25 
carrying the a -MSH-diphtheria toxin gene at BL2 containment with RL3 prac- 
tices. That recommendation was sent to the NIH Director for his approval . 
Dr. Gottesman said the concerns hypothesized by the working group for the 
IL-2 -diphtheria toxin proposal and the a -MSH-diphtheria toxin proposal 
were similar; i. e. , what are the target cells; vhat are the implications 
of a host-vector system producing such hybrid toxins; What is the toxicity 
of the diphtheria toxin fragment? 
Dr. Gottesman said the goal of the IL-2 proposal is the development and 
testing of novel therapeutic agents to combat organ rejection and/or create 
a state of tolerance in organ transplantation . As a by-product, seme of 
the agents may have therapeutic potential for treatment of leukemia and 
lymphoma. 
Dr. Waldmann said antigens binding to T cell surface receptors activate T 
cell function. Activation initiates second-stage events, including the 
production of IL-2. IL-2 interacts with high affinity receptors on the 
surface of certain cells. Resting T cells generally do not possess IL-2 
receptors. Dr. Waldmann said the only cells expressing IL-2 receptor are 
the activated T lymphocytes in lymph nodes and tonsils. 
Dr. Waldmann said in sane circumstances physicians might wish to eliminate 
IL-2 expressing cells; e.g. , in adult T-cell leukemia, in transplantation 
of mismatched organs, or in certain autoimmune states such as aplastic 
anemia. Dr. Waldmann said it would be very useful to have IL-2-diphtheria 
toxin conjugates for clinical use. These conjugate proteins would prbbably 
not be more toxic than diphtheria toxin itself. 
Dr. Waldmann said patients with aplastic anemia and with adult T cell 
leukemia have been treated with antibody against the IL-2 receptor. While 
the numbers of IL-2 expressing malignant cells have been reduced, no compli- 
cations such as reduction in numbers of platelets, granulocytes , or normal 
T cells have been noted. Dr. Waldmann said a patient has also been treated 
with a hybrid protein composed of Pseudomonas exotoxin and antibody to the 
IL-2 receptor. In this case, a slight reduction in number of granulocytes 
was observed but no other toxicity. He hypothesized that mature T cells, 
marrow and thymus cells as well as their precursors, would not be damaged 
by a ten day exposure to the IL-2 -diphtheria toxin fusion protein. 
Dr. Clowes noted that the Working Group on Toxins recommended use of EK2 
vectors; he questioned why the working group had not recommended use of 
EK2 hosts as well for these procedures. He felt use of these hosts might 
offer seme additional measure of security. 
Dr. Gottesman said it is more difficult to work with the debilitated EK2 
hosts. The working group had not actually recommended the use of EK2 
certified vectors but had recommended the use of poorly mobilizable vectors 
such as the EK2 vectors. 
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