A5031726220- HER2/EGFR in Cancer Research
- Monoclonal and Polyclonal Antibodies Research
- Cancer therapeutics and mechanisms
- Estrogen and related hormone effects
- Receptor Mechanisms and Signaling
- Parathyroid Disorders and Treatments
- Click Chemistry and Applications
- Medical Imaging and Pathology Studies
- Advanced Breast Cancer Therapies
- Nanofabrication and Lithography Techniques
- Microfluidic and Capillary Electrophoresis Applications
- Glycosylation and Glycoproteins Research
- Radiopharmaceutical Chemistry and Applications
- Chemical Synthesis and Analysis
- Amino Acid Enzymes and Metabolism
Zymeworks (Canada)
2023-2025
Abstract Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently approved for the treatment of breast gastric/gastric esophageal junction cancers resistance remains problem. Here, we engineer IgG1 bispecific, biparatopic antibody (Ab), zanidatamab, with unique enhanced functionalities compared to both trastuzumab combination plus pertuzumab (tras + pert)....
Abstract In recent years, the field of antibody drug conjugates (ADC) has seen a resurgence, largely driven by clinical benefit observed in patients treated with ADCs incorporating camptothecin-based topoisomerase I inhibitor payloads. Herein, we present development novel camptothecin ZD06519 (FD1), which been specifically designed for its application as an ADC payload. A panel analogs different substituents at C-7 and C-10 positions core was prepared tested vitro. Selected compounds...
Abstract Antibody-drug conjugates (ADCs) are one of the fastest-growing therapeutic modalities, with 11 FDA-approved ADCs and more than 250 different in clinical development. Despite their success, significant hurdles remain. Notably, translating preclinical findings to clinic remains challenging. Hematological toxicities commonly associated many may arise from direct killing hematopoietic cells by ADC itself or indirectly payload released elsewhere body. Therefore, development vitro assays...
Abstract Background: Antibody-drug conjugates (ADCs) are a class of cancer therapeutics comprised linker-payload conjugated to monoclonal antibody targeting tumor-associated antigen (TAA), enable the delivery cytotoxic payload cells. Presently, there is need for improved in vitro models that better recapitulate vivo tumor tissue complexity aid screening and evaluation novel ADCs during preclinical development. Specifically, we have developed 3D from cell lines yielding spheroids rapid,...
Synthetic analogs based on the DNA bis-intercalating natural product peptides sandramycin and quinaldopeptin were investigated as antibody drug conjugate (ADC) payloads. Synthesis, biophysical characterization, in vitro potency of 34 new are described. Conjugation an initial drug-linker derived from a novel peptide produced ADC that was hydrophobic prone to aggregation. Two strategies employed improve physiochemical properties: addition solubilizing group linker use enzymatically cleavable...
Abstract Background: Folate Receptor alpha (FRα) is a validated cancer target that prevalently expressed in multiple cancers with high unmet need, including ovarian and other gynecological cancers, NSCLC, endometrial TNBC. Due to FRα’s favorable expression profile, antibody-drug conjugates (ADCs) are being explored this setting. Here we present the preclinical characterization of new anti-FRα ADC, ZW191. ZW191 bystander active antibody drug conjugate (ADC) comprised humanized IgG1 conjugated...
Abstract Addressing inter-patient and intra-tumoral target heterogeneity is a challenge for antibody drug conjugates (ADCs). The most common approach to mitigate ADC employ bystander active payload. Once the internalized metabolized, payload can diffuse into tumor cells, independent of expression. This strategy has proven effective, as evidenced by all but one eleven FDA-approved ADCs incorporating Nevertheless, it important note that in cases there clear evidence an expression-response...
Abstract Background: Folate Receptor alpha (FRa) is a validated cell surface cancer target that prevalently expressed in multiple cancers with high unmet need, including ovarian and other gynecological cancers, while exhibiting minimal expression normal tissues. Due to FRa’s favorable profile, antibody-drug conjugates (ADCs) are being explored this setting. Here we present the preclinical characterization of new anti-FRa ADC, ZW191. ZW191 an antibody drug conjugate (ADC) comprised humanized...
Abstract Background: Antibody-drug conjugates (ADCs) are an effective class of cancer therapeutics which have gained prominence for the treatment several malignancies. A cytotoxic ADC consists a linker-payload conjugated to monoclonal antibody, targets distinct tumor-associated antigen (TAA) enable delivery payload cells. Presently, there is need in vitro models that better recapitulate vivo tumor tissue complexity aid screening and evaluation ADCs during preclinical development. Hence,...
<p>Supplementary Figure S2 shows the chemical stability of FD1 (ZD06519)</p>
<p>Supplementary Figure S3 shows the in vitro cytotoxicity assessment of trastuzumab-ADCs both two-dimensional (2D) and three-dimensional (3D) spheroid assays</p>
<p>Synthesis and characterization of free drugs drug-linkers</p>
<p>Supplementary Figure S4 shows the pharmacokinetic analysis of ADCs (total antibody PK) from tolerability study in rats</p>
<p>Supplementary Figure S4 shows the pharmacokinetic analysis of ADCs (total antibody PK) from tolerability study in rats</p>
<p>Synthesis and characterization of free drugs drug-linkers</p>
<p>HPLC-HIC, LC-MS, HPLC-SEC, residual free drug analysis, and endotoxin levels of ADCs</p>
<div>Abstract<p>In recent years, the field of antibody drug conjugates (ADC) has seen a resurgence, largely driven by clinical benefit observed in patients treated with ADCs incorporating camptothecin-based topoisomerase I inhibitor payloads. Herein, we present development novel camptothecin ZD06519 (FD1), which been specifically designed for its application as an ADC payload. A panel analogs different substituents at C-7 and C-10 positions core was prepared tested <i>in...
<p>Supplementary Figure S3 shows the in vitro cytotoxicity assessment of trastuzumab-ADCs both two-dimensional (2D) and three-dimensional (3D) spheroid assays</p>
<p>Supplementary Figure S1 shows the murine plasma stability of T-DL4 and T-DL13</p>