<div>Abstract<p>Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody–drug conjugates (ADC), some cancers do not respond to MTI-based ADCs. Efforts fill this therapeutic gap have led recent expansion of the ADC “toolbox” include payloads with novel mechanisms action such as topoisomerase inhibition and DNA cross-linking. We present here development mono-alkylator platform that exhibits sustained tumor growth suppression at single...
<p>Table shows Tabulated cell growth inhibition data for NCI-N87 and MDA-MB231 cells in monoculture coculture when treated with ADCs T-16, T-17, T-18</p>
<p>Figure shows Structures of Platforms 6, and 8-16</p>
<p>Supplementary Materials and Methods including Assays Synthetic Procedures</p>
<p>Figure shows In vitro activity of NaPi2b ADCs X-BG and X-19 payload 4 in the OVCAR3 cell line</p>
<p>Table shows Cytotoxicity Data for Platforms 18 vs 19</p>
<p>Table shows Tabulated cell growth inhibition data for NCI-N87 and MDA-MB231 cells in monoculture coculture when treated with ADCs T-16, T-17, T-18</p>