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JP-7855521-B2 - Human anti-CD33 antibody and its use

JP7855521B2JP 7855521 B2JP7855521 B2JP 7855521B2JP-7855521-B2

Inventors

  • ウォルター，ローランド・ビー
  • ラースロー，ジョージ・エス

Assignees

  • フレッド ハッチンソン キャンサー センター

Dates

Publication Date
20260508
Application Date
20210331
Priority Date
20200331

Claims (19)

  1. An anti-CD33 antibody or its antigen-binding fragment comprising a set of complementarity-determining regions (CDRs) of 1B9, 1H10, 1A9, 1E6, 1D2, 1H8, 2D3, or 2E3, 1B9 contains, according to North, CDRL1 containing SEQ ID NO: 60, CDRL2 containing SEQ ID NO: 73, CDRL3 containing SEQ ID NO: 68, CDRH1 containing SEQ ID NO: 74, CDRH2 containing SEQ ID NO: 70, and CDRH3 containing SEQ ID NO: 75. 1E6 contains, according to North, CDRL1 containing SEQ ID NO: 66, CDRL2 containing SEQ ID NO: 67, CDRL3 containing SEQ ID NO: 68, CDRH1 containing SEQ ID NO: 69, CDRH2 containing SEQ ID NO: 70, and CDRH3 containing SEQ ID NO: 71. 1H10 contains, according to North, CDRL1 containing SEQ ID NO: 54, CDRL2 containing SEQ ID NO: 55, CDRL3 containing SEQ ID NO: 56, CDRH1 containing SEQ ID NO: 57, CDRH2 containing SEQ ID NO: 58, and CDRH3 containing SEQ ID NO: 59. 1A9 contains CDRL1 containing SEQ ID NO: 60, CDRL2 containing SEQ ID NO: 61, CDRL3 containing SEQ ID NO: 62, CDRH1 containing SEQ ID NO: 63, CDRH2 containing SEQ ID NO: 64, and CDRH3 containing SEQ ID NO: 65, according to North. 1D2 contains, according to North, CDRL1 containing SEQ ID NO: 66, CDRL2 containing SEQ ID NO: 55, CDRL3 containing SEQ ID NO: 68, CDRH1 containing SEQ ID NO: 69, CDRH2 containing SEQ ID NO: 72, and CDRH3 containing SEQ ID NO: 71. 1H8 contains, according to North, CDRL1 containing SEQ ID NO: 34, CDRL2 containing SEQ ID NO: 163, CDRL3 containing SEQ ID NO: 36, CDRH1 containing SEQ ID NO: 164, CDRH2 containing SEQ ID NO: 165, and CDRH3 containing SEQ ID NO: 166. 2D3 contains, according to North, CDRL1 containing SEQ ID NO: 167, CDRL2 containing SEQ ID NO: 168, CDRL3 containing SEQ ID NO: 42, CDRH1 containing SEQ ID NO: 169, CDRH2 containing SEQ ID NO: 170, and CDRH3 containing SEQ ID NO: 171, or 2E3 contains, according to North, CDRL1 containing SEQ ID NO: 172, CDRL2 containing SEQ ID NO: 173, CDRL3 containing SEQ ID NO: 48, CDRH1 containing SEQ ID NO: 174, CDRH2 containing SEQ ID NO: 175, and CDRH3 containing SEQ ID NO: 176, an anti-CD33 antibody or its antigen-binding fragment.
  2. A CD33 targeting agent comprising an anti-CD33 binding domain including a set of complementarity-determining regions (CDRs) of 1B9, 1H10, 1A9, 1E6, 1D2, 1H8, 2D3, or 2E3 as part of an anti-CD33 immunotoxin, anti-CD33 antibody-drug conjugate, anti-CD33 antibody-radioisotope conjugate, anti-CD33 bispecific antibody, anti-CD33 bispecific immune cell-inducing antibody, anti-CD33 tripspecific antibody, and/or anti-CD33 quadruspecific antibody, 1B9 contains, according to North, CDRL1 containing SEQ ID NO: 60, CDRL2 containing SEQ ID NO: 73, CDRL3 containing SEQ ID NO: 68, CDRH1 containing SEQ ID NO: 74, CDRH2 containing SEQ ID NO: 70, and CDRH3 containing SEQ ID NO: 75. 1E6 contains, according to North, CDRL1 containing SEQ ID NO: 66, CDRL2 containing SEQ ID NO: 67, CDRL3 containing SEQ ID NO: 68, CDRH1 containing SEQ ID NO: 69, CDRH2 containing SEQ ID NO: 70, and CDRH3 containing SEQ ID NO: 71. 1H10 contains, according to North, CDRL1 containing SEQ ID NO: 54, CDRL2 containing SEQ ID NO: 55, CDRL3 containing SEQ ID NO: 56, CDRH1 containing SEQ ID NO: 57, CDRH2 containing SEQ ID NO: 58, and CDRH3 containing SEQ ID NO: 59. 1A9 contains CDRL1 containing SEQ ID NO: 60, CDRL2 containing SEQ ID NO: 61, CDRL3 containing SEQ ID NO: 62, CDRH1 containing SEQ ID NO: 63, CDRH2 containing SEQ ID NO: 64, and CDRH3 containing SEQ ID NO: 65, according to North. 1D2 contains, according to North, CDRL1 containing SEQ ID NO: 66, CDRL2 containing SEQ ID NO: 55, CDRL3 containing SEQ ID NO: 68, CDRH1 containing SEQ ID NO: 69, CDRH2 containing SEQ ID NO: 72, and CDRH3 containing SEQ ID NO: 71. 1H8 contains, according to North, CDRL1 containing SEQ ID NO: 34, CDRL2 containing SEQ ID NO: 163, CDRL3 containing SEQ ID NO: 36, CDRH1 containing SEQ ID NO: 164, CDRH2 containing SEQ ID NO: 165, and CDRH3 containing SEQ ID NO: 166. 2D3 contains CDRL1 containing SEQ ID NO: 167, CDRL2 containing SEQ ID NO: 168, CDRL3 containing SEQ ID NO: 42, CDRH1 containing SEQ ID NO: 169, CDRH2 containing SEQ ID NO: 170, and CDRH3 containing SEQ ID NO: 171, according to North, or 2E3 contains CDRL1 containing SEQ ID NO: 172, CDRL2 containing SEQ ID NO: 173, CDRL3 containing SEQ ID NO: 48, CDRH1 containing SEQ ID NO: 174, CDRH2 containing SEQ ID NO: 175, and CDRH3 containing SEQ ID NO: 176, according to North, a CD33 targeting agent.
  3. Anti-CD33 immunotoxin, anti-CD33 antibody-drug conjugate, anti-CD33 antibody-radioisotope conjugate, anti-CD33 bispecific antibody, anti-CD33 bispecific immune cell-inducing antibody, anti-CD33 trispecific antibody, and/or as part of an anti-CD33 quadruspecific antibody, variable light chains and variable heavy chains of 1B9, 1H10, 1A9, 1E6, 1D2, 1H8, 2D3, or 2E3; or 1B9, 1H10, 1A9, 1E6, 1D2, 1H8, 2D3, or 2E3 A sequence having at least 90% sequence identity to the variable light chain and containing the light chain complementarity determination regions of 1B9, 1H10, 1A9, 1E6, 1D2, 1H8, 2D3, or 2E3 , and a sequence having at least 90% sequence identity to the corresponding variable heavy chain of 1B9, 1H10, 1A9, 1E6, 1D2, 1H8, 2D3, or 2E3 and containing the heavy chain complementarity determination regions of 1B9, 1H10, 1A9, 1E6, 1D2, 1H8, 2D3, or 2E3, respectively. A CD33 targeting agent comprising an anti-CD33 binding domain, The variable light chain of 1B9 contains the sequence of sequence number 59, and the variable heavy chain of 1B9 contains the sequence of sequence number 60. The variable light chain of 1H10 contains the sequence of sequence number 51, and the variable heavy chain of 1H10 contains the sequence of sequence number 52. The variable light chain of 1A9 contains the sequence of sequence number 53, and the variable heavy chain of 1A9 contains the sequence of sequence number 54. The variable light chain of 1E6 contains the sequence of sequence number 55, and the variable heavy chain of 1E6 contains the sequence of sequence number 56. The variable light chain of 1D2 contains the sequence of sequence number 57, and the variable heavy chain of 1D2 contains the sequence of sequence number 58. The variable light chain of 1H8 contains the sequence of sequence number 61, and the variable heavy chain of 1H8 contains the sequence of sequence number 62. The variable light chain of 2D3 includes the sequence of sequence number 63, and the variable heavy chain of 2D3 includes the sequence of sequence number 64. The variable light chain of 2E3 contains the sequence of sequence number 65, and the variable heavy chain of 2E3 contains the sequence of sequence number 66. The 1B9 CDR set, according to North, contains CDRL1 containing SEQ ID NO: 60, CDRL2 containing SEQ ID NO: 73, CDRL3 containing SEQ ID NO: 68, CDRH1 containing SEQ ID NO: 74, CDRH2 containing SEQ ID NO: 70, and CDRH3 containing SEQ ID NO: 75. The 1H10 CDR set contains, according to North, CDRL1 containing SEQ ID NO: 54, CDRL2 containing SEQ ID NO: 55, CDRL3 containing SEQ ID NO: 56, CDRH1 containing SEQ ID NO: 57, CDRH2 containing SEQ ID NO: 58, and CDRH3 containing SEQ ID NO: 59. The 1A9 CDR set contains, according to North, CDRL1 containing SEQ ID NO: 60, CDRL2 containing SEQ ID NO: 61, CDRL3 containing SEQ ID NO: 62, CDRH1 containing SEQ ID NO: 63, CDRH2 containing SEQ ID NO: 64, and CDRH3 containing SEQ ID NO: 65. The 1E6 CDR set contains, according to North, CDRL1 containing SEQ ID NO: 66, CDRL2 containing SEQ ID NO: 67, CDRL3 containing SEQ ID NO: 68, CDRH1 containing SEQ ID NO: 69, CDRH2 containing SEQ ID NO: 70, and CDRH3 containing SEQ ID NO: 71. The 1D2 CDR set contains, according to North, CDRL1 containing SEQ ID NO: 66, CDRL2 containing SEQ ID NO: 55, CDRL3 containing SEQ ID NO: 68, CDRH1 containing SEQ ID NO: 69, CDRH2 containing SEQ ID NO: 72, and CDRH3 containing SEQ ID NO: 71. The 1H8 CDR set, according to North, contains CDRL1 containing SEQ ID NO: 34, CDRL2 containing SEQ ID NO: 163, CDRL3 containing SEQ ID NO: 36, CDRH1 containing SEQ ID NO: 164, CDRH2 containing SEQ ID NO: 165, and CDRH3 containing SEQ ID NO: 166. The 2D3 CDR set contains, according to North, CDRL1 containing SEQ ID NO: 167, CDRL2 containing SEQ ID NO: 168, CDRL3 containing SEQ ID NO: 42, CDRH1 containing SEQ ID NO: 169, CDRH2 containing SEQ ID NO: 170, and CDRH3 containing SEQ ID NO: 171, or The 2E3 CDR set contains, according to North, CDRL1 containing SEQ ID NO: 172, CDRL2 containing SEQ ID NO: 173, CDRL3 containing SEQ ID NO: 48, CDRH1 containing SEQ ID NO: 174, CDRH2 containing SEQ ID NO: 175, and CDRH3 containing SEQ ID NO: 176. CD33 targeting agent.
  4. A CD33 targeting agent according to claim 2 or 3, comprising a multispecific antibody.
  5. The CD33 targeting agent according to claim 4, wherein the multispecific antibody contains a binding domain that activates immune cells.
  6. The CD33 targeting agent according to claim 5, wherein the immune cells are T cells, natural killer (NK) cells, or macrophages.
  7. A CD33 targeting agent according to claim 5, having the sequence described in any one of sequence numbers 157 or 238-245.
  8. A CD33 targeting agent according to claim 5, wherein the binding domain activates T cells and comprises a CDR of OKT3 antibody, a CDR of 4B4-D7 antibody, a CDR of 4E7-C9 antibody, a CDR of 18F5-H10 antibody, a CDR of TGN1412 antibody, a CDR of OKT8 antibody, a variable light chain having the sequence described in SEQ ID NO: 162, and a variable heavy chain having the sequence described in SEQ ID NO: 161, or a TCR, The OKT3 antibody CDR includes CDRL1 containing SEQ ID NO: 46, CDRL2 containing SEQ ID NO: 47, CDRL3 containing SEQ ID NO: 48, CDRH1 containing SEQ ID NO: 49, CDRH2 containing SEQ ID NO: 50, and CDRH3 containing SEQ ID NO: 51. The CDR of the 4B4-D7 antibody includes CDRL1 containing SEQ ID NO: 58, CDRL2 sequence containing KVS, CDRL3 containing SEQ ID NO: 54, CDRH1 containing SEQ ID NO: 59, CDRH2 containing SEQ ID NO: 60, and CDRH3 containing SEQ ID NO: 61. The CDR of the 4E7-C9 antibody includes CDRL1 containing SEQ ID NO: 62, CDRL2 sequence containing KVS, CDRL3 containing SEQ ID NO: 54, CDRH1 containing SEQ ID NO: 59, CDRH2 containing SEQ ID NO: 63, and CDRH3 containing SEQ ID NO: 64. The CDR of the 18F5-H10 antibody includes CDRL1 containing SEQ ID NO: 65, CDRL2 sequence containing KVS, CDRL3 containing SEQ ID NO: 66, CDRH1 containing SEQ ID NO: 67, CDRH2 containing SEQ ID NO: 68, and CDRH3 containing SEQ ID NO: 69. The CDR of the TGN1412 antibody is derived from the variable light chain of SEQ ID NO: 71 and the variable heavy chain of SEQ ID NO: 70, and/or the CDR of the OKT8 antibody is a CD33 targeting agent comprising CDRL1 containing SEQ ID NO: 91, CDRL2 containing SEQ ID NO: 92, CDRL3 containing SEQ ID NO: 93, CDRH1 containing SEQ ID NO: 94, CDRH2 containing SEQ ID NO: 95, and CDRH3 containing SEQ ID NO: 96.
  9. A CD33 targeting agent according to claim 2 or 3, comprising a 1B9, 1H10, 1A9, 1E6, 1D2, 1H8, 2D3, or 2E3 Fv, Fab, Fab', F(ab') 2 , or single-stranded Fv fragment (scFv) having the sequence described in any one of sequence numbers 230 to 237.
  10. The anti-CD33 antibody or antigen-binding fragment according to claim 1, wherein the antibody or its antigen-binding fragment is PEG-modified, or the antibody contains an Fc modification.
  11. A composition comprising the anti-CD33 antibody or its antigen-binding fragment as described in claim 1, and/or the CD33 targeting agent as described in claim 2 or 3, formulated for administration to a target.
  12. Cells genetically modified to express the anti-CD33 antibody or its antigen-binding fragment according to claim 1 and/or the CD33 targeting agent according to claim 2 or 3, formulated for administration to a target.
  13. The cell according to claim 12, which is a T cell, B cell, natural killer (NK) cell, monocyte/macrophage, hematopoietic stem cell (HSC), or hematopoietic progenitor cell (HPC).
  14. The cell according to claim 12, wherein the cell is a CD8+ T cell.
  15. A formulation comprising the cell population described in claim 12 and a pharmaceutically acceptable carrier.
  16. A pharmaceutical composition for use in a method of treating CD33-related disorders in a subject requiring such treatment, wherein the pharmaceutical composition comprises a therapeutically effective amount of the composition and/or the formulation according to claim 15, and the method comprises administering a therapeutically effective amount of the composition and/or the formulation according to claim 15 to a subject, thereby treating CD33-related disorders in a subject requiring such treatment.
  17. The pharmaceutical composition according to claim 16, wherein the CD33-related disorder includes acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CML), mast cell leukemia, myelodysplastic syndrome (MDS), B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), or megakaryocytic leukemia.
  18. The method described above is To determine whether the subject expresses or lacks the V-set domain of CD33, and (i) if the subject expresses the V-set domain of CD33, The further comprising selecting a combination therapy comprising a composition comprising one or more anti-CD33 binding domains from 1B9, 1H10, 1A9, 1E6, and 1D2, and one or more anti-CD33 binding domains from 1H8, 2D3, and 2E3, or (ii) if the subject does not express the V set domain of CD33, The further includes selecting a therapy comprising a composition containing one or more anti-CD33 binding domains from among 1B9, 1H10, 1A9, 1E6, and 1D2. The pharmaceutical composition according to claim 16.
  19. (i) A composition comprising one or more anti-CD33 binding domains from among 1B9, 1H10, 1A9, 1E6, and 1D2 and one or more anti-CD33 binding domains from among 1H8, 2D3, and 2E3, or (ii) A kit comprising a composition comprising one or more anti-CD33 binding domains from among 1B9, 1H10, 1A9, 1E6, and 1D2 and one or more anti-CD33 binding domains from among 1H8, 2D3, and 2E3, 1B9 contains, according to North, CDRL1 containing SEQ ID NO: 60, CDRL2 containing SEQ ID NO: 73, CDRL3 containing SEQ ID NO: 68, CDRH1 containing SEQ ID NO: 74, CDRH2 containing SEQ ID NO: 70, and CDRH3 containing SEQ ID NO: 75. 1E6 contains, according to North, CDRL1 containing SEQ ID NO: 66, CDRL2 containing SEQ ID NO: 67, CDRL3 containing SEQ ID NO: 68, CDRH1 containing SEQ ID NO: 69, CDRH2 containing SEQ ID NO: 70, and CDRH3 containing SEQ ID NO: 71. 1H10 contains, according to North, CDRL1 containing SEQ ID NO: 54, CDRL2 containing SEQ ID NO: 55, CDRL3 containing SEQ ID NO: 56, CDRH1 containing SEQ ID NO: 57, CDRH2 containing SEQ ID NO: 58, and CDRH3 containing SEQ ID NO: 59. 1A9 contains CDRL1 containing SEQ ID NO: 60, CDRL2 containing SEQ ID NO: 61, CDRL3 containing SEQ ID NO: 62, CDRH1 containing SEQ ID NO: 63, CDRH2 containing SEQ ID NO: 64, and CDRH3 containing SEQ ID NO: 65, according to North. 1D2 contains, according to North, CDRL1 containing SEQ ID NO: 66, CDRL2 containing SEQ ID NO: 55, CDRL3 containing SEQ ID NO: 68, CDRH1 containing SEQ ID NO: 69, CDRH2 containing SEQ ID NO: 72, and CDRH3 containing SEQ ID NO: 71. 1H8 contains, according to North, CDRL1 containing SEQ ID NO: 34, CDRL2 containing SEQ ID NO: 163, CDRL3 containing SEQ ID NO: 36, CDRH1 containing SEQ ID NO: 164, CDRH2 containing SEQ ID NO: 165, and CDRH3 containing SEQ ID NO: 166. Kit 2D3 contains CDRL1 containing SEQ ID NO: 167, CDRL2 containing SEQ ID NO: 168, CDRL3 containing SEQ ID NO: 42, CDRH1 containing SEQ ID NO: 169, CDRH2 containing SEQ ID NO: 170, and CDRH3 containing SEQ ID NO: 171, according to North, or Kit 2E3 contains CDRL1 containing SEQ ID NO: 172, CDRL2 containing SEQ ID NO: 173, CDRL3 containing SEQ ID NO: 48, CDRH1 containing SEQ ID NO: 174, CDRH2 containing SEQ ID NO: 175, and CDRH3 containing SEQ ID NO: 176, according to North.

Description

This application claims priority to U.S. Provisional Patent Application No. 63/003,203, filed on March 31, 2020, which is incorporated herein by reference in its entirety as if it were fully contained herein. Federal Government-Supported Research or Development Statement: This invention was made with government support under CA234203 and CA223409 granted by the National Institutes of Health. The government has certain rights to this invention. Sequence Listing Reference The sequence listing relating to this application is provided in text format instead of being a paper copy and is incorporated herein by reference. The name of the text file containing the sequence listing is 2GU_ST25.txt. The text file is 196KB in size, was created on March 31, 2021, and filed electronically via EFS-Web. The field of this disclosure describes a set of novel anti-CD33 antibodies. The antibodies provided are pan-conjugates that bind to the C2-set Ig-like domain of CD33 in the presence or absence of the V-set Ig-like domain, C2-set conjugates that bind to the C2-set Ig-like domain only in the absence of the V-set Ig-like domain of CD33, or V-set conjugates that bind to the V-set Ig-like domain of CD33. These antibodies provide novel therapeutic and diagnostic means for CD33-related disorders such as acute myeloid leukemia (AML). According to the World Health Organization, cancer is the second leading cause of death globally, accounting for an estimated 9.6 million deaths in 2018. Acute myeloid leukemia (AML) is a type of cancer caused by malignant tumors of clonal proliferative myeloblastic cells. In the United States, there are 20,000 new cases of AML annually, and 11,000 people die from AML each year (Siegel et al., 2021, CA Cancer J Clin. 71(1): pp. 7-33). While conventional chemotherapy can achieve high complete remission rates of 60% to 80% in young patients with AML (Dohner et al., 2017. Blood. 129(4): 424-447), treatment outcomes for elderly patients aged 65 and over remain insufficient, with 70% dying from the disease within one year of diagnosis (Meyers et al., Appl Health Eco Health Policy, 11: 275-286, 2013). Unfortunately, relapse after conventional treatment is common due to chemotherapy resistance of leukemia stem cells (Eppert et al., 2011. Nat. Med. 17(9): 1086-1093), and current treatment options for relapsed/refractory (R/R) AML are poor, resulting in a 12-month overall survival rate of less than 30%. CD33 is a member of the sialic acid-binding immunoglobulin-like lectin (SIGLEC) protein family. It is a 67 kDa glycosylated transmembrane protein. CD33 (also known as SIGLEC-3) is a myeloid differentiation antigen found in at least some leukemia cells, and possibly in some cases in AML stem cells, in almost all patients with AML. Based on this widespread expression pattern, CD33 has been widely pursued as a therapeutic target in AML. Recent data from several randomized studies have demonstrated that gemtuzumab ozogamicin (GO), a CD33 antibody-drug conjugate, improves survival when added to chemotherapy in a defined subset of patients with newly diagnosed AML. This data confirms that CD33 is the first (and so far only) target for immunotherapy in AML. In parallel with the development of new and more effective CD33-targeted therapies (e.g., antibody-drug conjugates, radioactive immunoconjugates, bispecific antibodies, chimeric antigen receptor [CAR]-modified T cells) to overcome the limitations identified by GO, there is growing interest in CD33 as a drug target for other malignant and non-malignant disorders. These efforts include targeting CD33 splice variants not recognized by GO, as well as targeting CD33+ tumor cells in other hematological malignancies, CD33+ myeloid-derived suppressor cells (MDSCs) in various diseases, and normal CD33+ microglia in Alzheimer's disease (Walter, Expert Opin Biol Ther. 2020, 20(9): 955–958). The full-length CD33 protein (CD33 FL ) is characterized by a membrane-distal V-set immunoglobulin (Ig)-like domain at the amino terminus and a membrane-proximal C2-set Ig-like domain in its extracellular portion (Figure 1). Shorter isoforms of CD33 exist. These shorter isoforms of CD33 include one variant lacking exon 2, which encodes the V-set domain (CD33 ΔE2 ). At least at the mRNA level, CD33 ΔE2 is widely expressed in bone marrow and peripheral blood myeloid cells of patients with AML. However, almost all commercially and clinically available CD33 antibodies currently recognize the immunodominant V-set Ig-like domain. This means that these antibodies do not recognize shorter forms of CD33 that lack the V-set domain, such as CD33 ΔE2 . This can explain the observation made in a clinical trial in pediatric AML that patients with a single nucleotide polymorphism in the CD33 gene, resulting in reduced selective transcription of CD33 ΔE2 and translation of CD33 FL , did not benefit from the addition of GO (which also binds to the V-set domain of CD33) to intensive chemotherapy. Siegel et a