Treatment of metastatic, castration-resistant prostate cancer (mCRPC) remains a highly unmet medical need and current therapies ultimately result in disease progression. Immunotherapy is a rapidly growing approach for treatment of cancer but has shown limited success to date in the treatment of mCRPC. We have developed a novel humanized bispecific antibody, MOR209/ES414, built on the ADAPTIR (modular protein technology) platform, to redirect T-cell cytotoxicity toward prostate cancer cells by specifically targeting T cells through CD3e to prostate cancer cells expressing PSMA (prostate-specific membrane antigen). In vitro cross-linking of T cells with PSMAexpressing tumor cells by MOR209/ES414 triggered potent targetdependent tumor lysis and induction of target-dependent T-cell activation and proliferation. This activity occurred at low picomolar concentrations of MOR209/ES414 and was effective at low T-effector to tumor target cell ratios. In addition, cytotoxic activity was equivalent over a wide range of PSMA expression on target cells, suggesting that as few as 3,700 PSMA receptors per cell are sufficient for tumor lysis. In addition to high sensitivity and in vitro activity, MOR209/ES414 induced limited production of cytokines compared with other bispecific antibody formats. Pharmacokinetic analysis of MOR209/ES414 demonstrated a serum elimination half-life in NOD/SCID g (NSG) mice of 4 days. Administration of MOR209/ES414 in murine xenograft models of human prostate cancer significantly inhibited tumor growth, prolonged survival, and decreased serum prostate-specific antigen levels only in the presence of adoptively transferred human T cells. On the basis of these preclinical findings, MOR209/ES414 warrants further investigation as a potential therapeutic for the treatment of CRPC. Mol Cancer Ther; 15(9); 2155-65. Ó2016 AACR.
Introduction: Depletion of CD123 over-expressing malignant cells provides a potential new treatment option which may improve patient outcomes in several hematological malignancies. CD123 is over-expressed in AML, MDS, ALL, CML, HCL and BPDCN and infrequently expressed by normal cells making it an attractive target which is being pursued using a number of different approaches including T-cell engaging immunotherapy. Cytokine release syndrome is a significant concern with T-cell activating therapeutics which has led to severe complications in clinical trials. We have developed APVO436, a bispecific anti-CD123 x anti-CD3 ADAPTIR molecule for redirecting T-cell cytotoxicity to CD123-expressing tumor cells. A potential advantage of the ADAPTIR platform is reduced cytokine release upon T-cell engagement compared to other formats (Mol Cancer Ther. 2016 Sep;15(9):2155-65). Here we present in vitro and in vivo activity of APVO436 and compare the activity of APVO436 to another anti-CD123 x anti-CD3 bispecific containing the amino acid sequence of MGD006.Methods: Binding, T-cell activation and proliferation were assessed using multi-color flow cytometry. Cytotoxic activity was determined using chromium release assays and flow cytometry. PBMC samples were obtained from normal donors and AML patients. In vivo studies were performed using NSG mice transplanted with human PBMC's. The CD123 and CD3 binding domain sequences for flotuzumab (MGD006) were obtained from patent W02015026892 engineered in Macrogenic's dual-affinity re-targeting format as reported in Sci Transl Med. 2015 May 27;7(289):289ra82.Results: Dose-dependent cytotoxicity of CD123 expressing tumor cell lines and primary AML cells was induced by APVO436 at low effector to target ratios, accompanied by T-cell activation and proliferation. APVO436 induced significantly lower levels of several T-cell cytokines including IFNγ, IL-2, and TNFα compared to the molecule in the dual-affinity re-targeting format. In vivo, APVO436 significantly reduced established tumor burden in xenograft murine models.Conclusions: APVO436 potently induces T-cell activation, proliferation and CD123+ cell depletion with AML and normal donor samples and CD123 expressing tumor cell lines with limited levels of T-cell cytokine release compared to another CD123 x CD3 targeting bispecific format suggesting a potential safety advantage. APVO436 inhibits tumor-growth in sub-cutaneous tumor models with IV-implanted human T cells, indicating migration and engagement of T cells at the tumor site. These data are supportive of further investigation of APVO436 as a potential treatment option for AML and other hematological malignancies. GLP toxicology studies have been completed in non-human primates and APVO436 is advancing to clinical testing. Citation Format: Michael R. Comeau, Robert E. Miller, Robert Bader, Rebecca Gottschalk, Mollie Daugherty, Toddy Sewell, Lynda Misher, Lara Parr, Melissa DeFrancesco, David Bienvenue, Catherine J. McMahan, Gabriela H. Hoyos, Jane A. Gross. APVO436, a bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecule for redirected T-cell cytotoxicity, induces potent T-cell activation, proliferation and cytotoxicity with limited cytokine release [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1786.
Introduction: Depletion of CD123 over-expressing tumor cells may improve patient outcomes in several hematological malignancies including AML, MDS, ALL, CML, HCL and BPDCN. CD123 is infrequently expressed by normal cells making it an attractive tumor target, currently being pursued using several different approaches including T-cell engaging immunotherapies. Cytokine release syndrome (CRS) is a concern with T-cell engaging immunotherapies that may require complex clinical development strategies to manage safely. We have developed APVO436, a bispecific anti-CD123 x anti-CD3 ADAPTIR molecule for redirecting T-cell cytotoxicity to CD123-expressing tumor cells, currently in Phase I clinical testing in AML and MDS. A potential advantage of the ADAPTIR platform is reduced cytokine release compared to other formats (Mol Cancer Ther; 15(9):2155-65). We previously compared APVO436 activity to another CD123 x CD3 bispecific antibody containing the amino acid sequence of MGD006. We also demonstrated that APVO436 induces activation of AML patient T cells to kill endogenous tumor cells. Here we extend these studies to test the capacity of APVO436 to induce memory T-cell generation and describe the results of repeat dose toxicology studies in cynomolgus macaques. Methods: Binding, T-cell activation and proliferation were assessed using flow cytometry. Cytotoxic activity was determined using chromium release and flow cytometry assays. Cytokine levels were assessed using multi-plex technology. Repeat dose toxicology studies were performed in cynomolgus macaques. Results: In vitro, APVO436 induced lower levels of several T-cell cytokines while demonstrating similar levels of tumor cell lysis potency compared to other CD123 x CD3 bispecific antibodies. APVO436 induced extensive T-cell proliferation and the development of fully functional memory T cells with cytolytic function. Repeat-dose administration of APVO436 in NHP for 4 weeks by IV bolus injection induced transient changes in T lymphocytes and CD123+ leukocytes. Terminal elimination half-life ranged up to 108 hours with dose proportional exposure after first and last dose; some impact on serum concentration was observed from anti-drug antibodies at late time points. Conclusions: APVO436 induced lower levels of T-cell cytokines associated with CRS compared to other CD123 x CD3 targeting bispecific antibodies and induced the generation of functional memory T cells. Repeat-dose toxicology studies in cynomolgus monkeys demonstrate that APVO436 has antibody-like clearance and volume of distribution parameters and a serum half-life of about 4.5 days. These data support clinical studies with APVO436 as a potential treatment for AML and other hematological malignancies with possible safety advantages over other CD123 targeting therapies. Citation Format: Michael R. Comeau, Rebecca Gottschalk, Mollie Daugherty, Toddy Sewell, Lynda Misher, Bannink Jeannette, Starrla Johnson, Lara Parr, John Kumer, David Jablonski, Melissa DeFrancesco, David Bienvenue, Gabriela H. Hoyos, Catherine J. McMahan, Jane A. Gross. APVO436, a bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecule for redirected T-cell cytotoxicity with limited cytokine release, is well tolerated in repeat dose toxicology studies in cynomolgus macaques [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-199.
Introduction: CD123 is a component of the IL-3 receptor expressed in several hematological malignancies including AML, ALL, HCL, and MDS. CD123 is a compelling target in AML due to its overexpression on AML blasts as well as leukemic stem cells, which are thought to be resistant to chemotherapy and may be responsible for relapse of disease following treatment. While CD123 is expressed by some normal leukocyte populations in circulation and hematopoietic progenitor cells in the bone marrow, the low frequency of expression on normal cell types provides a therapeutic window for targeting CD123 in tumor settings with the potential for durable response and reversible side effects. We have developed bispecific anti-CD123 x anti-CD3 ADAPTIR molecules APVO436 and APVO437 for redirecting T-cell cytotoxicity to CD123-expressing tumor cells. Results are presented that examine the in vitro and in vivo activity of these molecules in preclinical models of AML. Methods: APVO436 and APVO437 proteins were expressed in CHO cells. Affinity SPR studies were performed using recombinant CD123-ectodomain. In vitro functional studies were conducted with CD123+ AML tumor cell lines and primary human and cynomolgus macaque T-cell populations. Cytotoxic activity was determined using chromium release assays. On-cell binding, T-cell activation and proliferation were assessed using multi-color flow cytometry. Pharmacokinetic parameters were determined in BALB/c mice using a single IV dose of approximately 10 mg/kg. In vivo studies to examine tumor growth inhibition activity were performed with NOD/SCID mice co-implanted subcutaneously with AML tumor cells and human T-cells followed by treatment with APVO436 or APVO437. Tumor growth was assessed by measuring tumor volume and Bioluminescent Imaging. Results: APVO436 and APVO437 bound human CD123 protein with high affinity and binding to CD123 and CD3 expressing cell lines was confirmed by flow cytometry. Both APVO436 and APVO437 induced concentration-dependent lysis of CD123+ AML cell lines with primary human effector T-cells, accompanied by T-cell activation and proliferation. Comparable redirected T-cell cytotoxicity function was observed using primary cynomolgus macaque T cells. These activities were dependent on the expression of CD123 by the tumor target cells. APVO436 and APVO437 demonstrated an extended elimination half-life in mouse serum, typical of molecules capable of binding the neo-natal Fc receptor. In vivo, growth of AML tumor cells was inhibited by treatment with low doses of APVO436 and APVO437, significantly improving host survival. Conclusion: Taken together these data demonstrate potent in vitro and in vivo activity of APVO436 and APVO437 against CD123 expressing tumor cells and are supportive of further investigation of this approach as a potential treatment option for AML and other hematological malignancies. Citation Format: Michael R. Comeau, Danielle Mitchell, Rebecca Gottschalk, Lynda Misher, Mollie Daugherty, Lara Parr, Peter Pavlik, Brian Woodruff, Hang Fang, Megan Aguilar, Jeannette Bannink, Starrla Johnson, Gary Li, Robert E. Miller, Robert Bader, Nicole Zhang, Toddy Sewell, Maria Dasovich, Gabriela H. Hoyos, John W. Blankenship, Catherine McMahan, David Bienvenue, Jane A. Gross. Bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecules for redirected T-cell cytotoxicity in hematological malignancies [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 597. doi:10.1158/1538-7445.AM2017-597
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