The CD70/CD27 pathway plays a significant role in the control of immunity and tolerance, and previous studies demonstrated that targeting murine CD27 (mCD27) with agonist mAbs can mediate antitumor efficacy. We sought to exploit the potential of this pathway for immunotherapy by developing 1F5, a fully human IgG1 mAb to human CD27 (hCD27) with agonist activity. We developed transgenic mice expressing hCD27 under control of its native promoter for in vivo testing of the Ab. The expression and regulation of hCD27 in hCD27-transgenic (hCD27-Tg) mice were consistent with the understood biology of CD27 in humans. In vitro, 1F5 effectively induced proliferation and cytokine production from hCD27-Tg–derived T cells when combined with TCR stimulation. Administration of 1F5 to hCD27-Tg mice enhanced Ag-specific CD8+ T cell responses to protein vaccination comparably to an agonist anti-mCD27 mAb. In syngeneic mouse tumor models, 1F5 showed potent antitumor efficacy and induction of protective immunity, which was dependent on CD4+ and CD8+ T cells. The requirement of FcR engagement for the agonistic and antitumor activities of 1F5 was demonstrated using an aglycosylated version of the 1F5 mAb. These data with regard to the targeting of hCD27 are consistent with previous reports on targeting mCD27 and provide a rationale for the clinical development of the 1F5 mAb, for which studies in advanced cancer patients have been initiated under the name CDX-1127.
T-cell immunoglobulin and mucin domain 1 (TIM-1) is a type I transmembrane protein that was originally described as kidney injury molecule 1 (KIM-1) due to its elevated expression in kidney and urine after renal injury. TIM-1 expression is also upregulated in several human cancers, most notably in renal and ovarian carcinomas, but has very restricted expression in healthy tissues, thus representing a promising target for antibody-mediated therapy. To this end, we have developed a fully human monoclonal IgG1 antibody specific for the extracellular domain of TIM-1. This antibody was shown to bind purified recombinant chimeric TIM-1-Fc protein and TIM-1 expressed on a variety of transformed cell lines, including Caki-1 (human renal clear cell carcinoma), IGROV-1 (human ovarian adenocarcinoma), and A549 (human lung carcinoma). Internalization studies using confocal microscopy revealed the antibody was rapidly internalized by cells in vitro, and internalization was confirmed by quantitative imaging flow cytometry. An antibody-drug conjugate (ADC) was produced with the anti-TIM-1 antibody covalently linked to the potent cytotoxin, monomethyl auristatin E (MMAE), and designated CDX-014. The ADC was shown to exhibit in vitro cytostatic or cytotoxic activity against a variety of TIM-1-expressing cell lines, but not on TIM-1-negative cell lines. Using the Caki-1, IGROV-1, and A549 xenograft mouse models, CDX-014 showed significant antitumor activity in a clinically relevant dose range. Safety evaluation in nonhuman primates has demonstrated a good profile and led to the initiation of clinical studies of CDX-014 in renal cell carcinoma and potentially other TIM-1-expressing tumors. Mol Cancer Ther; 15(12); 2946-54. ©2016 AACR.
Adult rats were treated acutely with peripheral kainic acid (KA), and changes in brain-derived neurotrophic factor (BDNF) mRNA and protein were tracked over time across multiple brain regions. Despite robust elevation in both mRNA and protein in multiple brain regions, plasma BDNF was unchanged and cerebrospinal fluid (CSF) BDNF levels remained undetectable. Primary neurons were then treated with KA. BDNF was similarly elevated within neurons, but was undetectable in neuronal media. Thus, while deficits in BDNF signaling have been implicated in a number of diseases, these data suggest that extracellular concentrations of BDNF may not be a facile biomarker for changes in neurons.
CD40 on antigen presenting cells plays a critical role in the induction of effective innate and adaptive immune responses. In contrast, CD40 signaling on certain malignant cells, particularly B cell lymphomas, inhibits proliferation or triggers apoptotic cell death. Thus, two independent mechanisms provide opportunities for the use of agonist anti-CD40 monoclonal antibodies in cancer therapy: enhancement of anti-tumor immunity, and direct inhibition of tumor growth. CDX-1140 is a human IgG2 antibody selected from a panel of fully human mAbs specific for CD40 generated by hybridoma technology from human Ig transgenic mice. We previously demonstrated the potent immune enhancing effects of CDX-1140 using in vitro models and in non-human primates. CDX-1140 was shown to activate dendritic cells and B cells in an Fc receptor independent manner. CDX-1140 does not bind to the CD40L binding site, and synergizes with CD40L in stimulation of the CD40 receptor and subsequent functional activities. Here we further characterized the anti-tumor activity of CDX-1140 on CD40 positive tumors using xenograft models in immunodeficient mice. Using the Ramos and Raji human lymphoblastoma cell lines, CDX-1140 was shown to attenuate tumor growth and prolong survival. Addition of CDX-1140 and human PBMC was highly effective at promoting complete rejection of both Ramos and Raji tumors. Importantly, the epithelial EJ138 bladder carcinoma cell line was also highly sensitive to CDX-1140 treatment. For example, in a study where mice received EJ138 cells subcutaneously, all animals that were treated with 300 µg of CDX-1140 on days 1, 8, and 15, showed suppression of tumor growth through day 60, in comparison to saline-treated animals which developed significant tumors in 7 of 8 animals. These data support the potential of CDX-1140 for direct anti-tumor effects on CD40-positive tumors (including epithelial tumors) that may supplement its activity as an immune activating agent. CDX-1140 is currently in a phase 1 dose-escalation study in patients with advanced solid tumors. Citation Format: Lawrence J. Thomas, Li-Zhen He, James Testa, Anna Wasiuk, Jeffrey Weidlick, Crystal Sisson, Laura A. Vitale, Thomas O'Neill, Eric Forsberg, Catherine D. Pilsmaker, Lauren E. Gergel, Elizabeth Q. Do, James Boyer, April R. Baronas, Mallary Rocheleau, Michelle E. Grealish, Kathleen M. Borrelli, Henry C. Marsh, Tibor Keler. Efficacy of CDX-1140, an agonist CD40 antibody, in preclinical tumor models [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 3816.
<p>Epitope mapping using overlapping TIM-1 fragments. A series of peptides from the amino acid sequence 209-222 of TIM-1 were synthesized and coated to plates to demonstrate direct binding by CDX-014 mAb.</p>
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