15 results on '"Michael Zakharian"'
Search Results
2. 695 Combination of click chemistry-based SQ3370 with immunotherapies enhances antitumor effect in murine tumors with minimized systemic toxicity
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Jose Mejia Oneto, Sangeetha Srinivasan, Nathan Yee, Amir Mahmoodi, Michael Zakharian, and Jesse McFarland
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
- Full Text
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3. 82 SQ3370 is a novel approach that decreases adverse drug exposure and achieves robust injected and non-injected anti-tumor responses
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Kui Wu, Amir Mahmoodi, Michael Zakharian, and Maksim Royzen
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
- Full Text
- View/download PDF
4. Click activated protodrugs against cancer increase the therapeutic potential of chemotherapy through local capture and activation†
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Sangeetha Srinivasan, Michael Zakharian, Amir Mahmoodi, Nathan Yee, Maksim Royzen, Jose M. Mejia Oneto, and Kui Wu
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0303 health sciences ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Cancer ,General Chemistry ,medicine.disease ,Gemcitabine ,Targeted therapy ,03 medical and health sciences ,chemistry.chemical_compound ,Chemistry ,0302 clinical medicine ,Paclitaxel ,chemistry ,Pharmacokinetics ,In vivo ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Doxorubicin ,business ,Etoposide ,030304 developmental biology ,medicine.drug - Abstract
A desired goal of targeted cancer treatments is to achieve high tumor specificity with minimal side effects. Despite recent advances, this remains difficult to achieve in practice as most approaches rely on biomarkers or physiological differences between malignant and healthy tissue, and thus benefit only a subset of patients in need of treatment. To address this unmet need, we introduced a Click Activated Protodrugs Against Cancer (CAPAC) platform that enables targeted activation of drugs at a specific site in the body, i.e., a tumor. In contrast to antibodies (mAbs, ADCs) and other targeted approaches, the mechanism of action is based on in vivo click chemistry, and is thus independent of tumor biomarker expression or factors such as enzymatic activity, pH, or oxygen levels. The CAPAC platform consists of a tetrazine-modified sodium hyaluronate-based biopolymer injected at a tumor site, followed by one or more doses of a trans-cyclooctene (TCO)-modified cytotoxic protodrug with attenuated activity administered systemically. The protodrug is captured locally by the biopolymer through an inverse electron-demand Diels–Alder reaction between tetrazine and TCO, followed by conversion to the active drug directly at the tumor site, thereby overcoming the systemic limitations of conventional chemotherapy or the need for specific biomarkers of traditional targeted therapies. Here, TCO-modified protodrugs of four prominent cytotoxics (doxorubicin, paclitaxel, etoposide and gemcitabine) are used, highlighting the modularity of the CAPAC platform. In vitro evaluation of cytotoxicity, solubility, stability and activation rendered the protodrug of doxorubicin, SQP33, as the most promising candidate for in vivo studies. In mice, the maximum tolerated dose (MTD) of SQP33 in combination with locally injected tetrazine-modified biopolymer (SQL70) was determined to be 19.1-times the MTD of conventional doxorubicin. Pharmacokinetics studies in rats show that a single injection of SQL70 efficiently captures multiple SQP33 protodrug doses given cumulatively at 10.8-times the MTD of conventional doxorubicin with greatly reduced systemic toxicity. Finally, combined treatment with SQL70 and SQP33 (together called SQ3370) showed antitumor activity in a syngeneic tumor model in mice., The Click Activated Protodrugs Against Cancer (CAPAC) platform uses click chemistry to activate cytotoxic drugs directly at a target site with minimal toxicity, overcoming limitations of conventional chemotherapy and traditional targeted therapies.
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- 2021
5. Abstract 1894: Click Activated Protodrugs Against Cancer (CAPAC™): A modular platform for tumor directed oncology therapeutics
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Jesse M. McFarland, Amir Mahmoodi, Michael Zakharian, Sangeetha Srinivasan, Nathan A. Yee, and José M. Mejía Oneto
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Cancer Research ,Oncology - Abstract
The CAPAC platform aims to help patients beat cancer by activating powerful cancer therapies at the tumor site(s). The core click chemistry technology is agnostic to therapeutic agent or indication. The modular nature of the platform allows targeting strategies based on tumor’s location, antigens, or both to be combined with therapeutics utilizing multiple mechanisms of action to deliver highly effective treatments tailored to each patient. The lead clinical candidate SQ3370 consists of a tetrazine-modified sodium hyaluronate biopolymer (SQL70) that is injected at the tumor site and followed by multiple systemic doses of trans-cyclooctene (TCO)-modified protodrug based on doxorubicin (Dox). Efficient covalent reaction between tetrazine and TCO moieties activates the protodrug and releases active Dox. SQ3370 provides enhanced safety and efficacy in preclinical models compared to conventional Dox, and is being evaluated in a Phase I study in advanced solid tumors (NCT04106492). The efficacy of SQ3370 is from biopolymer-induced activation of protodrug at the tumor site. Data will be presented from mice treated with biopolymer injected peritumorally versus distal-to-tumor, prior to protodrug dosing. Results show significant improvement in tumor growth inhibition and survival in peritumorally-activated SQ3370 compared to distally-activated SQ3370 or conventional Dox. Quantification of protodrug activation in a pharmacokinetic model in rats showed at least 10 to 20% of the protodrug dose is activated by the biopolymer, resulting in over 300 times higher exposure of Dox to tumor versus systemic (plasma) exposure. New TCO-modified protodrugs have been synthesized and preclinical results for the candidate based on monomethyl auristatin E (MMAE) paired with SQL70 will be presented. TCO-MMAE was selected for in vivo evaluation because of its high cytotoxicity-attenuation (93-fold) in vitro. In naive mice, the maximum tolerated dose (MTD) of TCO-MMAE, given as 5 daily doses after an injection of SQL70 biopolymer, was established at 20-times higher than the MTD of conventional MMAE. The antitumor efficacy of TCO-MMAE will be evaluated in future studies. In addition, preliminary results on the use of tetrazine-conjugated antibodies as a targeting agent capable of treating disperse disease when paired with an appropriate TCO-protodrug will be presented. In conclusion, the CAPAC platform is a novel approach that enables targeting of injectable and non-injectable tumors. CAPAC expands the therapeutic potential of anticancer drugs by increasing exposure to tumors and minimizing systemic adverse effects. The CAPAC platform can also be combined with other therapies to modulate the immune response and modify the tumor microenvironment. Citation Format: Jesse M. McFarland, Amir Mahmoodi, Michael Zakharian, Sangeetha Srinivasan, Nathan A. Yee, José M. Mejía Oneto. Click Activated Protodrugs Against Cancer (CAPAC™): A modular platform for tumor directed oncology therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1894.
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- 2022
6. Interim phase 1 results for SQ3370 in advanced solid tumors
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Sant P. Chawla, Kathleen Batty, Masa Aleckovic, Vivek Bhadri, Nam Bui, Alexander David Guminski, Jose Manuel Mejia Oneto, Sangeetha Srinivasan, James Fredric Strauss, Vivek Subbiah, Mia C. Weiss, Rosalind Wilson, Nathan A. Yee, Michael Zakharian, and Vineet Kwatra
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Cancer Research ,Oncology - Abstract
3085 Background: SQ3370, a novel therapy, utilizes Shasqi’s proprietary Click Activated Protodrugs Against Cancer (CAPAC) platform where mutually-reactive click chemistry groups release Doxorubicin (Dox) at the tumor site minimizing systemic exposure. In animals, SQ3370 enhanced survival, T-cell infiltration and antitumor responses in injected and non-injected tumors. Minimal to no toxicity, including no cardiotoxicity was seen in up to 9-fold dose increases in animals. Conventional Dox can induce cardiomyopathy at incidences of 1-20% for cumulative doses from 300-500 mg/m2 in humans and re-treatment with Dox is less effective in heavily pre-treated patients (pts). Here we report interim results of the Phase 1 ( NCT04106492 ). Methods: SQ3370 has 2 components: 1) Intratumoral injection of a protodrug-activating biopolymer (SQL70: 10 mL or 20 mL); 2) 5 consecutive daily IV infusions of an attenuated protodrug of Dox (SQP33). Key eligibility includes locally advanced or metastatic solid tumors, ≤300 mg/m2 prior exposure to Dox, ECOG 0-1 and no limit to prior systemic therapies. Primary objectives include safety and determining Phase 2 dose. Dose escalation was assessed in 2 stages: 1) accelerated titration; 2) 3+3 design. Results: As of 31JAN2022 data cut, 26 pts were treated, 21 with 10 mL biopolymer (bp) and 5 with 20 mL bp over 9 dose escalation protodrug cohorts. MTD has not been reached. Median age was 61 years (26-84), 62% were females, and 69% were ECOG 1. Prior procedures included surgery (89%) and radiation (62%). At study entry, 77% of pts had metastases with a median number of metastatic sites being 2 (1-5); most frequently lung (50%). Tumors were sarcoma (73%), breast cancer (7.7%), gyne (7.7%) and other (11.5%). Twenty-four of 26 (92%) pts received prior systemic therapies with 50% receiving prior Dox. Median number of prior systemic therapies was 2 (1-7). Of the 26 pts, 62% received > 500 mg/m2 cumulative Dox given as SQP33. Median duration of treatment was 2 cycles (1-12). Most frequent AEs, regardless of causality, for the 10 mL bp group included nausea (n = 11), fatigue (n = 9) and anemia (n = 6), and for the 20 mL bp group included anemia (n = 3) and nausea (n = 2). Ejection fraction (LVEF) remained normal during the study period. No AEs that led to discontinuation or death were related to SQ3370 by investigator. At a median follow-up of 9.2 wks (3-37), 21 pts were evaluable. SD was best response in 71%. Median duration of SD was 80-dys (37-186) corresponding to an overall disease control rate (CR+ PR+ SD x 30-dys) of 71% (68% in 10 mL bp; 100% in 20 mL bp). The remainder of pts had PD as best response. Over 38% of pts remain on drug. Conclusions: SQ3370 with 10 mL or 20 mL biopolymer was well tolerated in pts with half being re-treated with Dox. Although > 60% of pts received > 500 mg/m2 cumulative Dox given as SQP33, LVEF remained normal. Preliminary evidence of disease control was observed in pts despite heavy prior pre-treatment and high cancer burden. Dose escalation is ongoing. Clinical trial information: NCT04106492.
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- 2022
7. 82 SQ3370 is a novel approach that decreases adverse drug exposure and achieves robust injected and non-injected anti-tumor responses
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Maksim Royzen, Sangeetha Srinivasan, Jose M. Mejia Oneto, Amir Mahmoodi, Michael Zakharian, Kui Wu, and Nathan Yee
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Cardiotoxicity ,business.industry ,medicine.medical_treatment ,Institutional Animal Care and Use Committee ,Immunosuppression ,Prodrug ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Immune system ,Cancer research ,medicine ,Cytotoxic T cell ,Doxorubicin ,business ,CD8 ,medicine.drug - Abstract
Background Cancer immunotherapies are dependent on endogenous biomarker expression and other biological factors that often result in varying response rates across tumor types and benefit only a subset of patients. Conversely, conventional cytotoxics, the first-line treatment against solid tumors, are effective in a large patient population, but lack specificity, and often result in dose-limiting systemic toxicity. Here, we present SQ3370, a modular approach that activates doxorubicin (Dox) directly at the tumor site with reduced toxicity and potentially activates an immune response against tumor. The technology is independent of biomarkers, enzymatic activity, pH or oxygen levels and is hence expected to be effective in a wider group of patients. SQ3370 consists of a local intratumoral injection of a prodrug-capturing biomaterial (SQL70) followed by 5 daily infusions of SQP33, an attenuated prodrug of Dox. Complementary click chemistry groups in both components allow active Dox release at the tumor site (figure 1). SQP33 prodrug is ~82-fold less cytotoxic than Dox in vitro. We safely administered SQ3370 in dogs at 8.95-times the veterinary clinical dose of Dox, thus widening the therapeutic window, and showed minimal side effects including cardiotoxicity and immunosuppression. We hypothesize that releasing Dox at a local site with SQ3370 may also promote immune activation against the tumor. We evaluated this in a dual-tumor model of syngeneic MC38 tumors. Methods Immunocompetent mice were inoculated with MC38 tumor cells in two subcutaneous flanks. One tumor was intratumorally injected with the biomaterial, SQL70. SQP33 prodrug, control Dox, or saline was administered intravenously as per treatment schedule (figure 2A). Tumors harvested from a subset of mice at 2 weeks were assessed for immune biomarkers. Results In mice bearing two tumors, SQ3370 significantly increased overall survival and the anti-tumor response against injected tumors (figure 2B,C). Surprisingly, SQ3370 also induced regression of the non-injected tumors (figure 2D). Assessment of tumor-Infiltrating immune cells showed an increase in CD3+, CD4+, and CD8+ T cells and a decrease in regulatory T cells in both injected and non-injected lesions (figure 3). The T-cell response correlated with the anti-tumor efficacy data, supporting the immune activation hypothesis. Conclusions SQ3370 is a proof of concept example for a novel modular approach that addresses limitations of current immuno- and cytotoxic therapies for patients with solid tumors. Local release of Dox with SQ3370 expands the therapeutic window of Dox, minimizes toxicities and leads to a robust anti-tumor response that potentially also causes immune activation against the tumors. Acknowledgements The authors would like to thank the National Institutes of Health (NIH), the National Science Foundation (NSF), and Y Combinator. Ethics Approval This study, project number: SQI-FFS-ON-20181119_04_v4, was approved by the Institutional Animal Care and Use Committee (IACUC) of the vendor, following the guidance of Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC), accreditation number 001516.
- Published
- 2020
8. SQ3370 Activates Cytotoxic Drug via Click Chemistry at Tumor and Elicits Sustained Responses in Injected & Non-injected Lesions
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Michael Zakharian, Kui Wu, Sangeetha Srinivasan, Amir Mahmoodi, Maksim Royzen, J.M. Mejía Oneto, and Nathan Yee
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Cytotoxic drug ,business.industry ,Cancer ,medicine.disease ,Systemic toxicity ,Maximum dose ,Click chemistry ,Cancer research ,Medicine ,Doxorubicin ,business ,Single lesion ,medicine.drug ,Immune activation - Abstract
While systemic immuno-oncology therapies have shown remarkable success, only a limited subset of patients benefit from them. Our Click Activated Protodrugs Against Cancer (CAPAC™) Platform is a click chemistry-based approach that activates cancer drugs at a specific tumor with minimal systemic toxicity. CAPAC Platform is agnostic to tumor characteristics that can vary across patients and hence applicable to several types of tumors. We describe the benefits of SQ3370 (lead candidate of CAPAC) to achieve systemic anti-tumor responses in mice bearing two tumors. SQ3370 consists of a biopolymer, injected in a single lesion, followed by systemic doses of an attenuated protodrug of doxorubicin (Dox). SQ3370 was well-tolerated at 5.9-times the maximum dose of conventional Dox, increased survival by 63% and induced a systemic antitumor response against injected and non-injected lesions. The sustained anti-tumor response also correlated with immune activation measured at both lesions. SQ3370 could potentially benefit patients with micro-metastatic lesions.
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- 2020
9. Cancer Cell-Derived, Drug-Loaded Nanovesicles Induced by Sulfhydryl-Blocking for Effective and Safe Cancer Therapy
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Julius A. Edson, Young Jik Kwon, Dominique Ingato, and Michael Zakharian
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0301 basic medicine ,Drug ,Biocompatibility ,Cell Survival ,media_common.quotation_subject ,Cancer therapy ,General Physics and Astronomy ,Antineoplastic Agents ,Biocompatible Materials ,Pharmacology ,Extracellular vesicles ,Extracellular Vesicles ,03 medical and health sciences ,0302 clinical medicine ,Nanocapsules ,Cell Line, Tumor ,polycyclic compounds ,medicine ,Animals ,Humans ,General Materials Science ,Doxorubicin ,Sulfhydryl Compounds ,media_common ,Liposome ,Chemistry ,General Engineering ,Mice, Inbred C57BL ,Drug Liberation ,030104 developmental biology ,030220 oncology & carcinogenesis ,Liposomes ,Cancer cell ,Female ,Intracellular ,medicine.drug - Abstract
Extracellular vesicles (EVs) pose great promise as therapeutic carriers due to their ideal size range and intrinsic biocompatibility. Limited scalability, poor quality control during production, and cumbersome isolation and purification processes have caused major setbacks in the progression of EV therapeutics to the clinic. Here, we overcome these setbacks by preparing cell-derived nanovesicles induced by sulfhydryl-blocking (NIbS), in the desirable size range for therapeutic delivery, that can be further loaded with the chemotherapeutic drug, doxorubicin (DOX), resulting in NIbS/DOX. Applicable to most cell types, this chemical blebbing approach enables efficient, quick, and simple harvest and purification as well as easily scalable production. Cellular uptake and intracellular release of DOX was improved using NIbS/DOX compared to a liposomal formulation. We also confirmed that in tumor-challenged C57BL/6 mice NIbS/DOX significantly slowed tumor growth and led to improved survival compared to treatment with free drug or liposomal drug. NIbS are a promising therapeutic carrier for improving cancer treatment outcomes since they are easy to prepare at a large scale, good candidates for drug loading, and capable of efficient administration of therapeutic agents with avoided nonspecific major distribution in vital organs. In addition, the utility of NIbS can be easily expanded to immunotherapy, gene therapy, and cell therapy when they are derived from applicable cell types.
- Published
- 2018
10. 367 Pharmacokinetic and immunologic data from a phase I study of the click chemistry-based therapy SQ3370 in advanced solid tumors and soft-tissue sarcoma provides proof-of-concept for the CAPAC platform
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M. Wayne Saville, Mia C. Weiss, Vivek Bhadri, Jose M. Mejia Oneto, Vivek Subbiah, Nam Bui, Alexander Guminski, Vineet Kwatra, Kathleen Batty, Sangeetha Srinivasan, Michael Zakharian, Nathan Yee, Rosalind Wilson, Sant P. Chawla, and James Strauss
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Pharmacology ,Cancer Research ,Computer science ,Soft tissue sarcoma ,Immunology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Phase i study ,Oncology ,Proof of concept ,Click chemistry ,medicine ,Molecular Medicine ,Immunology and Allergy ,RC254-282 ,Biomedical engineering - Abstract
BackgroundConventional chemotherapeutics lack specificity for tumor tissue and usually have anarrow therapeutic index. SQ3370, a novel therapy that activates doxorubicin (Dox) at the tumor sitewhile minimizing systemic exposure, is based on intratumoral injection of a protodrug-activatinghyaluronic acid-based biopolymer (SQL70) followed by five daily intravenous (IV) doses of an attenuatedprotodrug of Dox (SQP33). SQ3370 utilizes Shasqi’s proprietary Click Activated Protodrugs AgainstCancer (CAPAC) platform where mutually-reactive click chemistry groups in the two components allowrelease of active Dox specifically at the tumor site. In animals, SQ3370 allowed for an 8.95-fold increase in dosing with minimal systemic adverse eventsand no cardiotoxicity. SQ3370 treatment of mouse tumor models showed improved overall survival,enhanced T-cell infiltration, and a robust anti-tumor response against both biopolymer-injected andnon-injected lesions,1 suggesting that SQ3370 promotes activation of the native immune systemagainst the tumor.MethodsSQ3370-001 (NCT04106492) is a phase 1 trial open to patients with relapsed/refractory soft-tissue sarcoma or other advanced, potentially anthracycline-responsive solid tumors with an injectablelocal or metastatic lesion and =300 mg/m 2 prior exposure to Dox (or equivalent). Primary objectivesinclude safety, tolerability, and recommended Phase 2 dose. Additional objectives include preliminaryefficacy, plasma and tumor biopsy pharmacokinetics (PK), and immune response by peripheral bloodmass cytometry/tumor IHC.ResultsTo date, ten patients have been enrolled. SQ3370 treatment has been well-tolerated with nodose-limiting toxicities observed. Plasma PK appeared consistent with preclinical data; rapid conversionof SQP33 protodrug to active Dox occurred but slowed as the residence time of the injected biopolymerlengthened. Systemic exposure to active Dox peaked on days 1–2 post biopolymer injection, followed bya decline on days 3–5. Preliminary tumor analysis shows that substantial local exposure to Dox continues2 weeks after the last SQP33 dose. Immune response analysis of early patient samples suggestsincreased tumor immune cell infiltration that dynamically changes with each cycle of treatment.ConclusionsSQ3370 appears to be well-tolerated and demonstrates proof-of-concept for the first click-chemistry-based therapy in the clinic. Preclinical and clinical PK are consistent; high tumor exposure canbe achieved, so far without the typical clinical adverse events seen with IV Dox and potentiallyimproving the therapeutic index of a frequently-used chemotherapeutic agent.Trial RegistrationNCT04106492ReferenceSrinivasan S, Yee NA, Wu K, et al. SQ3370 activates cytotoxic drug via click chemistry at tumor andelicits sustained responses in injected and non-injected lesions. Advanced Therapeutics 2021;4(3):2000243.
- Published
- 2021
11. 9P Click Activated Protodrugs Against Cancer (CAPAC) platform enhances the safety, pharmacokinetics, and antitumor efficacy of cancer therapies in vivo
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Michael Zakharian, Sangeetha Srinivasan, Nathan Yee, J.M. Mejía Oneto, Amir Mahmoodi, and M.W. Saville
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Oncology ,Pharmacokinetics ,business.industry ,In vivo ,Cancer research ,Medicine ,Cancer ,Hematology ,business ,medicine.disease - Published
- 2021
12. Correction: Click activated protodrugs against cancer increase the therapeutic potential of chemotherapy through local capture and activation
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Kui Wu, Nathan A. Yee, Sangeetha Srinivasan, Amir Mahmoodi, Michael Zakharian, Jose M. Mejia Oneto, and Maksim Royzen
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Chemistry ,General Chemistry - Abstract
A desired goal of targeted cancer treatments is to achieve high tumor specificity with minimal side effects. Despite recent advances, this remains difficult to achieve in practice as most approaches rely on biomarkers or physiological differences between malignant and healthy tissue, and thus benefit only a subset of patients in need of treatment. To address this unmet need, we introduced a Click Activated Protodrugs Against Cancer (CAPAC) platform that enables targeted activation of drugs at a specific site in the body
- Published
- 2021
13. SQ3370 Activates Cytotoxic Drug via Click Chemistry at Tumor and Elicits Sustained Responses in Injected and Non‐Injected Lesions
- Author
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Maksim Royzen, Michael Zakharian, Nathan Yee, Kui Wu, Jose M. Mejia Oneto, Sangeetha Srinivasan, and Amir Mahmoodi
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Pharmacology ,Cytotoxic drug ,business.industry ,Biochemistry (medical) ,Cancer drugs ,Pharmaceutical Science ,Medicine (miscellaneous) ,Abscopal effect ,Cancer ,medicine.disease ,Article ,Maximum dose ,Click chemistry ,Cancer research ,medicine ,Pharmacology (medical) ,Doxorubicin ,Single lesion ,business ,Genetics (clinical) ,medicine.drug - Abstract
While systemic immuno-oncology therapies have shown remarkable success, only a limited subset of patients benefit from them. Our Click Activated Protodrugs Against Cancer (CAPAC™) Platform is a click chemistry-based approach that activates cancer drugs at a specific tumor with minimal systemic toxicity. CAPAC Platform is agnostic to tumor characteristics that can vary across patients and hence applicable to several types of tumors. We describe the benefits of SQ3370 (lead candidate of CAPAC) to achieve systemic anti-tumor responses in mice bearing two tumors. SQ3370 consists of a biopolymer, injected in a single lesion, followed by systemic doses of an attenuated protodrug™ of doxorubicin (Dox). SQ3370 was well-tolerated at 5.9-times the maximum dose of conventional Dox, increased survival by 63% and induced a systemic anti-tumor response against injected and non-injected lesions. The sustained anti-tumor response also correlated with immune activation measured at both lesions. SQ3370 could potentially benefit patients with micro-metastatic lesions.
- Published
- 2021
14. Abstract 6245: SQ3370 enhances the safety and therapeutic index of cytotoxic agents via local activation therapy with improved local and systemic immune response
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Michael Zakharian, Jose M. Mejia Oneto, Amir Mahmoodi, Maksim Royzen, Nathan Yee, and Sangeetha Srinivasan
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Drug ,Cancer Research ,business.industry ,medicine.medical_treatment ,media_common.quotation_subject ,Cancer ,Immunosuppression ,Prodrug ,Pharmacology ,medicine.disease ,Immune system ,Therapeutic index ,Oncology ,Pharmacokinetics ,medicine ,Doxorubicin ,business ,media_common ,medicine.drug - Abstract
With systemic chemotherapy, only 1-2% of the administered dose reaches a localized tumor, while the remaining leads to adverse off-target toxicities, including immunosuppression. Hence, there is a critical need to locally deliver cytotoxics directly to the tumor. Our patented approach (SQ3370) consists of: 1. SQL70 - a drug-activating biomaterial carrying no payload 2. SQP33 - a chemically-modified prodrug of doxorubicin (Dox) with attenuated activity. SQL70 is injected at the tumor site followed by SQP33 administered systemically. The prodrug is first captured by the biomaterial due to their complementary chemical reactivities. The active drug is then spontaneously released, providing local delivery directly to the tumor region while reducing systemic side effects. Previously, we have shown that the greater safety of SQP33 allows it to be given at over 38 times the dose of standard Dox in SQL70-injected mice. Pharmacokinetic and biodistribution studies in SQ3370-treated rodents and dogs show highly efficient capture and activation of the prodrug, likely due to the rapid reaction of SQP33 with SQL70. Without SQL70, SQP33 shows minimal spontaneous conversion to activated Dox. Additionally, after SQL70 injection, increased dosing of SQP33 led to higher active drug levels at the injection site but not to other tissues. These studies indicate that a single injection of SQL70 can selectively activate multiple doses of SQP33 at the target site, maximizing the local therapeutic index. Recent studies demonstrate that SQ3370 treatment enhances therapeutic response and survival in tumor-bearing mice: In a syngeneic MC38 colorectal cancer model, SQ3370 treatment showed significantly improved anti-tumor response and overall survival compared to conventional Dox therapy. In mice bearing two tumors, we observed that SQL70 injection at one tumor site followed by systemic SQP33 treatment induced an anti-tumor response in both the injected and non-injected tumors. Furthermore, we found that SQ3370 increased CD4 and CD8 TILs and decreased regulatory T-cells in both injected and non-injected tumors. These findings suggest that SQ3370 is capable of inducing an immune-mediated anti-tumor effect, thus expanding potential treatment options in the clinic and highlighting the advantages of immune-sparing cytotoxic therapy. Collectively, our results demonstrate that SQ3370 enables delivery of cytotoxic drugs to a target site while limiting exposure in off-target tissues in small and large animals, leading to improvements in both safety and efficacy. Citation Format: Nathan Yee, Sangeetha Srinivasan, Amir Mahmoodi, Michael Zakharian, Maksim Royzen, Jose Mejia Oneto. SQ3370 enhances the safety and therapeutic index of cytotoxic agents via local activation therapy with improved local and systemic immune response [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 6245.
- Published
- 2020
15. Effect of local activation via SQ3370 on the safety of chemotherapy with concomitant anti-tumor immune response
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Michael Zakharian, Amir Mahmoodi, Sangeetha Srinivasan, Nathan Yee, and Jose M. Mejia Oneto
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Antitumor activity ,Cancer Research ,Chemotherapy ,Immune system ,Oncology ,Systemic chemotherapy ,business.industry ,Concomitant ,medicine.medical_treatment ,Cancer research ,Medicine ,business - Abstract
e15525 Background: With systemic chemotherapy, only 1-2% of the dose given reaches a local tumor, while the remaining leads to off-target toxicities. Hence, there is a critical need to locally deliver cytotoxics directly to the tumor. Our approach (SQ3370) consists of: 1. SQL70 - drug-activating biomaterial carrying 2. SQP33 - chemically-modified prodrug of doxorubicin (Dox) with attenuated activity. Methods: SQL70 is injected at the tumor site followed by SQP33 given systemically. The prodrug is captured by the biomaterial due to their complementary chemical reactivities. The active drug is then spontaneously released, providing local delivery directly to the tumor region while reducing systemic side effects. Results: We have shown that the greater safety of SQ3370 allows significantly higher doses to be administered compared to conventional Dox. PK studies in rodents and dogs show highly efficient capture and activation of the prodrug, likely due to the rapid reaction of SQP33 with SQL70. Without SQL70, SQP33 shows minimal spontaneous conversion to active Dox. A single SQL70 injection selectively activated multiple doses of SQP33 at the target site, maximizing the local therapeutic index. Additionally, SQP33 was capable of being activated by SQL70 injected in various regions in the body, including peri/intratumoral, intraperitoneal, subcutaneous and intramuscular sites. SQ3370 treatment also enhances efficacy in tumor-bearing mice: In a syngeneic MC38 colorectal cancer model, SQ3370 significantly improved anti-tumor response and overall survival compared to conventional Dox. In mice bearing two tumors, SQL70 injection at one tumor site followed by systemic SQP33 treatment induced an anti-tumor response in both the injected and non-injected tumors. This technology also enabled a sustained anti-tumor response upon rechallenge with MC38 tumor cells, without additional treatment. Furthermore, SQ3370 increased CD4 and CD8 TILs and decreased regulatory T-cells in both injected and non-injected tumors, suggesting that SQ3370 can induce an immune-mediated anti-tumor effect, thus expanding potential treatment options in the clinic and highlighting the advantages of immune-sparing cytotoxic therapy. Conclusions: SQ3370 enables delivery of cytotoxic drugs to multiple target sites while limiting off-target exposure, leading to improved safety and efficacy. A multicenter, first-in-human, Phase 1 dose-escalation clinical trial (NCT04106492) in patients with advanced solid tumor malignancies is planned to commence enrollment in April, 2020.
- Published
- 2020
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