Blocking CD38 using anti-CD38 F(ab′)2 to protect NK cells
Inventors
Childs, Richard W. • Berg, Maria • Espinoza Calderon, Luis • Sasser, Kate • Attar, Ricardo
Assignees
Janssen Biotech Inc • US Department of Health and Human Services
Publication Number
US-10106620-B2
Publication Date
2018-10-23
Expiration Date
2035-06-15
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Abstract
Provided herein are methods of inhibiting growth or proliferation of cells expressing CD38 by contacting the CD38-expressing cells with 1) NK cells bound to an anti-CD38 F(ab′)2 fragment and 2) an anti-CD38 antibody, in either order or simultaneously. Also provided herein are methods of treating or inhibiting a hyperproliferative disorder or an autoimmune disorder in a subject by administering to the subject 1) NK cells bound to an anti-CD38 F(ab′)2 fragment and 2) an anti-CD38 antibody, in either order or simultaneously.
Core Innovation
The invention provides methods of inhibiting the growth or proliferation of cells expressing CD38 by contacting these cells with a population of natural killer (NK) cells bound to an anti-CD38 F(ab′)2 fragment and an anti-CD38 antibody, in either order or simultaneously. It also includes methods of treating or inhibiting hyperproliferative disorders or autoimmune disorders in subjects by administering NK cells bound to the anti-CD38 F(ab′)2 fragment and an anti-CD38 antibody.
The problem addressed is that anti-CD38 antibodies cause antibody-dependent cell-mediated cytotoxicity (ADCC)-mediated cell death of NK cells by a mechanism involving CD16. This NK cell death presumably reduces the efficacy of anti-CD38 antibody therapies in treating disorders by decreasing the NK cells available to kill target cells. The invention solves this problem by pre-contacting NK cells with an anti-CD38 F(ab′)2 fragment prior to exposure to intact anti-CD38 antibody and target cells, protecting NK cells from antibody-induced death and enhancing their ability to kill target cells.
Claims Coverage
The patent includes multiple independent claims covering methods of inhibiting CD38-expressing cell growth, methods of treating disorders using NK cells bound to anti-CD38 F(ab′)2 fragments with anti-CD38 antibodies, and pharmaceutical compositions comprising such NK cells.
Method of inhibiting growth or proliferation of CD38-expressing cells
1. Contacting a population of NK cells with a F(ab′)2 fragment of a first anti-CD38 antibody to produce NK cells bound to the fragment. 2. Contacting CD38-expressing cells with a second anti-CD38 antibody and the population of NK cells bound to the F(ab′)2 fragment to inhibit cell growth or proliferation.
Method of treating or inhibiting a hyperproliferative or autoimmune disorder
Administering to a subject an effective amount of NK cells bound to a F(ab′)2 fragment of a first anti-CD38 antibody and an effective amount of a second anti-CD38 antibody, with administration in any order or simultaneously, to treat or inhibit the disorder.
Production of NK cells bound to F(ab′)2 fragments and pharmaceutical composition
Producing NK cells bound to anti-CD38 F(ab′)2 fragments in vitro or ex vivo by contacting NK cells with the F(ab′)2 fragment, optionally after expansion; and pharmaceutical compositions comprising NK cells bound to F(ab′)2 fragments with a pharmaceutically acceptable carrier.
The claims cover inventive methods combining NK cells pre-bound with anti-CD38 F(ab′)2 fragments and anti-CD38 antibodies to inhibit growth of CD38-expressing cells and treat disorders, along with compositions comprising these NK cells, emphasizing the protection of NK cells from antibody-induced death while enhancing therapeutic efficacy.
Stated Advantages
Protecting NK cells from anti-CD38 antibody-mediated cell death increases the efficacy of anti-CD38 antibody therapies by preserving NK cell populations for target cell killing.
Pre-treating NK cells with anti-CD38 F(ab′)2 fragments prevents their killing by intact anti-CD38 antibodies, allowing enhanced killing of tumor cells expressing CD38.
The method allows combination therapies that improve survival and quality of life for patients with hyperproliferative or autoimmune disorders.
Documented Applications
Treating hyperproliferative disorders including multiple myeloma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and other hematological malignancies.
Treating solid tumors such as colorectal tumors, lung carcinoma, prostate cancer, pancreatic cancer, breast cancer, neuroblastoma, testicular cancer, and ovarian cancer expressing CD38.
Treating autoimmune disorders including systemic lupus, rheumatoid arthritis, multiple sclerosis, erythematosus, asthma, and other antibody-mediated diseases.
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