BIOMAT Database Logo BIOMAT Database Logo

A humanized, bispecific immunoadhesin-antibody that retargets CD3+ effectors to kill HIV-1-infected cells. 1994

S M Chamow, and D Z Zhang, and X Y Tan, and S M Mhatre, and S A Marsters, and D H Peers, and R A Byrn, and A Ashkenazi, and R P Junghans
Department of Recovery Sciences, Genentech Inc., South San Francisco, CA 94080.

HIV infection depletes the immune system of the coordinating functions of CD4+ T cells and APCs, whereas the population of CD8+ CTLs remains largely intact: functional but undirected. We have developed a humanized bispecific immunoadhesin-antibody (BIA) that redirects these remaining T cells to kill HIV-infected cells. This BIA expresses effector cell retargeting via a targeting activity that exploits the natural affinity of CD4 for gp120, and a recruiting activity that employs an anti-CD3 moiety to engage CTLs. The resultant molecule is 97% human in origin. In functional tests, this BIA mediated killing of HIV-infected cells using either pure CTL preparations, or whole PBL fractions that additionally include Fc gamma receptor-bearing large granular lymphocyte effectors. In contrast, a human anti-gp120 Ab induced target lysis via Ab-dependent cellular cytotoxicity (ADCC) only with large granular lymphocyte-containing fractions and not with CTLs. ADCC with this Ab was blocked in human serum, whereas BIA-mediated effector cell retargeting lysis of HIV-infected cells by CTLs was preserved. The affinity of the BIA for HIV-gp120 on infected cells and for CD3 epsilon on CTLs was derived in a flow cytometric Scatchard procedure. Relative to the bivalent parent molecules, CD4/gp120 affinity on cells was unchanged in the BIA (Ka 7 x 10(7) M-1), whereas the anti-CD3 affinity was diminished 50-fold (Ka 2 x 10(6) M-1 vs 1 x 10(8) M-1). Physical association of CD3+ effectors and gp120-expressing targets was confirmed by fluorescence microscopy and was dependent upon the presence of BIA and expression of target gp120. The unimpaired cytocidal activity of the BIA in the presence of serum highlights a potentially important advantage of this type of construct over native Abs for HIV-directed therapy.

UI MeSH Term Description Entries
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D003602 Cytotoxicity, Immunologic The phenomenon of target cell destruction by immunologically active effector cells. It may be brought about directly by sensitized T-lymphocytes or by lymphoid or myeloid "killer" cells, or it may be mediated by cytotoxic antibody, cytotoxic factor released by lymphoid cells, or complement. Tumoricidal Activity, Immunologic,Immunologic Cytotoxicity,Immunologic Tumoricidal Activities,Immunologic Tumoricidal Activity,Tumoricidal Activities, Immunologic
D004591 Electrophoresis, Polyacrylamide Gel Electrophoresis in which a polyacrylamide gel is used as the diffusion medium. Polyacrylamide Gel Electrophoresis,SDS-PAGE,Sodium Dodecyl Sulfate-PAGE,Gel Electrophoresis, Polyacrylamide,SDS PAGE,Sodium Dodecyl Sulfate PAGE,Sodium Dodecyl Sulfate-PAGEs
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006825 Hybridomas Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure MONOCLONAL ANTIBODIES or T-cell products, identical to those produced by the immunologically competent parent cell. Hybridoma
D000915 Antibody Affinity A measure of the binding strength between antibody and a simple hapten or antigen determinant. It depends on the closeness of stereochemical fit between antibody combining sites and antigen determinants, on the size of the area of contact between them, and on the distribution of charged and hydrophobic groups. It includes the concept of "avidity," which refers to the strength of the antigen-antibody bond after formation of reversible complexes. Affinity, Antibody,Antibody Avidity,Avidity, Antibody,Affinities, Antibody,Antibody Affinities,Antibody Avidities,Avidities, Antibody
D013602 T-Lymphocytes, Cytotoxic Immunized T-lymphocytes which can directly destroy appropriate target cells. These cytotoxic lymphocytes may be generated in vitro in mixed lymphocyte cultures (MLC), in vivo during a graft-versus-host (GVH) reaction, or after immunization with an allograft, tumor cell or virally transformed or chemically modified target cell. The lytic phenomenon is sometimes referred to as cell-mediated lympholysis (CML). These CD8-positive cells are distinct from NATURAL KILLER CELLS and NATURAL KILLER T-CELLS. There are two effector phenotypes: TC1 and TC2. Cell-Mediated Lympholytic Cells,Cytotoxic T Cells,Cytotoxic T Lymphocyte,Cytotoxic T-Lymphocytes,TC1 Cell,TC1 Cells,TC2 Cell,TC2 Cells,Cell Mediated Lympholytic Cells,Cell, Cell-Mediated Lympholytic,Cell, TC1,Cell, TC2,Cell-Mediated Lympholytic Cell,Cytotoxic T Cell,Cytotoxic T Lymphocytes,Cytotoxic T-Lymphocyte,Lymphocyte, Cytotoxic T,Lympholytic Cell, Cell-Mediated,Lympholytic Cells, Cell-Mediated,T Cell, Cytotoxic,T Lymphocyte, Cytotoxic,T Lymphocytes, Cytotoxic,T-Lymphocyte, Cytotoxic
D014162 Transfection The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES. Transfections
D015153 Blotting, Western Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes. Immunoblotting, Western,Western Blotting,Western Immunoblotting,Blot, Western,Immunoblot, Western,Western Blot,Western Immunoblot,Blots, Western,Blottings, Western,Immunoblots, Western,Immunoblottings, Western,Western Blots,Western Blottings,Western Immunoblots,Western Immunoblottings
D015497 HIV-1 The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. Human immunodeficiency virus 1,HIV-I,Human Immunodeficiency Virus Type 1,Immunodeficiency Virus Type 1, Human

Related Publications

S M Chamow, and D Z Zhang, and X Y Tan, and S M Mhatre, and S A Marsters, and D H Peers, and R A Byrn, and A Ashkenazi, and R P Junghans
[Antibodies that kill HIV-1-infected cells].
January 2016, Medecine sciences : M/S,
S M Chamow, and D Z Zhang, and X Y Tan, and S M Mhatre, and S A Marsters, and D H Peers, and R A Byrn, and A Ashkenazi, and R P Junghans
Tandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized mice.
June 2018, The Journal of clinical investigation,
S M Chamow, and D Z Zhang, and X Y Tan, and S M Mhatre, and S A Marsters, and D H Peers, and R A Byrn, and A Ashkenazi, and R P Junghans
A gB/CD3 bispecific BiTE antibody construct for targeting Human Cytomegalovirus-infected cells.
November 2018, Scientific reports,
S M Chamow, and D Z Zhang, and X Y Tan, and S M Mhatre, and S A Marsters, and D H Peers, and R A Byrn, and A Ashkenazi, and R P Junghans
Anti-CS1 × Anti-CD3 Bispecific Antibody (BiAb)-Armed Anti-CD3 Activated T Cells (CS1-BATs) Kill CS1+ Myeloma Cells and Release Type-1 Cytokines.
January 2020, Frontiers in oncology,
S M Chamow, and D Z Zhang, and X Y Tan, and S M Mhatre, and S A Marsters, and D H Peers, and R A Byrn, and A Ashkenazi, and R P Junghans
A CD3 humanized mouse model unmasked unique features of T-cell responses to bispecific antibody treatment.
January 2024, Blood advances,
S M Chamow, and D Z Zhang, and X Y Tan, and S M Mhatre, and S A Marsters, and D H Peers, and R A Byrn, and A Ashkenazi, and R P Junghans
Immunoconjugates that neutralize HIV virions kill T cells infected with diverse strains of HIV-1.
February 1990, Journal of immunology (Baltimore, Md. : 1950),
S M Chamow, and D Z Zhang, and X Y Tan, and S M Mhatre, and S A Marsters, and D H Peers, and R A Byrn, and A Ashkenazi, and R P Junghans
Targeting cytomegalovirus-infected cells using T cells armed with anti-CD3 × anti-CMV bispecific antibody.
July 2012, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation,
S M Chamow, and D Z Zhang, and X Y Tan, and S M Mhatre, and S A Marsters, and D H Peers, and R A Byrn, and A Ashkenazi, and R P Junghans
A Chemo-enzymatically Linked Bispecific Antibody Retargets T Cells to a Sialylated Epitope on CD43 in Acute Myeloid Leukemia.
July 2019, Cancer research,
S M Chamow, and D Z Zhang, and X Y Tan, and S M Mhatre, and S A Marsters, and D H Peers, and R A Byrn, and A Ashkenazi, and R P Junghans
A novel, nonanaphylactogenic, bispecific IgE-CD3 antibody eliminates IgE(+) B cells.
September 2015, The Journal of allergy and clinical immunology,
S M Chamow, and D Z Zhang, and X Y Tan, and S M Mhatre, and S A Marsters, and D H Peers, and R A Byrn, and A Ashkenazi, and R P Junghans
Redirection of T cells with a first fully humanized bispecific CD33-CD3 antibody efficiently eliminates AML blasts without harming hematopoietic stem cells.
April 2013, Leukemia,
Copied contents to your clipboard!