Document 0874
 DOCN  M9650874
 TI    A humanized, bispecific immunoadhesin-antibody that retargets CD3+
       effectors to kill HIV-1-infected cells.
 DT    9605
 AU    Chamow SM; Zhang D; Tan XY; Mhatre SM; Marsters SA; Peers DH; Byrn RA;
       Ashkenazi A; Junghans RP; Department of Recovery Sciences, Genentech,
       Inc., S. San; Francisco, CA 94080, USA.
 SO    J Hematother. 1995 Oct;4(5):439-46. Unique Identifier : AIDSLINE
       MED/96129480
 AB    We have developed a humanized, bispecific immunoadhesin-antibody (BsIAb)
       that targets and kills HIV-infected cells. Comprised of CD4-IgG and
       humanized anti-CD3-IgG, this BsIAb is bifunctional. First, in targeting,
       it exploits the natural affinity of CD4 for gp120 to target the BsIAb to
       HIV-infected cells, and second, it recruits and activates, through its
       anti-CD3 moiety, cytotoxic T lymphocytes (CTL) to lyse target cells in a
       non-MHC restricted manner. To produce purified BsIAb from supernantants
       of transfected mammalian cells, we designed a three-step recovery scheme
       based on the structural elements of this heterotrimeric protein. The
       ability of purified BsIAb to specifically lyse HIV-infected target cells
       was demonstrated using CTL from two different sources: whole peripheral
       blood lymphocyte (PBL) fractions and pure CTL preparations. In contrast,
       a human anti-gp120 antibody mediated lysis of HIV-infected target cells
       only with PBL fractions and not with purified CTL. Moreover, lysis
       observed in the presence of the human anti-gp120 antibody was completely
       blocked in the presence of human serum (which competes for Fc gamma
       receptor binding), whereas BsIAb-mediated lysis of target cells was not
       affected. We measured the monovalent affinities of BsIAb for HIV-gp120
       on infected cells and for CD3 epsilon on CTL. Relative to the bivalent
       parent molecules, CD4/gp120 affinity in the BsIAb is unchanged, whereas
       anti-CD3/CD3 is substantially decreased. We further demonstrated by
       fluorescence microscopy that physical association of CD3+ cells with
       gp120-expressing cells occurs only in the presence of BsIAb. Thus, the
       cytocidal activity of BsIAb in the presence of serum reflects its unique
       ability to recruit CTL as effector cells and highlights a potentially
       important advantage of this type of construct over antibodies for
       HIV-directed therapy.
 DE    Antibodies, Bispecific/*IMMUNOLOGY  Antibody Affinity  Antibody
       Specificity  Antibody-Dependent Cell Cytotoxicity  Antigens,
       CD4/*IMMUNOLOGY/METABOLISM  Cell Separation  Cytotoxicity Tests,
       Immunologic  Cytotoxicity, Immunologic  CD4-Positive
       T-Lymphocytes/IMMUNOLOGY/*VIROLOGY  Human  HIV Antibodies/IMMUNOLOGY
       HIV Envelope Protein gp120/IMMUNOLOGY/METABOLISM  *HIV-1  IgG/IMMUNOLOGY
       Interleukin-2/PHARMACOLOGY  Killer Cells,
       Lymphokine-Activated/IMMUNOLOGY  Muromonab-CD3/*IMMUNOLOGY  Recombinant
       Proteins/PHARMACOLOGY  Support, Non-U.S. Gov't  T-Lymphocytes,
       Cytotoxic/IMMUNOLOGY  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).