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  • 1
    Online Resource
    Online Resource
    cDNA Expression Cloning of the IL-1 Receptor, a Member of the Immunoglobulin Superfamily
    American Association for the Advancement of Science (AAAS) ; 1988
    In:  Science Vol. 241, No. 4865 ( 1988-07-29), p. 585-589
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 241, No. 4865 ( 1988-07-29), p. 585-589
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.2969618
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 1988
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
    SSG: 11
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  • 2
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    Online Resource
    Characterization of immune responses in fully vaccinated individuals after breakthrough infection with the SARS-CoV-2 delta variant
    American Association for the Advancement of Science (AAAS) ; 2022
    In:  Science Translational Medicine Vol. 14, No. 641 ( 2022-04-20)
    Details
    In: Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 14, No. 641 ( 2022-04-20)
    Abstract: Breakthrough infections with SARS-CoV-2 have increased in frequency due to both waning immunity and emergence of variants. For example, a cluster of breakthrough infections with the delta variant occurred in a highly vaccinated population in Provincetown, Massachusetts in July 2021. Here, Collier et al. characterized the humoral and cellular immune responses in vaccinated individuals from Provincetown who did or did not develop a breakthrough case of SARS-CoV-2. Vaccinated individuals that tested positive for SARS-CoV-2 had increased mucosal and serum antibody responses, as well as boosted CD8 + T cell responses relative to those who were not infected. Together, these results suggest that, through both vaccination and breakthrough infections, population-level immunity to SARS-CoV-2 will continue to increase.
    Type of Medium: Online Resource
    ISSN: 1946-6234 , 1946-6242
    URL: Article
    DOI: 10.1126/scitranslmed.abn6150
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2022
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  • 3
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    Online Resource
    A KIR x CD8 targeting bispecific modulator enhances regulatory CD8 T cell functions, and reduces inflammation in models of autoimmune disease
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 85.17-85.17
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 85.17-85.17
    Abstract: We have characterized a subset of CD8 T cells (CD8 Treg) with immunosuppressive characteristics in inflammatory disease settings. CD8 Treg activation results in their oligoclonal expansion and elimination of pathogenic CD4 T cells. Here we describe a bispecific CD8 Treg modulator that activates autoimmune patient derived CD8 Treg resulting in the cytolytic elimination of pathogenic CD4 T cell in vitro, ex vivo, and in vivo. METHODS: We tested target and cell binding of a novel bispecific CD8 Treg modulator by Octet and flow cytometry. The functional impact was evaluated using cytotoxicity assays and supernatant analysis in vitro, using Celiac patient derived biopsies ex vivo, and in acute GVHD studies using human PBMCs. RESULTS: We evaluated the efficacy and mechanism of action of a novel bispecific CD8 Treg modulator directed toward CD8 and inhibitory KIR2DL1/2/3. The modulator enhanced cytolytic CD8 Treg functions in vitro using autoimmune patient PBMCs, increased activated CD4 T cell death, and decreased pro-inflammatory cytokines. In Celiac patient derived duodenal tissues, the modulator increased CD8 Treg prevalence and reduced epithelial cell death after gliadin peptide stimulation. In acute GVHD studies, CD8 Treg modulator treated mice had CD8 Treg expansion in a dose dependent fashion and reduced inflammation. CONCLUSIONS: A novel KIR x CD8 targeting bispecific modulator restores cytolytic function of CD8 Treg, resulting in a decrease of pathogenic CD4 T cells. We postulate that the bispecific CD8 T cell modulator can reduce autoreactive CD4 T cell prevalence to reestablish immune balance and may represent a selective and broadly applicable therapeutic approach for the treatment of autoimmune disease.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.85.17
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
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  • 4
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    Online Resource
    Abstract 2855: Anti-PSMA x anti-CD3 SCORPIONTM molecule inhibits tumor growth in vivo in mouse models of prostate cancer.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2855-2855
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2855-2855
    Abstract: Background: Treatment of metastatic, castrate-resistant prostate cancer (CRPC) remains a highly unmet medical need. We have developed a bispecific SCORPIONTM (multi-specific protein therapeutic) molecule that redirects T cell cytotoxicity against cells expressing PSMA (Prostate Specific Membrane Antigen), a common prostate-cancer related antigen. The SCORPION molecule described here contains two pairs of binding domains, each targeting a unique antigen, linked to opposite ends of an immunoglobulin Fc domain to extend the half-life of the molecule in vivo. In these studies, we examine the ability of a SCORPION molecule targeting both CD3 and PSMA, to inhibit the growth of PSMA expressing tumors in vivo. Materials and Methods: NOD/SCID mice were implanted with the PSMA(+) prostate tumor cell line C4-2B and purified human T cells in one of two models. In a first model of residual disease, C4-2B cells were coimplanted subcutaneously with human T cells, and treatment with drug was initiated immediately. This model was run twice with T cells from two different human donors. In a second model of established disease, C4-2B cells were implanted subcutaneously and allowed to develop for 20 days, after which human T cells were injected intra-peritoneally, with subsequent administration of drug. Tumor growth was assessed by tumor volume and serum PSA, and tumor volume and weight loss were used as endpoints. Results: SCORPION molecules targeting PSMA and CD3 inhibited growth of PSMA(+) tumors in both model settings and significantly improved overall survival. Reduction in circulating serum PSA was also observed. Repeat studies using a second human T cell donor showed similar inhibition of tumor growth and overall survival. Inhibition of tumor growth was seen at doses in the low pmol range per mouse. Conclusions: These studies show that anti-PSMA x anti-CD3 SCORPION therapeutics redirect T cell cytotoxicity in in vivo xenograft models and merit further investigation as potential therapeutics in CRPC. Citation Format: Robert Miller, Hang Fang, Jessica Luke, Megan Aguilar, Ruth Chenault, John Kumer, Jennifer Wiens, Paul Algate, David Bienvenue, Catherine McMahan, Holly Nguyen, Robert Vessella, John Blankenship. Anti-PSMA x anti-CD3 SCORPIONTM molecule inhibits tumor growth in vivo in mouse models of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2855. doi:10.1158/1538-7445.AM2013-2855
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-2855
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
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    Abstract 1236: Pharmacokinetic evaluation and tolerability assessment of anti-PSMA x anti-CD3 SCORPIONTM molecule in humanized mice and non-human primates.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1236-1236
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1236-1236
    Abstract: Background: Treatment of metastatic, castrate-resistant prostate cancer (CRPC) remains a highly unmet medical need. We have developed a bispecific SCORPIONTM (multi-specific protein therapeutic) molecule that redirects T-cell cytotoxicity against cells expressing PSMA (Prostate Specific Membrane Antigen), a prostate cancer antigen. SCORPION molecules are antibody-like therapeutics containing two sets of binding domains linked to immunoglobulin Fc domains, which extend the half-life of the molecules in vivo. In these studies, we examine the pharmacokinetics and tolerability of our bispecific SCORPION molecule in humanized mice and non-human primates to assess the potential for clinical development. Materials and Methods: Cross-reactivity of the SCORPION molecule to cynomolgus antigens was first assessed by measuring binding to recombinant PSMA and primary cynomolgus T cells in vitro. Cross-reactivity was further assessed in redirected T-cell cytotoxicity assays using cynomolgus T cells. Pharmacokinetics of the SCORPION molecule were determined from single intravenous injections in BALB/c mice and cynomolgus monkeys. Serum draws at timepoints ranging from 15 minutes to 504 hours were used to determine the serum half-life in each species. Tolerability was assessed following single intravenous injections in both humanized NOD scid gamma (NSG) mice and cynomolgus monkeys. Cytokine release was measured using multiplex immunoassays; T-cell redistribution was followed using flow cytometry. Results: SCORPION molecules targeting PSMA and CD3 showed comparable in vitro binding and cytotoxic activity with human and cynomolgus T cells. Pharmacokinetic analysis showed an extended serum half-life in BALB/c mice and cynomolgus monkeys. Tolerability experiments in humanized NSG mice and cynomolgus monkeys showed a limited dose-dependent effect on cytokine release and T cell redistribution. Conclusions: These studies show that anti-PSMA x anti-CD3 SCORPION therapeutics possess suitable characteristics for further in vivo toxicology studies and merit further investigation as potential therapeutics in CRPC. Citation Format: Catherine J. McMahan, Gabriela Hernandez-Hoyos, Jeannette Bannink, Robert R. Bader, Padma Ravikumar, Toddy Sewell, Kenneth M. Bannink, Rebecca J. Gottschalk, Hang Fang, Starrla Johnson, Megan Aguilar, John Kumer, Paul A. Algate, David L. Bienvenue, John W. Blankenship. Pharmacokinetic evaluation and tolerability assessment of anti-PSMA x anti-CD3 SCORPIONTM molecule in humanized mice and non-human primates. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1236. doi:10.1158/1538-7445.AM2013-1236
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-1236
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
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    Abstract LB173: APVO603: A dual 4-1BB and OX40 bispecific approach utilizing ADAPTIRTMtechnology designed to deliver a conditional T cell/NK response against solid tumors
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. LB173-LB173
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. LB173-LB173
    Abstract: APVO603 is Aptevo's bispecific candidate targeting 4-1BB and OX40. It was designed to have unique properties with the potential to overcome some of the clinical challenges observed with monoclonal antibody targeting these receptors. APVO603 is engineered as an FcγR-signaling deficient bispecific antibody that utilizes Aptevo's ADAPTIR technology for a distinct approach for dual targeting of 4-1BB and OX40 in the absence of additional effector activity. The distinct characteristics of APVO603 may enable conditional activation of 4-1BB and OX40 via agonism of these receptors only when cross-linked via engagement of the other receptor via cis and/or trans cellular interactions. Thus, APVO603 is designed with the potential to overcome both the on-target toxicity and limited efficacy observed with 4-1BB and OX40 monoclonal antibody treatment in the clinic. Anti-4-1BB and OX40 binding domains were optimized to increase affinity, function and stability, then incorporated into the ADAPTIR bispecific antibody platform to produce the APVO603 lead candidate. APVO603 was found to augment 4-1BB and OX40 activity in a dose-dependent manner and is strictly dependent on engagement of the reciprocal receptor to elicit 4-1BB or OX40 signaling in vitro. In preclinical assays using PBMCs sub-optimally stimulated with anti-CD3, APVO603 induces synergistic proliferation of CD4+, CD8+ T and NK cells when compared to anti-OX40 or 4-1BB antibodies with a wt Fc, included either individually or in combination. Additionally, APVO603 enhances proinflammatory cytokine production, granzyme B expression, and reduces the T cell exhaustion phenotype. The mechanistic activity of APVO603 resulted in dose-dependent control of in vivo tumor growth in a preclinical humanized murine xenograft model using established murine MB49 bladder tumors in human 4-1BB and OX40 double knock-in mice. APVO603 is a dual-agonistic bispecific antibody that augments the effector function of activated CD4+ and CD8+ T cells and NK cells in a dose-dependent manner and reduces growth of established tumors in vivo. This preclinical data demonstrates conditional dual stimulation of 4-1BB and OX40 and supports further development of APVO603, a promising immuno-oncology therapeutic with potential for benefit in solid tumors. This program is progressing into IND-enabling studies later this year. Citation Format: Michelle H. Nelson, Robert E. Miller, Secil Franke-Welch, Ruth Chenault, Hang Fang, Allison Chunyk, Gabriela Hernandez-Hoyos, Hilario J. Ramos, David Bienvenue, Catherine McMahan. APVO603: A dual 4-1BB and OX40 bispecific approach utilizing ADAPTIRTMtechnology designed to deliver a conditional T cell/NK response against solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB173.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-LB173
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
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    Online Resource
    Abstract LB172: APVO442: A bispecific T cell-engaging candidate utilizing the ADAPTIR-FLEXTMplatform technology with unique properties designed for optimal tumor distribution and cytotoxic response against PSMA-expressing solid tumors
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. LB172-LB172
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. LB172-LB172
    Abstract: Prostate-Specific Membrane Antigen (PSMA), is a tumor-associated antigen (TAA) that is expressed on prostate cancers, including metastatic castration-resistant prostate cancer (mCRPC). Current chemotherapeutic approaches for mCRPC are challenged by development of resistance resulting in limited clinical benefit. Immuno-oncology therapeutic candidates such as bispecifics re-directing T-cell responses to eliminate tumors, are a promising strategy to overcome the limitations of current approaches and provide benefit to patients with aggressive cancers. Here we present preclinical data demonstrating a potential new approach using low affinity targeting of CD3 and high affinity targeting of PSMA for treatment of a solid tumor cancer.APVO442 is Aptevo's bispecific candidate targeting PSMA and CD3. This candidate was designed to have unique pharmacokinetic and safety properties to potentially maximize potent anti-tumor responses against mCRPC. The APVO442 bispecific T-cell engager uses Aptevo's ADAPTIR-FLEX technology to generate a molecule with low-affinity monovalent CD3 engagement, paired with high-affinity bivalent PSMA binding designed to deliver a highly selective T-cell response at the tumor. The unique engineering of APVO442 reduces the potential of binding to CD3 expressed on peripheral T cells, thus minimizing the potential for on-target toxicity, such as cytokine release, and increasing the potential to deliver the effective concentration of the molecule localized to solid tumors.Preclinical testing demonstrated that APVO442 exhibits optimal manufacturability and functional characteristics for lead candidate selection. Anti-PSMA x anti-CD3 constructs with varying binding strengths to CD3 were evaluated for specificity of CD3 binding, ability to enhance T-cell activation, and ability to elicit T-cell-mediated cytotoxicity against PSMA-expressing tumor targets with varying levels of PSMA expression. APVO442 demonstrated 10-fold reduced binding to CD3 and EC50 compared to the highest affinity constructs tested while retaining equivalent binding to tumor cells expressing various levels of PSMA. The differences in CD3 affinity were associated in a slightly lower EC50 of potency however, the maximal responses for in vitro activation of CD4+ and CD8+ T cells including upregulation of CD25/CD69 expression, proliferation and in vitro tumor lysis were comparable between low and high affinity CD3 constructs. Finally, APVO442 induced reduced levels of multiple cytokines in vitro when compared to high affinity competitor molecules.In vivo, APVO442 elicited robust anti-tumor responses of human PSMA-expressing tumors in a murine xenograft tumor model. The in vivo activity of APVO442 was comparable to high affinity CD3 engaging comparators with similarly measured PK profiles. Additional in vivo characterization of APVO442 is ongoing and continued pre-clinical studies are planned for 2021. Citation Format: Rebecca Gottschalk, Robert E. Miller, Lynda Misher, Michelle H. Nelson, Allison Chunyk, Brian Woodruff, Elizabeth Haglin, Gabriela Hernandez-Hoyos, Peter Pavlik, Catherine McMahan, Hilario J. Ramos, David Bienvenue. APVO442: A bispecific T cell-engaging candidate utilizing the ADAPTIR-FLEXTMplatform technology with unique properties designed for optimal tumor distribution and cytotoxic response against PSMA-expressing solid tumors [abstract] . In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB172.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-LB172
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
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    Online Resource
    The Bispecific Tumor Antigen-Conditional 4–1BB x 5T4 Agonist, ALG.APV-527, Mediates Strong T-Cell Activation and Potent Antitumor Activity in Preclinical Studies
    American Association for Cancer Research (AACR) ; 2023
    In:  Molecular Cancer Therapeutics Vol. 22, No. 1 ( 2023-01-03), p. 89-101
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 22, No. 1 ( 2023-01-03), p. 89-101
    Abstract: 4–1BB (CD137) is an activation-induced costimulatory receptor that regulates immune responses of activated CD8 T and natural killer cells, by enhancing proliferation, survival, cytolytic activity, and IFNγ production. The ability to induce potent antitumor activity by stimulating 4–1BB on tumor-specific cytotoxic T cells makes 4–1BB an attractive target for designing novel immuno-oncology therapeutics. To minimize systemic immune toxicities and enhance activity at the tumor site, we have developed a novel bispecific antibody that stimulates 4–1BB function when co-engaged with the tumor-associated antigen 5T4. ALG.APV-527 was built on the basis of the ADAPTIR bispecific platform with optimized binding domains to 4–1BB and 5T4 originating from the ALLIGATOR-GOLD human single-chain variable fragment library. The epitope of ALG.APV-527 was determined to be located at domain 1 and 2 on 4–1BB using X-ray crystallography. As shown in reporter and primary cell assays in vitro, ALG.APV-527 triggers dose-dependent 4–1BB activity mediated only by 5T4 crosslinking. In vivo, ALG.APV-527 demonstrates robust antitumor responses, by inhibiting growth of established tumors expressing human 5T4 followed by a long-lasting memory immune response. ALG.APV-527 has an antibody-like half-life in cynomolgus macaques and was well tolerated at 50.5 mg/kg. ALG.APV-527 is uniquely designed for 5T4-conditional 4–1BB–mediated antitumor activity with potential to minimize systemic immune activation and hepatotoxicity while providing efficacious tumor-specific responses in a range of 5T4-expressing tumor indications as shown by robust activity in preclinical in vitro and in vivo models. On the basis of the combined preclinical dataset, ALG.APV-527 has potential as a promising anticancer therapeutic for the treatment of 5T4-expressing tumors.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-22-0395
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 9
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    Online Resource
    Abstract B111: Characterization of APVO436, a bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecule for redirected T-cell cytotoxicity, in preclinical models of AML and nonhuman primates
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 1_Supplement ( 2018-01-01), p. B111-B111
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 1_Supplement ( 2018-01-01), p. B111-B111
    Abstract: Introduction: CD123 has emerged as a promising target for T-cell directed immunotherapy in acute myeloid leukemia due to its high level of expression on leukemic blasts and stem cells and low frequency of expression on normal cell types. CD123 is expressed by rare normal leukocyte populations, including basophils and plasmacytoid dendritic cells in circulation and hematopoietic progenitor cells in the bone marrow. We have developed APVO436, a bispecific anti-CD123 x anti-CD3 ADAPTIR molecule for redirecting T-cell cytotoxicity to CD123-expressing tumor cells. Results are presented that examine the in vitro and in vivo activity of APVO436 in preclinical models of AML, as well as pharmacokinetics and tolerability in nonhuman primates. Methods: CHO-produced APVO436 protein was used for in vitro functional studies with CD123+ AML tumor cell lines and primary human T-cell populations. Cytotoxic activity was determined using chromium release assays. On-cell binding, T-cell activation and proliferation were assessed using multicolor flow cytometry. Cytokine levels were measured using multiplex assay kits. In vivo studies to examine tumor growth inhibition activity were performed using NSG mice with established AML tumors followed by treatment with APVO436 coadministered with T cells. Tumor growth was assessed by bioluminescent imaging. In vivo studies to determine pharmacokinetics of APVO436 following single intravenous injections were performed in healthy BALB/c mice and cynomolgus monkeys. Results: APVO436 bound to CD123 and CD3 expressing cells with high affinity. APVO436 induced concentration-dependent lysis of CD123+ AML cell lines with primary human T cells at low effector-to-target ratios, accompanied by T-cell activation and proliferation. These activities were dependent on the expression of CD123 by the tumor target cells. Treatment of established disseminated tumors in mice with APVO436 resulted in a significant reduction in tumor burden. A single 10 mg/kg IV injection of APVO436 in normal BALB/c mice demonstrated an extended elimination serum half-life of approximately 300 hours. Single IV injections of APVO436 ranging from 0.25 mg/kg to 1 mg/kg were well tolerated in cynomolgus monkeys. The observed elimination half-life in cynomolgus serum was up to 84 hours with normal clearance and volume distribution. Conclusions: These data demonstrate APVO436 has potent in vitro activity against a number of CD123-expressing tumor cell lines and in vivo significantly reduces established tumor burden in xenograft models. APVO436 demonstrates an extended serum half-life in normal mice and cynomolgus monkeys. These data are supportive of further investigation of APVO436 as a potential treatment option for AML and other hematologic malignancies. Citation Format: Michael R. Comeau, Robert E. Miller, Jeannette Bannink, Starrla Johnson, Robert Bader, Rebecca Gottschalk, Lynda Misher, Danielle Mitchell, Lara Parr, Melissa DeFrancesco, David Bienvenue, Catherine J. McMahan, Gabriela H. Hoyos, Jane A. Gross. Characterization of APVO436, a bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecule for redirected T-cell cytotoxicity, in preclinical models of AML and nonhuman primates [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B111.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-17-B111
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 10
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    Online Resource
    Small Modular ImmunoPharmaceutical (SMIPTM) Molecules Directed at the TCR Complex Block Acute Graft Versus Host Disease and Cause Minimal Cytokine Release In Vivo (145.30)
    The American Association of Immunologists ; 2010
    In:  The Journal of Immunology Vol. 184, No. 1_Supplement ( 2010-04-01), p. 145.30-145.30
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 184, No. 1_Supplement ( 2010-04-01), p. 145.30-145.30
    Abstract: The T cell receptor complex (TCR) is a powerful therapeutic target for modulating autoimmunity and transplantation biology. A number of studies have shown that TCR/CD3-directed molecules are beneficial in mouse models of disease (e.g, acute graft vs host disease, aGVHD). However, both 145-2C11 (anti-CD3ϵ) and H57-597 (anti-TCRβ) are T cell mitogens and stimulate the activation of T cells and cytokine release in vitro and in vivo . In contrast to conventional antibodies, SMIP molecules are single chain binding proteins based on a scFv-CH2-CH3 format. Compared to their corresponding parent antibodies, SMIP molecules utilizing the 2C11 and H57 binding domains demonstrate a more robust down modulation of the TCR complex, enhanced efficacy in in vitro assays of T cell function, and significantly reduced levels of pro-inflammatory cytokines. Administration of these compounds in vivo results in significantly lower levels of cytokine release with no measurable changes in animal weight loss or adverse clinical symptoms despite dosage of 60 fold molar excess compared to the original full-length antibody. In addition, our SMIPs significantly abrogate donor cell engraftment in spleens of host animals in a parent into F1 model of aGVHD. These observations indicate that features in the SMIP format could generate novel anti-human CD3-directed therapeutics with greatly reduced levels of cytokine release in vivo.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.184.Supp.145.30
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2010
    detail.hit.zdb_id: 1475085-5
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