THF-.gamma.2 analogs and pharmaceutical compositions comprising

Details THF-.gamma.2 analogs and pharmaceutical compositions comprising THF-.gamma.2 analogs and pharmaceutical compositions comprising

1996-03-29

1998-07-21

Hill, Jr., Robert J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 2, 514 13, 514 14, 514 15, 514 16, 514 17, 514 18, 514 21, 514885, 530301, 530327, 530328, 530329, 530330, 530331, 530326, 424 95, A61K 3800, A01N 3718, C04K 500, C04K 700

Patent

active

057835578

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to synthetic immunoregulatory peptides which are analogs of thymic humoral factor THF-.gamma.2 (hereinafter THF-.gamma.2) and to pharmaceutical compositions comprising them.


BACKGROUND OF THE INVENTION

THF-.gamma.2, an immunologically active peptide of the sequence Leu-Glu-Asp-Gly-Pro-Lys-Phe-Leu(SEQ ID No:1), has been isolated and purified from calf thymus homogenates and also prepared synthetically (U.S. Pat. No. 4,621,135; Burstein et al., 1988).
THF-.gamma.2 has been shown to possess many biological activities. For example, it was found to augment T cell functions, such as the proliferative response to the T cell mitogens phytohemagglutinin (PHA) and concanavalin A (ConA), the mixed lymphocyte reaction (MLR) and the ConA induced IL-2 production. Increased IL-2 production was shown by spleen cell cultures treated with THF-.gamma.2 prior to their triggering with ConA. THF-.gamma.2 was effective in augmenting IL-2 activity in low IL-2 producer mouse strain C3B6F1 spleen cell cultures by 100-150%, relative to control untreated cultures, at an optimal concentration of 100-300 ng/ml (Burstein et al., 1988).
THF-.gamma.2 modulates the immune state and response of human umbilical cord blood lymphocytes (UCBL). Thus, preincubation of UCBL with THF-.gamma.2 increased the percentage of cells expressing the CD4 or the CD8 differentiation antigens. THF-.gamma.2 increased likewise PHA-induced IL-2 secretion of UCBL cultures by treatment prior to suboptimal PHA stimulation. This effect was THF-.gamma.2 dose dependent with an optimum in the range of 300-600 ng/ml and was not influenced by irradiation of the UCBL (Ben-Hur et al., 1990).
THF-.gamma.2 was shown to have an effect on the immune competence of neonatally thymectomized (NTx) mice, which show a depressed immune response compared to intact age-matched mice. A biweekly course of THF-.gamma.2 injections caused a partial to complete restoration of the immune functions as determined ex-vivo by PHA, ConA, MLR and IL-2 activity. In dose escalation studies, using THF-.gamma.2 at doses of 4, 40 and 400 ng/Kg, the optimal daily dose was found to be 4 ng/Kg (Handzel et al., 1990). Neonatal thymectomy (NTx) of BALB/c mice caused a decrease in myeloid progenitors, which was repaired by serial injections of THF-.gamma.2. The repair of the stem cell compartment in the bone marrow correlated with an increased percentage of Thy1.sup.30 cells in the spleen of THF-.gamma.2 treated NTx mice, indicating that THF-.gamma.2 is able to regulate committed stem cell functions in the bone marrow of immune deprived NTx mice (Pecht et al., 1993).
THF-.gamma.2 was also shown to cause restoration of immune response in mice infected with murine cytomegalovirus (MCMV), which represents a model for the study of the role of the immune system in the pathogenesis of human CMV. Cytomegalovirus causes T cell immune impairment in infected mice, reflected by a decreased response to the T cell mitogens PHA and ConA, reduction of ConA-induced IL-2 secretion, a marked increase in the spleen weight and development of liver focal hepatitis. Systemic treatment of MCMV-infected mice with THF-.gamma.2 resulted in a reconstitution of the mitogenic responses, IL-2 secretion, normalization of spleen weight and recovery of liver inflammation. Unlike other thymic hormones, THF-,y2 did not affect interferon synthesis and NK (Natural Killer) cytotoxicity in MCMV-infected mice, suggesting that THF-.gamma.2 restores immune competence of these immunosuppressed mice through modulation of the T cell compartment (Katorza et al., 1987). Adoptive transfer experiments were performed to evaluate the prospects of enhancing the antiviral potential of MCMV immune spleen cells by THF-.gamma.2. MCMV-resistant adult BALB/c mice become highly susceptible following immunosuppression by cyclophos-phamide (CY). Recipient mice were injected with MCMV and CY concomitantly and 24 hours later, adoptive transfers of syngeneic MCMV-immune spleen cells were performed. It was shown that

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The following were cited in the International Search Report of PCT/US94/07304 and were provided with the file as forwarded from the PCT, however, enclosed are copies.
deCastiglione, "Solution synthesis of an octapeptide" EP, A, 0311392 (Apr. 12, 1989).
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Trainin, et al. "Novel THF compositions" U.S.P.N. 4,621,135, issued Nov. 4, 1986, filed Jun. 6, 1985.

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