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  • 1
    Online Resource
    Online Resource
    Washout of heme-containing proteins dramatically improves tetrazolium-based infarct staining
    Elsevier BV ; 2007
    In:  Journal of Pharmacological and Toxicological Methods Vol. 55, No. 2 ( 2007-3), p. 201-208
    Details
    In: Journal of Pharmacological and Toxicological Methods, Elsevier BV, Vol. 55, No. 2 ( 2007-3), p. 201-208
    Type of Medium: Online Resource
    ISSN: 1056-8719
    URL: Article
    DOI: 10.1016/j.vascn.2006.06.005
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2007
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    SSG: 15,3
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  • 2
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    Distal Interstitial Epididymitis in Young Rats
    SAGE Publications ; 2015
    In:  Toxicologic Pathology Vol. 43, No. 3 ( 2015-04), p. 449-452
    Details
    In: Toxicologic Pathology, SAGE Publications, Vol. 43, No. 3 ( 2015-04), p. 449-452
    Abstract: A sporadic, diffuse, interstitial mixed cell epididymitis of unknown etiology was noted in the epididymal cauda and distal corpus of young control Sprague-Dawley (SD) rats. Rats from 2 different suppliers were examined as part of routine toxicology studies. The incidence of this finding was 5/5 (study 1), 2/7 (study 2), and 2/7 (study 3). Although 2 of these studies partially overlapped temporally, none of the affected animals from any study was maintained concurrently with affected animals from any of the other 2 studies, and infectious causes, control article toxicity, or autoimmune processes were considered unlikely etiologies. Inflammation similar to that noted in the epididymides of these young rats was not present in other tissues and was not noted in study cohorts sacrificed at ages older than approximately 11 weeks or in rats of similar age from other concurrent studies. Similar findings were noted sporadically in historical control data, and consequently an age-related finding of unknown etiology and occurring in sporadic clusters is reported in SD rats ≤11 weeks old.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    URL: Article
    DOI: 10.1177/0192623314526320
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2015
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  • 3
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    Ocular Safety and Toxicokinetics of Bevacizumab-bvzr (Zirabev), a Bevacizumab Biosimilar, Administered to Cynomolgus Monkeys by Intravitreal Injection
    Mary Ann Liebert Inc ; 2023
    In:  Journal of Ocular Pharmacology and Therapeutics Vol. 39, No. 3 ( 2023-04-01), p. 215-224
    Details
    In: Journal of Ocular Pharmacology and Therapeutics, Mary Ann Liebert Inc, Vol. 39, No. 3 ( 2023-04-01), p. 215-224
    Type of Medium: Online Resource
    ISSN: 1080-7683 , 1557-7732
    URL: Article
    DOI: 10.1089/jop.2022.0059
    Language: English
    Publisher: Mary Ann Liebert Inc
    Publication Date: 2023
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    SSG: 15,3
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  • 4
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    Validation of a clinically relevant humanized mouse model for the safety assessment of 4-1BB agonists utomilumab and urelumab.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. e14602-e14602
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. e14602-e14602
    Abstract: e14602 Background: Immunotherapy is proven to be powerful and effective in treating cancer. One of the strategies for the therapy is to boost a patient’s immune system by stimulating tumor necrosis factor receptors via the activation of 4-1BB (CD137) costimulatory molecule. Urelumab was the first 4-1BB agonist investigated in clinical trials and showed clinical promise but doses were limited by severe liver toxicity. Preclinical assessment of toxicity failed to predict the clinical safety outcome. Methods: To address the critical needs of in vivo evaluation of toxicity in a preclinical setting, we have developed an animal model using PBMC humanized mice to assess the safety of immunotherapy. In this model, agents targeting human immune system including monoclonal and bispecific antibodies can induce an acute response of cytokine release within hours of treatment and with some therapies a systemic response can manifest in tissue damage and lethality of mice days later. Results: The potential clinical relevance of the PBMC humanized mouse model was demonstrated using 4-1BB agonists urelumab and utomilumab. The antibody-treated PBMC humanized mice were evaluated daily for clinical score and assessed for clinical chemistry and liver histopathology at study terminus. Animals dosed with urelumab at 10 mg/kg exhibited body weight loss and underwent early euthanasia, while animals dosed with utomilumab survived to scheduled euthanasia with minimum body weight loss. Urelumab showed marked liver toxicity relative to utomilumab and controls with more necrosis in the tissue and higher mean ALT, AST and GLDH activities, and the tolerability of urelumab was increased by lowering the dose to 1 mg/kg. The differences captured by the humanized mouse model presented a safety profile similar to the findings about urelumab and utomilumab from the clinical trials. Utomilumab was well tolerated at the dose that caused severe toxicity for urelumab in patients, and the toxicity of urelumab could be reduced by lowering the dose. Conclusions: Our data suggest that the PBMC humanized mouse model could identify human 4-1BB agonists that caused potentially severe liver toxicity. Preclinical safety assessment using humanized mouse models as used for these studies could be an important step in the course of the development of novel immunotherapy for the safety of patients as well as mitigating drug development cost.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.e14602
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 5
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    Abstract 2283: A novel GUCY2C - CD3 bispecific engages T cells to induce cytotoxicity in gastrointestinal tumors
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2283-2283
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2283-2283
    Abstract: Gastrointestinal malignancies, including colorectal cancer (CRC) remain an area of high unmet need. Here we demonstrate tumor selective and potent in vitro and in vivo efficacy with PF-07062119, a novel T cell engaging CD3 bispecific against tumors expressing the Guanylyl Cyclase C (GUCY2C) receptor, a target expressed in more than 90% of CRC, and in other gastrointestinal cancers. Additionally, to address immune evasion mechanisms, combinations of the GUCY2C-CD3 bispecific are explored with immune checkpoint blockade therapy, as well as with chemotherapeutic and anti-angiogenic agents that could enhance immune infiltration into tumors. Our preclinical in vivo data demonstrate that GUCY2C-positive tumors can be targeted with an anti-GUCY2C/anti-CD3ϵ bispecific, with selective drug biodistribution to tumors. PF-07062119 showed potent T cell mediated anti-tumor activity in several human xenograft models of CRC, using adoptive transfer of human T cells, including those with KRAS and BRAF mutations, as well as in models with syngeneic tumors in immunocompetent human CD3 transgenic mice. PF-07062119 activity was further enhanced when combined with anti PD-1/PD-L1 treatment or in combination with chemotherapy or anti-angiogenic therapy. A combination of immunohistochemistry, flow cytometry and CyTOF analyses was used to demonstrate the mechanism of action of PF-07062119 in single agent and combination studies in vivo. Toxicity and pharmacokinetic studies were done in cynomolgus macaques and indicated a monitorable and manageable toxicity profile. These data highlight the potential for PF-07062119 to demonstrate efficacy and improve patient outcomes in CRC and other gastrointestinal malignancies. A clinical Phase I study has been initiated in patients with CRC, gastric and esophageal adenocarcinomas (NCT04171141). Citation Format: Divya Mathur, Adam Root, Bozena Bugaj-Gaweda, Xingzhi Tan, Wei Fang, Stephanie Bisulco, Jonathan Golas, Diane Fernandez, Jessica Kearney, Eric Upeslacis, Johnny Yao, Edward Rosfjord, Chad Stevens, Keith Kobylarz, Lindsay King, Jatin Narula, Kerry Kelleher, David Schaer, Cris Kamperschroer, Bernard Buetow, Cynthia Rohde, Allison Moreau, Gilbert Wong, Puja Sapra. A novel GUCY2C - CD3 bispecific engages T cells to induce cytotoxicity in gastrointestinal tumors [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 2283.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-2283
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 6
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    Chimera Analysis Supports a Predominant Role of PDGFRβ in Promoting Smooth-Muscle Cell Chemotaxis after Arterial Injury
    Elsevier BV ; 2003
    In:  The American Journal of Pathology Vol. 163, No. 3 ( 2003-09), p. 979-984
    Details
    In: The American Journal of Pathology, Elsevier BV, Vol. 163, No. 3 ( 2003-09), p. 979-984
    Type of Medium: Online Resource
    ISSN: 0002-9440
    URL: Article
    DOI: 10.1016/S0002-9440(10)63457-8
    RVK:
    XA 10000
    RVK:
    XA 19800
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2003
    detail.hit.zdb_id: 2943-9
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  • 7
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    Optimal design, anti-tumour efficacy and tolerability of anti-CXCR4 antibody drug conjugates
    Springer Science and Business Media LLC ; 2019
    In:  Scientific Reports Vol. 9, No. 1 ( 2019-02-21)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2019-02-21)
    Abstract: Antibody-drug conjugates (ADCs) are promising therapies for haematological cancers. Historically, their therapeutic benefit is due to ADC targeting of lineage-restricted antigens. The C - X - C motif chemokine r eceptor 4 (CXCR4) is attractive for targeted therapy of haematological cancers, given its expression in multiple tumour types and role in cancer “homing” to bone marrow. However, CXCR4 is also expressed in haematopoietic cells and other normal tissues, raising safety challenges to the development of anti-CXCR4 ADCs for cancer treatment. Here, we designed the first anti-CXCR4 ADC with favourable therapeutic index, effective in xenografts of haematopoietic cancers resistant to standard of care and anti-CXCR4 antibodies. We screened multiple ADC configurations, by varying type of linker-payload, drug-to-antibody ratio (DAR), affinity and Fc format. The optimal ADC bears a non-cleavable linker, auristatin as payload at DAR = 4 and a low affinity antibody with effector–reduced Fc. Contrary to other drugs targeting CXCR4, anti-CXCR4 ADCs effectively eliminated cancer cells as monotherapy, while minimizing leucocytosis. The optimal ADC selectively eliminated CXCR4 + cancer cells in solid tumours, but showed limited toxicity to normal CXCR4 + tissues, sparing haematopoietic stem cells and progenitors. Our work provides proof-of-concept that through empirical ADC design, it is possible to target proteins with broad normal tissue expression.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-019-38745-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2615211-3
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  • 8
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    Regulatory Experience Assessing the Carcinogenic Potential of a Monoclonal Antibody Inhibiting PCSK9, Bococizumab, Including a 2-Year Carcinogenicity Study in Rats
    SAGE Publications ; 2022
    In:  International Journal of Toxicology Vol. 41, No. 5 ( 2022-09), p. 389-401
    Details
    In: International Journal of Toxicology, SAGE Publications, Vol. 41, No. 5 ( 2022-09), p. 389-401
    Abstract: Bococizumab is an anti-PCSK9 monoclonal antibody that was intended for the treatment of hypercholesterolemia. After reviewing the 6-month rat toxicity study data, in which there was a low spontaneous tumor incidence, unrelated to bococizumab administration, the U.S. FDA granted a carcinogenicity waiver request based on a weight-of-evidence assessment of low carcinogenic risk. Subsequently, after reviewing 6-month rat toxicity study data from another anti-PCSK9 antibody, RN317, with a similar low tumor incidence (unrelated to RN317), the U.S. FDA rescinded the bococizumab carcinogenicity study waiver and requested a full 2-year rat carcinogenicity study be conducted. The resulting 2-year carcinogenicity study demonstrated no bococizumab-related increase in tumors, confirming the weight-of-evidence evaluation and alleviating concerns regarding the carcinogenic potential. Here we report the scientific and regulatory background that led to the request for a rat carcinogenicity study, the feedback on the design of the carcinogenicity study, and the results from this study which affirmed the original weight-of-evidence assessment of low carcinogenic risk.
    Type of Medium: Online Resource
    ISSN: 1091-5818 , 1092-874X
    URL: Article
    DOI: 10.1177/10915818221106397
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2022
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  • 9
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    Pharmacokinetics, pharmacodynamics, and toxicity of a PD-1-targeted IL-15 in cynomolgus monkeys.
    American Society of Clinical Oncology (ASCO) ; 2024
    In:  Journal of Clinical Oncology Vol. 42, No. 16_suppl ( 2024-06-01), p. e14568-e14568
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 42, No. 16_suppl ( 2024-06-01), p. e14568-e14568
    Abstract: e14568 Background: Interleukin (IL)-15 is a potent cytokine that enhances the proliferation and effector functions of IL-2Rβ/γ-expressing lymphocytes, such as NK cells and T cell subtypes (CD8+, CD4+, gd, and NKT). PF-07209960 is a novel bispecific fusion protein composed of an anti-PD-1 antibody and engineered IL-15 cytokine mutein with reduced binding affinity to its receptors. PD-1 is expressed on tumor-infiltrating T cells at relatively high levels. PF-07209960 has reduced activity on PD-1-negative NK cells and enhanced activity on PD-1-expressing intratumoral CD8+ T cells, therefore is expected to have improved therapeutic window. Methods: The pharmacokinetics (PK), pharmacodynamics (PD), and toxicity of PF-07209960 were evaluated following once every other week subcutaneous (SC) or intravenous (IV) administration to cynomolgus monkeys in a two-dose PKPD (0.01 – 0.3 mg/kg/dose) study and in a three-dose (SC route) GLP toxicity study (0.1 – 3 mg/kg/dose). Results: PF-07209960 showed dose-dependent pharmacokinetics with a terminal T1/2 of 8 and 13 hours following IV administration at 0.03 and 0.1 mg/kg, respectively. The clearance is faster than a typical IgG1 antibody. Slightly faster clearance was also observed following the second dose, likely due to increased target pool and formation of anti-drug antibodies (ADA). Despite a high incidence rate of ADA (92%) observed in GLP toxicity study, PD-1 receptor occupancy, IL-15 signaling (STAT5 phosphorylation) and T cell expansion were comparable following the first and second doses. Activation and proliferation of T cells were observed with largest increase in cell numbers found in gamma delta T cells, followed by CD4+ and CD8+ T cells, and then NK cells. The expansion of T cells and NK cells in peripheral blood peaked around Day 8 and waned to near baseline levels by Day 15. Release of cytokines IL-6, IFNɣ, and IL-10 were detected, which peaked at 72 hours postdose. All animals at 3 mg/kg/dose were euthanized in a moribund condition on Day 4 of the dosing phase, coincident with the peak of cytokine release. Four out of six monkeys administered 1 mg/kg were euthanized between Day 6 and Day 16 due to thrombocytopenia, bleeding, and poor physical condition. Microscopic evaluations revealed generalized mononuclear infiltration in various tissues. Both the no observed adverse effect level (NOAEL) and the highest non severely toxic dose (HNSTD) were determined to be 0.3 mg/kg/dose, which corresponded to mean Cmax and AUC48 values of 1.15 µg/mL and 37.9 µg*h/mL, respectively. Conclusions: PF-07209960 demonstrated dose-dependent exposure and robust PD (T cell and NK cell subsets expansion and cytokine release) in cynomolgus monkeys, with well-characterized safety profile. In summary, the results of the present study support Phase I clinical evaluation of PF-07209960 in cancer patients.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2024.42.16_suppl.e14568
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2024
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    detail.hit.zdb_id: 604914-X
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  • 10
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    CD40 agonist-induced IL-12p40 potentiates hepatotoxicity
    BMJ ; 2020
    In:  Journal for ImmunoTherapy of Cancer Vol. 8, No. 1 ( 2020-05), p. e000624-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 8, No. 1 ( 2020-05), p. e000624-
    Abstract: CD40 is a compelling target for cancer immunotherapy, however, attempts to successfully target this pathway have consistently been hampered by dose-limiting toxicity issues in the clinic that prevents the administration of efficacious doses. Methods Here, using cytokine and cytokine receptor depletion strategies in conjunction with a potent CD40 agonist, we investigated mechanisms underlying the two primary sources of CD40 agonist-associated toxicity, hepatotoxicity and cytokine release syndrome (CRS). Results We demonstrate that CD40 agonist -induced hepatotoxicity and CRS are mechanistically independent. Historical data have supported a role for interleukin-6 (IL-6) in CRS-associated wasting, however, our findings instead show that an inflammatory cytokine network involving TNF, IL-12p40, and IFNγ underlie this process. Deficiency of TNF or IFNγ did not influence CD40-induced hepatitis however loss of IL-12p40 significantly decreased circulating concentrations of liver enzymes and reduced the frequency of activated CD14 + MHCII + myeloid cells in the liver, indicating a role for IL-12p40 in liver pathology. Conclusions As clinical research programs aim to circumnavigate toxicity concerns while maintaining antitumor efficacy it will be essential to understand which features of CD40 biology mediate antitumor function to develop both safe and efficacious agonists.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2020-000624
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 2719863-7
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