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Facing the future challenges in immunosuppression

The latest issue of Transplantation Proceedings reports on 3 exciting prospects for immunosuppression, bactobolamine, spanidin and tacrolimus. Another noteworthy immunosuppressant under development is Sandoz' cyclosporin derivative, SDZ IMM 125, discussed at an International Symposium held in Basle, Switzerland last year and reported in the August supplement of the journal.

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Bactobolamine - another potential immunosuppressant

Bactobolamine prolonged survival of skin allografts in mice across major histocompatibilty complex barriers, ' ... comparable to the results of treatment by CyA [cyclosporinl', according to Japanese researchers. Both skin and liver allografts were significantly prolonged in bactobolamine recipients compared with control mice [see tables].

Table I. kin fran plantation J Group Mean survival (days)

Bactobolamlne 17

Cyclosporin 16

Control 14

Bactobolamine, produced by Meifiseika, is a derivative of the bacterial metabolite, bactobolin, which suppresses proliferative lymphocytic responses. Compared with the parent compound, toxic adverse effects are greatly reduced with bactobolamine.

Tabl I. ur i al after Ii

Grou

Bactobolamlne

Control

Mean survival da s

28

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In their series of experiments, the researchers showed that bactobolamine suppressed proliferative lymphocytic responses in a dose-dependent manner. Concanavalin A- or lipopolysaccharide- induced lymphoblastic transformation, mixed lymphocyte reaction and cell-mediated lympholysis were all inhibited by the agent.

Bactobolamine was less effective in suppressing interleukin 2 production by mice spleen cells after the addition of concanavalin A. This suggests that the agent's mode of suppressive action may differ from that of cyclosporin. Bekku Y, Watanabe K, Nishimura Y, Meigata K, Ishida Y, et al. Immunosuppressive effect of bactobolamine. Transplantation Proceedings 24: 1368-1371, Aug 1992 '''lIS4235

Sandoz' successor to cydosporin

The novel cyclosporin derivative, SDZ IMM 125, is equipotent to cyclosporin, according to company researchers, and is much less toxic 1. They

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believe this makes SDZ IMM 125 a promising candidate to succeed the parent compound in clinical use.2

Researchers at Sandoz have been working on a successor compound to cyclosporin that has equal efficacy but a lower potential to cause adverse effects. Although cyclosporin has been used successfully to prevent allograft rejection for a number of years, more extended use of the drug (e.g. autoimmune disease, asthma) is limited by its toxicity.

Their requirements for a successor compound included l

;

.. equivalent efficacy, both in vitro and in vivo

.. reduced toxicity

.. improved pharmacokinetics, regarding absorption, distribution, metabolism and excretion

.. reduced daily variation in drug exposure associated with low and/or variable absorption.

The latter involved selecting a compound whose galenical formulation could be modified to maximise intestinal absorption.

Sandoz believes SDZ IMM 125 best fulfills these requirements. It has been tested extensively in a number of in vitro assays, in which it has displayed immunosuppressive properties with a potency identical to cyclosporin . SDZ IMM 125 and cyclosporin have shown comparable efficacy during extensive in vivo testing in various models of allograft transplantation and induced autoimmune disease I. In addition, SDZ IMM 125 is much less toxic compared with cyclosporin3

. It is this reduced toxicity that give SDZ IMM

125 ' ... relevant clinical advantages over CyA [cyclosporinJ and other immunosuppressants'. 1. Hiestand PC, et al. The new cyclosporine derivative. SDZ IMM 125: in vitro and in vivo pharmacologic effects. Transplantation Proceedings 24 (Suppl. 2): 31-38, Aug 19922. Baumann G, et al. Cyclosporine and its analogue SDZ IMM 125 mediate very similar effects on T-cell activation - a comparative analysis in vitro. Transplantation Proceedings 24 (Suppl. 2): 43-48, Aug 19923. Donatsch P, et al. Toxicologic evaluation of the new cyclosporin derivative, SDZ IMM 125, in a comparative, subchronic toxicity study in rats. Transplantation Proceedings 24 (Suppl. 2): 39-42, Aug

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Spanidin to the rescue

The newly developed Japanese immunosuppressant, spanidin, is effective for rescue therapy of acute rejection after another treatment has failed, report Japanese investigators. This includes rejection episodes refractory to steroids

l antilymphocyte globulin (AHLG) and

OKT3 .. Spanidin [15-deoxyspergualin, deoxyspurgiline;

preregistration] successfully reversed 6/7 rejection episodes occurring within 6 months of renal transplantation. Although rejection recurred within 2 weeks in 3/6 reversed rejection episodes, all were reversed again with AHLG. Serum creatinine concentrations remained low during long term follow-up.

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RESEARCH & DEVELOPMENT

In contrast, spanidin showed only temporary effectiveness in treating late-onset, acute-type rejection episodes. All 10 rejection episodes occurring ~ 6 months after renal transplantation were reversed but this time rejection recurred in 7/10 episodes. Of these, 5 could not be reversed and all progressed to chronic rejection.

Subjective adverse effects were mild, occurring within 12 hours after spanidin administration and needed no treatment. Eight patients developed leucopenia (treated with granulocyte colony-stimulating factor) and mild thrombocytopenia, which occurred in all patients (no treatment).

There may also be a role for spanidin in treating chronic impairment of transplanted kidneys2. Further Japanese trials have shown improved tubular function in spanidin recipients, in terms of phosphate and sodium absorption.

Among 6 cases of chronic rejection following renal transplantation, the most notable change in electrolyte transport was the increase in fractional tubular phosphate absorption (55 vs 70%). This suggests that spanidin improves renal proximal tubular function.

Spanidin's beneficial effects may result from ' ... improvement of chronic rejection by better suppression of immune responses,2.

1. Takahara S, et al. Experience gained from the administration of 15-deoxyspergualin for recurrent grati rejection in kidney transplant recipients. Transplantation-Proceedings 24: 1377 -13RO, Aug 19922. Lino Y, et aI. Improvement of renal function in transplanted kidneys with a new immunosuppressive drug, 15-deoxyspergualin: treatment of chronic rejection. Transplantation Proceedings 24: 1381-1382, Aug 1992

~ Editorial comment: Spanidin is an analogue of spergualin, an antitumolll; antihacterial compound isolated from Bacillus laterosporus. Spanidin is heing jointly developed hy Nippon Kayaku and Takara Shuzo in Japan, where a registration suhmission has heen flIed for treating rejection following renal transplantation. The agent is also undergoing phase 11 testing for graft-vs-host disease in bone marrow tramplant recipients. Spanidin has heen licensed to Bristol-Myers Squihh for the US and Canada. The National Institutes of Health in the US has completed phase I trials with spanidin in cancer.

Thcrolimus tackles pancreatic transplantation

Japanese researchers have successfully used Fujisawa's novel macrolide immunosuppressant, tacrolimus [FK 506, 'Prograf'; awaiting registration in Japan], in both pancreaticoduodenal and abdominal organ cluster transplantation in animals, However, graft survival in pancreatic transplantation is still less than satisfactory compared with other organ transplants I.

A combination of tacrolimus, cyclosporin and mizoribine produced a synergistic effect in a canine model of pancreatoduodenal transplantation I, Mean survival was significantly prolonged in combination recipients compared with control dogs and dogs treated with either cyclosporin or tacrolimus alone. or with a combination of 2 of the 3 study drugs.

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There was a trend towards fewer histological changes in the transplanted pancreas for the triple immunosuppression group than for the other treatment groups,

Almost no evidence of rejection was noted in pigs treated daily with 1M tacrolimus following abdominal organ cluster transplantation2, This group also showed a dramatic reduction in the histological signs of rejection. Almost normal pancreatic structure was maintained in 4/6 tacrolimus-treated pigs.

Tacrolimus appears to have negligible toxic effects on ~ cells. 1. Sato K. et al. Effectiveness of triple drug immunosuppression for pancreaticoduodenal allotransplantation in dogs. Transplantation Proceedings 24: 1363-1365, Aug 1992 2. Kobayashi N, et al. Abdominal organ cluster transplantation in pigs receiving FK 506. Transplantation Proceedings 24: 1366-1367, Aug 1992

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