67 research outputs found
Abstract 2670: Combination of anti-HER2 ADC XMT-1522 and checkpoint inhibitor pembrolizumab for treatment of NSCLC in preclinical models
No full textAbstract
The combination of antibody-drug conjugates (ADCs) and immunomodulatory cancer therapies is emerging as a powerful strategy for cancer treatment. Tumor-targeted delivery of a cytotoxic payload capable of inducing immunogenic cell death (ICD) can trigger both an innate and an adaptive immune response, whereby increased recruitment of effector T-cells to the tumor and formation of tumor specific immunological memory can result in a durable treatment response. The ADC XMT-1522 consists of a novel human IgG1 anti-HER2 monoclonal antibody and a novel, auristatin-based cytotoxic payload (Auristatin F-hydroxypropylamide, AF-HPA). An average DAR of 12 AF-HPA molecules is achieved via a biodegradable polymer conjugation platform. We have characterized the ability of both the free payload AF-HPA and the ADC XMT-1522 to induce ICD in vitro in multiple cell lines (NCI-N87, HT-29, SKBR3), as measured by the cell surface expression of the ICD marker calreticulin (CRT) by microscopy and flow cytometry (FACS). CRT, usually contained in the lumen of the endoplasmic reticulum, translocated to the cell surface within a few hours after treatment with AF-HPA or XMT-1522. XMT-1522 as a single agent induced significant tumor regressions in two patient-derived xenograft (PDX) models of HER2-espressing non-small cell lung cancer (NSCLC) at a dose of 3 mg/kg weekly for 3 doses. The combination of XMT-1522 in combination with the checkpoint inhibitor pembrolizumab was tested in one of these patient-derived HER2-expressing PDX models in a mouse with a humanized immune system. Expression of huPD-L1 in the tumor was confirmed by FACS and immunohistochemistry (IHC). Lymphocyte sub-populations were quantified in whole blood and in tumor by FACS and IHC. XMT-1522 treatment alone induced tumor growth delay after 3 weekly doses of 1 mg/kg. Pembrolizumab as a single agent administered every 5 days for 6 doses (q5dx6) at a dose of 2.5 mg/kg led to less tumor growth delay than XMT-1522 treatment. The combination of these two treatment regimens resulted in a better response than either of the two monotherapies. These data provide a rationale for XMT-1522 to be tested clinically as a single agent in HER2-expressing NSCLC, as well as a rationale for combination of XMT-1522 and immunomodulatory therapies in NSCLC.
Citation Format: Natalya Bodyak, Marina Protopopova, Qingxiu Zhang, Alex Yurkovetskiy, Mao Yin, LiuLiang Qin, Laura L. Poling, Rebecca Mosher, Donald A. Bergstrom, Timothy B. Lowinger. Combination of anti-HER2 ADC XMT-1522 and checkpoint inhibitor pembrolizumab for treatment of NSCLC in preclinical models [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 2670. doi:10.1158/1538-7445.AM2017-2670</jats:p
Antibody drug conjugates for treatment of breast cancer: Novel targets and diverse approaches in ADC design
No full textAbstract 2894: XMT-1592, a site-specific Dolasynthen-based NaPi2b-targeted antibody-drug conjugate for the treatment of ovarian cancer and lung adenocarcinoma
No full textAbstract The Dolasynthen platform incorporates the highly potent anti-mitotic agent auristatin F-HPA (AF-HPA), with its associated DolaLock mechanism of controlled bystander effect, and enables the synthesis of antibody-drug conjugates (ADCs) with precise control of the drug-to-antibody ratio (DAR) and site-specific bioconjugation. XMT-1592 is a novel ADC comprised of an anti-NaPi2b antibody and Dolasynthen, conjugated in a site-specific manner to yield DAR 6. NaPi2b, also known as SLC34A2, is a transmembrane sodium-phosphate transporter that is broadly expressed on tumor cells in ovarian carcinoma, NSCLC lung adenocarcinoma and other tumor types. Recent studies have shown that NaPi2b expression is enriched in the EGFR and KRAS mutant subtypes of lung adenocarcinoma. Binding studies showed a specific, high-affinity interaction of XMT-1592 with NaPi2b that was not affected by conjugated Dolasynthen. XMT-1592 elicited potent and specific in vitro cytotoxicity against NaPi2b-expressing ovarian carcinoma cells. XMT-1592 exhibited potent and specific in vivo activity in NaPi2b-expressing tumor xenografts derived from ovarian carcinoma or lung adenocarcinoma. Consistent with the targeted delivery benefits of the ADC approach, XMT-1592 yielded high and sustained concentrations of AF-HPA to tumors but not normal tissues. To evaluate the benefits of site-specific bioconjugation of Dolasynthen, we conducted in vitro and in vivo comparisons of XMT-1592 to a stochastically conjugated version of the ADC. XMT-1592 had improved in vivo activity, pharmacokinetics, and clinical pathology relative to its stochastic counterpart. Taken together, these results support XMT-1592 as a development candidate for the treatment of NaPi2b-expressing tumors. Citation Format: Shawn Fessler, Anouk Dirksen, Scott D. Collins, Ling Xu, Winnie Lee, Jason Wang, Ron Eydelloth, Elena Ter-Ovanesyen, Jeffrey Zurita, Elizabeth Ditty, Barrett Nehilla, Susan Clardy, Susan Clardy, Tyler Carter, Kenneth Avocetien, Mark Nazzaro, Nam Le, Kalli C. Catcott, Alex Uttard, Bingfan Du, Chen-Ni Chin, Rebecca Mosher, Kelly Slocum, Liuliang Qin, David Lee, Dorin Toader, Marc Damelin, Timothy B. Lowinger. XMT-1592, a site-specific Dolasynthen-based NaPi2b-targeted antibody-drug conjugate for the treatment of ovarian cancer and lung adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2894
Abstract 2664: Pharmacokinetics of a novel fumagillol conjugate XMT-1107 in the rat and the dog
No full textAbstract
XMT-1107 is a novel polymer fumagillol derivative, comprised of the small molecule XMT-1191 conjugated to a 70 kDa biodegradable, hydrophilic polyacetal, poly(1-hydroxymethylethylene hydroxymethylformal) (PHF). The conjugated drug XMT-1107 is a prodrug that improves the pharmacokinetics (PK) of the active compound XMT-1191 and demonstrates significant antitumor activity in multiple rodent xenograft models providing a compelling rationale for clinical development. We evaluated the metabolism and PK of XMT-1107 in the rat and the dog and expect that the preclinical dog toxicokinetic (TK) data provide better guidance than the rat data for the assessment of XMT-1107 safety/PK in humans.
XMT-1107 metabolism was studied in rodent, dog and human plasma as well as in liver microsomes. The PK of XMT-1107 was studied in rat and dog at a variety of doses and schedules. The extent and duration of the exposure was monitored over 120 hours post dosing. The analytical determinations of XMT-1107 and small molecule metabolites were carried out by LC/MS/MS.
XMT-1107 was metabolized in rodent, dog and human plasma producing XMT-1191 and XMT-1201 (via conjugated XMT-1201) as major and minor metabolites, respectively. Considering that XMT-1201 does not bind to or inhibit MetAP2, the molecular target of XMT-1107, conjugated and free XMT-1191 are of most interest since conjugated XMT-1191 is a prodrug and XMT-1191 is its active release product.
In both species the PK of conjugated and free XMT-1191 was approximately dose proportional with no marked gender differences. Consistent 2,000-4,000 fold differences between conjugated XMT-1191 and free XMT-1191 plasma exposure (AUC0–120) and Cmax suggest that observed pharmacological effects may result from extravascular distribution of conjugated XMT-1191 and local release of XMT-1191 rather than from systemic exposure to free XMT-1191. Conjugated XMT-1191 has a low volume of distribution, slow systemic clearance and is characterized by a t1/2 ranging from 27-35 hours in rat and 47-68 hours in dog. The 1.8-2.0-fold increase in conjugated XMT-1191 plasma t1/2 observed in dog relative to rat was accompanied by an approximately proportional increase in dose normalized exposure (AUC0–120) to conjugated XMT-1191 and conjugated XMT-1201. The rates for in vitro release of XMT-1191 and XMT-1201 from XMT-1107 in dog and human plasma were similar and at least 2 times lower than the release rates for corresponding compounds in rat plasma, suggesting that dog TK may be more predictive of human XMT-1107 PK compared to rat TK.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2664.</jats:p
<i>trans,anti,trans</i>-Tetra(spirotetrahydrofuranyl)cyclohexane-1,2-dione. Stereocontrolled Synthesis and Definition of Its Susceptibility to Photoisomerization
No full textThe title α-diketone (18) has been synthesized in
stereocontrolled fashion. The ability to introduce
the four contiguous spirocyclic ether oxygens in extended trans fashion
rests on the ability of the
Normant reagent
(ClMgCH2CH2CH2OMgCl)
to engage in chelation control during 1,2-addition to
an α-oxy substituted cyclohexanone. The successful pathway is
dependent on the ability of osmium
tetraoxide to add (slowly) across the double bond of the cyclohexene
precursor. The highly
substituted 1,2-cyclohexanedione is quite sensitive to light and
rearranges by means of an interesting
photoisomerization process to a laterally fused pyran system. A
likely mechanistic pathway for
this intramolecular isomerization is presented
Acid-catalyzed cyclization of 1,4-diols tethered to (butadiene)iron tricarbonyl segments. Isotopic labeling as a mechanistic probe of stereochemical retention during tetrahydrofuran formation
No full text- …
