Preclinical studies with IRX‐2 and thymosin α1 in combination therapy

Abstract

Thymosin alpha1 (Talpha1) is a 28 amino acid biologically active protein with pleiotropic immune enhancing activity. IRX-2 is a primary cell-derived biologic containing multiple cytokines that enhance dendritic cell maturation, promote T-cell growth and differentiation, and inhibit tumor-mediated apoptosis of T cells. IRX-2 is being developed as an immunotherapeutic agent as a novel T-cell adjuvant platform for vaccines as well. Based on their biological activities, thymosin alpha1 and IRX-2 were predicted to exhibit synergistic effects when evaluated in animal and human studies. In animal studies, the combination of IRX-2 and Talpha1 (IRX-3) increased T-cell numbers compared to either alone during recovery from hydrocortisone mediated reduction. IRX-3 further enhanced reduction in tumor burden following chemotherapy compared to IRX-2. Based on these studies, IRX-3 is predicted to be especially important in a setting where reversal of immune suppression due to the presence of tumor, irradiation, and/or chemotherapy is likely to be an important factor in cytokine activity.

Transcriptional signatures measured in whole blood correlate with protection against tuberculosis in inbred and outbred mice

“…Irx3 belongs to a superfamily of transcription factors that can act as either repressors or activators of gene expression ([ 44 , 45 ] and is commonly linked with embryonic development of neuronal and cardiac tissue. Irx3 is also associated with malignancies in humans, such as particular subtypes of leukemia, where it may influence T cell maturation checkpoints [ 46 , 47 ]. While the role that irx3 plays in immunity to M .…”

Overlapping molecular signaling of IRX-2 and Ta1 resulting in synergistic biological activity

“…Early studies by the Hadden group, with the combination of Ta1 and IRX-2, were performed in hydrocortisone-suppressed mice and the combination was shown to be superior to either agent alone [19]. Based on those studies and the observation by the Garaci group that Ta1 and IL-2 were superior to either alone, studies were undertaken to combine Ta1 with IRX-2 [20,21,23,24]. The studies suggested synergy, and as shown in Figure 1, significant decrease in tumor growth and survival can be demonstrated in the LLC model.…”

“…Although the majority of patients benefit as defined by enhanced survival due to lymphocyte infiltration, a number of patients failed to benefit. Thus, the combination of IRX-2 with another biologic such as Ta1 is an attractive hypothesis with respect to generating lymphoid cells which may be missing in those individuals who fail to respond to IRX-2 [19][20][21][22][23][24][25].…”

Expression of Bioactive Thymosin Alpha 1 (Tα1) in Marker-free Transgenic Lettuce (Lactuca sativa)

“…Tα1 is a 28-amino acid peptide hormone which was isolated from animal thymus originally, and plays vital roles in immune regulation, promoting natural killer cell activity, enhancing the anti-infection ability of the host and inhibiting the growth of cancer cells (Zavaglia et al 2000). Tα1 increase T-cell markers on immature T cells and enhance immune responses in a wide variety of animal models (Hadden 2001;Naylor and Hadden 2010). Currently, Tα1 is widely used in curing chronic hepatitis B and C and reducing adverse effects on tumors treatment from chemotherapy or radiotherapy (Billich 2002;Ciancio and Rizzetto 2010;Garaci et al 2007;Goldstein and Goldstein 2009).…”