JPWO2019222082A5

JPWO2019222082A5 -

Info

Publication number: JPWO2019222082A5
Application number: JP2020564389A
Authority: JP
Publication date: 2022-05-19
Anticipated expiration: 2039-05-13

Description

実施例９
糖鎖で遮蔽されているエピトープを有する抗ＣＤ２４抗体は、ＣＤ２４を高発現する正常細胞には結合しない
抗体に基づく免疫治療剤の重要な要件は、正常組織に対する反応性が最小限であることである。ＣＤ２４は造血細胞、特に顆粒球、Ｂ細胞、赤血球の一部、単球の一部に豊富に発現しているため、ＰＰ６３７３並びにその２つのヒト化クローンＨ２Ｌ３及びＨ３Ｌ３を従来の抗ＣＤ２４ｍＡｂであるＭＬ５と比較した。図３３に示すように、ＭＬ５は通常高レベルのＣＤ２４を発現する細胞に強い結合を示すが、Ｈ２Ｌ３及びＨ３Ｌ３はＢ細胞や赤血球には結合せず、顆粒球にはほとんど結合しない。この結果は、マクロファージ及び非Ｂリンパ球の一部などの他の細胞種への結合が最小限であることを示している。本発明の例示的な態様を以下に記載する。
＜１＞
非がん性細胞上では糖鎖で遮蔽されている（glycan-shielded）ががん細胞上では露出するエピトープに結合する抗体を含む、組成物。
＜２＞
前記抗体がＣＤ２４に結合する、＜１＞に記載の組成物。
＜３＞
前記抗体が、配列番号４８に示される配列を含むペプチドに結合する、＜１＞に記載の組成物。
＜４＞
前記抗体が、配列番号１に示される配列を含む重鎖可変領域及び配列番号２に示される配列を含む軽鎖可変領域を含む、＜１＞に記載の組成物。
＜５＞
前記抗体が、配列番号３～配列番号１０のいずれか１つに示される配列を含む重鎖可変領域及び配列番号１１～配列番号１６のいずれか１つに示される配列を含む軽鎖可変領域を含む、＜１＞に記載の組成物。
＜６＞
前記抗体が、配列番号６に示される配列を含む重鎖可変領域及び配列番号１６に示される配列を含む軽鎖可変領域を含む、＜５＞に記載の組成物。
＜７＞
前記抗体が、配列番号２９～配列番号３２のいずれか１つに示される配列を含む重鎖可変領域及び配列番号３３～配列番号３６のいずれか１つに示される配列を含む軽鎖可変領域を含む、＜１＞に記載の組成物。
＜８＞
前記抗体が、配列番号３０に示される配列を含む重鎖可変領域及び配列番号３５に示される配列を含む軽鎖可変領域を含む、＜７＞に記載の組成物。
＜９＞
前記抗体が、配列番号３１に示される配列を含む重鎖可変領域及び配列番号３５に示される配列を含む軽鎖可変領域を含む、＜７＞に記載の組成物。
＜１０＞
＜１＞～＜９＞のいずれか一つに記載の組成物を含む第１の抗体ドメイン及び第２の抗体又はその抗原結合断片を含む第２の抗体ドメインを含む、二重特異性抗体。
＜１１＞
前記第２の抗体ドメインががん免疫療法のために免疫エフェクターＴ細胞を前記がん細胞に引き付ける、＜１０＞に記載の二重特異性抗体。
＜１２＞
前記第２の抗体又はその抗原結合断片がＣＤ３に結合する、＜１０＞に記載の二重特異性抗体。
＜１３＞
配列番号１７に示される配列及び配列番号１８に示される配列を含む、＜１０＞に記載の二重特異性抗体。
＜１４＞
配列番号２３～配列番号２７及び配列番号３７～配列番号４１のいずれか１つに示される配列を含む、＜１０＞に記載の二重特異性抗体。
＜１５＞
前記第２の抗体又はその抗原結合断片がＴＣＲ－α鎖、ＴＣＲ－β鎖、ＴＣＲ－γ鎖又はＴＣＲ－δ鎖に結合する、＜１０＞に記載の二重特異性抗体。
＜１６＞
抗体介在性細胞傷害（ＡＤＣＣ）活性を有する、＜１＞～＜１５＞のいずれか一つに記載の抗体又は二重特異性抗体。
＜１７＞
増強されたＡＤＣＣ活性を有するように設計されている、＜１６＞に記載の抗体又は二重特異性抗体。
＜１８＞
抗体介在性細胞貪食（ＡＤＣＰ）活性を有する、＜１＞～＜１７＞のいずれか一つに記載の抗体又は二重特異性抗体。
＜１９＞
増強されたＡＤＣＰ活性を有するように設計されている、＜１８＞に記載の抗体又は二重特異性抗体。
＜２０＞
＜４＞～＜９＞のいずれか一つに記載の組成物を含む一本鎖抗体を含む、キメラ抗原受容体。
＜２１＞
配列番号２８に示される配列を含む、＜２０＞に記載のキメラ抗原受容体。
＜２２＞
＜１＞～＜２１＞のいずれか一つに記載の抗体、二重特異性抗体又はキメラ抗原受容体及び第二の抗がん治療剤を含む、組成物。
＜２３＞
＜１＞～＜２２＞のいずれか一つに記載の抗体、二重特異性抗体、キメラ抗原受容体又は組成物を、がん処置を必要としている患者に投与することを含む、前記患者におけるがんを処置する方法。
＜２４＞
前記がんが肺がん、卵巣がん、乳がん、肝臓がん、脳がん、子宮頸がん、腎がん、精巣がん、前立腺がん又は神経芽細胞腫である、＜２３＞に記載の方法。
＜２５＞
抗ＣＤ２４抗体又はＣＤ２４に結合する受容体を発現する細胞を含む治療に関連する有害作用を処置する必要がある患者に、配列番号４８に示される配列を含む組成物を投与することを含む、前記患者における前記有害作用を処置する方法。
＜２６＞
がんを処置又は予防（prophylaxis）する必要がある患者に、配列番号４８を含む組成物を投与することを含む、前記患者におけるがんを処置又は予防する方法。
＜２７＞
＜１＞に記載の抗体の使用を含む、悪性組織又は転移性病変を診断する方法。
＜２８＞
＜１＞に記載の抗体の使用を含む、循環がん細胞を識別する方法。
＜２９＞
がんを処置するための薬剤の製造における、＜１＞～＜２２＞のいずれか一つに記載の抗体、二重特異性抗体、キメラ抗原受容体又は組成物の使用。
＜３０＞
前記がんが肺がん、卵巣がん、乳がん、肝臓がん、脳がん、子宮頸がん、卵巣がん、腎がん、精巣がん、前立腺がん又は神経芽細胞腫である、＜２９＞に記載の方法。
＜３１＞
抗ＣＤ２４抗体又はＣＤ２４に結合する受容体を発現する細胞の治療的使用に関連する有害作用を処置するための薬剤の製造における、配列番号４８に示される配列を含む組成物の使用。
＜３２＞
がんを処置又は予防するための薬剤の製造における、配列番号４８を含む組成物の使用。
Example 9
Anti-CD24 antibodies with glycan-shielded epitopes do not bind to normal cells that highly express CD24 An important requirement for antibody-based immunotherapeutic agents is minimal reactivity to normal tissues. be. Since CD24 is abundantly expressed in hematopoietic cells, especially granulocytes, B cells, some erythrocytes, and some monocytes, PP6373 and its two humanized clones H2L3 and H3L3 are conventional anti-CD24 mAbs. Compared with ML5. As shown in FIG. 33, ML5 normally exhibits strong binding to cells expressing high levels of CD24, whereas H2L3 and H3L3 do not bind to B cells or erythrocytes and rarely to granulocytes. This result indicates minimal binding to other cell types such as macrophages and some non-B lymphocytes. Exemplary embodiments of the present invention are described below.
<1>
A composition comprising an antibody that binds to an epitope that is glycoan-shielded on non-cancerous cells but is exposed on cancer cells.
<2>
The composition according to <1>, wherein the antibody binds to CD24.
<3>
The composition according to <1>, wherein the antibody binds to a peptide containing the sequence shown in SEQ ID NO: 48.
<4>
The composition of <1>, wherein the antibody comprises a heavy chain variable region comprising the sequence set forth in SEQ ID NO: 1 and a light chain variable region comprising the sequence set forth in SEQ ID NO: 2.
<5>
The antibody comprises a heavy chain variable region containing the sequence set forth in any one of SEQ ID NOs: 3 to SEQ ID NO: 10 and a light chain variable region containing the sequence set forth in any one of SEQ ID NOs: 11 to SEQ ID NO: 16. The composition according to <1>.
<6>
The composition of <5>, wherein the antibody comprises a heavy chain variable region comprising the sequence set forth in SEQ ID NO: 6 and a light chain variable region comprising the sequence set forth in SEQ ID NO: 16.
<7>
The antibody comprises a heavy chain variable region comprising the sequence set forth in any one of SEQ ID NOs: 29 to SEQ ID NO: 32 and a light chain variable region containing the sequence set forth in any one of SEQ ID NOs: 33 to SEQ ID NO: 36. The composition according to <1>.
<8>
The composition according to <7>, wherein the antibody comprises a heavy chain variable region comprising the sequence set forth in SEQ ID NO: 30 and a light chain variable region comprising the sequence set forth in SEQ ID NO: 35.
<9>
The composition according to <7>, wherein the antibody comprises a heavy chain variable region comprising the sequence set forth in SEQ ID NO: 31 and a light chain variable region comprising the sequence set forth in SEQ ID NO: 35.
<10>
A bispecific antibody comprising a first antibody domain comprising the composition according to any one of <1> to <9> and a second antibody domain containing the second antibody or an antigen-binding fragment thereof.
<11>
The bispecific antibody according to <10>, wherein the second antibody domain attracts immune effector T cells to the cancer cells for cancer immunotherapy.
<12>
The bispecific antibody according to <10>, wherein the second antibody or an antigen-binding fragment thereof binds to CD3.
<13>
The bispecific antibody of <10>, comprising the sequence set forth in SEQ ID NO: 17 and the sequence set forth in SEQ ID NO: 18.
<14>
The bispecific antibody according to <10>, which comprises the sequence shown in any one of SEQ ID NO: 23 to SEQ ID NO: 27 and SEQ ID NO: 37 to SEQ ID NO: 41.
<15>
The bispecific antibody according to <10>, wherein the second antibody or an antigen-binding fragment thereof binds to a TCR-α chain, a TCR-β chain, a TCR-γ chain or a TCR-δ chain.
<16>
The antibody or bispecific antibody according to any one of <1> to <15>, which has antibody-mediated cellular cytotoxicity (ADCC) activity.
<17>
The antibody or bispecific antibody according to <16>, which is designed to have enhanced ADCC activity.
<18>
The antibody or bispecific antibody according to any one of <1> to <17>, which has antibody-mediated cell phagocytosis (ADCP) activity.
<19>
The antibody or bispecific antibody according to <18>, which is designed to have enhanced ADCP activity.
<20>
A chimeric antigen receptor comprising a single-chain antibody comprising the composition according to any one of <4> to <9>.
<21>
The chimeric antigen receptor according to <20>, which comprises the sequence shown in SEQ ID NO: 28.
<22>
A composition comprising the antibody, bispecific antibody or chimeric antigen receptor according to any one of <1> to <21>, and a second anticancer therapeutic agent.
<23>
In the patient, comprising administering the antibody, bispecific antibody, chimeric antigen receptor or composition according to any one of <1> to <22> to a patient in need of cancer treatment. How to treat cancer.
<24>
23>, wherein the cancer is lung cancer, ovarian cancer, breast cancer, liver cancer, brain cancer, cervical cancer, renal cancer, testis cancer, prostate cancer or neuroblastoma. Method.
<25>
Supra. A method of treating the adverse effects in a patient.
<26>
A method of treating or preventing cancer in said patient, comprising administering to the patient in need of treating or prophylaxis the cancer a composition comprising SEQ ID NO: 48.
<27>
A method for diagnosing malignant tissue or metastatic lesions, which comprises the use of the antibody according to <1>.
<28>
A method for identifying circulating cancer cells, which comprises the use of the antibody according to <1>.
<29>
Use of the antibody, bispecific antibody, chimeric antigen receptor or composition according to any one of <1> to <22> in the manufacture of a drug for treating cancer.
<30>
The cancer is lung cancer, ovarian cancer, breast cancer, liver cancer, brain cancer, cervical cancer, ovarian cancer, renal cancer, testis cancer, prostate cancer or neuroblastoma, <29. > The method described in.
<31>
Use of a composition comprising the sequence set forth in SEQ ID NO: 48 in the manufacture of an agent for treating an adverse effect associated with the therapeutic use of cells expressing an anti-CD24 antibody or receptor that binds to CD24.
<32>
Use of a composition comprising SEQ ID NO: 48 in the manufacture of a drug for treating or preventing cancer.

Claims

(A) Heavy chain variable region comprising the sequence set forth in SEQ ID NO: 31 or SEQ ID NO: 30 and light chain variable region comprising the sequence set forth in SEQ ID NO: 35; or
(B) Heavy chain variable region containing the sequence shown in SEQ ID NO: 6 and light chain variable region containing the sequence shown in SEQ ID NO: 16.
Anti-CD24 antibody comprising.

The anti-CD24 antibody according to claim 1, which is a single-chain antibody.

The anti-CD24 antibody of claim 1 or 2 , wherein the heavy chain variable region comprises the sequence set forth in SEQ ID NO: 31 and the light chain variable region comprises the sequence set forth in SEQ ID NO: 35.

The anti-CD24 antibody of claim 1 or 2 , wherein the heavy chain variable region comprises the sequence set forth in SEQ ID NO: 30 and the light chain variable region comprises the sequence set forth in SEQ ID NO: 35.

The anti-CD24 antibody of claim 1 or 2 , wherein the heavy chain variable region comprises the sequence set forth in SEQ ID NO: 6 and the light chain variable region comprises the sequence set forth in SEQ ID NO: 16.

A bispecific antibody comprising a first antibody domain comprising the anti-CD24 antibody according to any one of claims 1 to 5 and a second antibody domain comprising the second antibody or an antigen-binding fragment thereof. ..

The second antibody domain attracts immune effector T cells to cancer cells for cancer immunotherapy and / or
The bispecific antibody of claim 6, wherein the second antibody domain binds to a CD3, TCR-α chain, TCR-β chain, TCR-γ chain or TCR-δ chain .

The bispecific antibody according to claim 7 , wherein the second antibody domain binds to CD3.

The bispecific antibody of claim 8 , wherein the second antibody domain comprises the sequence set forth in SEQ ID NO: 18.

The antibody or bispecific antibody according to any one of claims 1 to 9 , which has antibody-mediated cellular cytotoxicity (ADCC) activity or antibody-mediated cellular cytotoxicity (ADCP) activity .

A chimeric antigen receptor comprising a single-chain antibody comprising the anti-CD24 antibody according to any one of claims 1 to 5 .

An antibody drug conjugate comprising the anti-CD24 antibody according to any one of claims 1 to 5, which is bound to an effector moiety selected from the group consisting of cytotoxic agents, protein toxins, and radionuclides. ..

A composition comprising the antibody according to any one of claims 1 to 12 , a bispecific antibody , a chimeric antigen receptor , or an antibody drug conjugate and a second anticancer therapeutic agent.

13. The composition of claim 13, wherein the second anti-cancer therapeutic agent comprises an anti-PD-1 antibody, an anti-CTLA-4 antibody or LAG3.

A pharmaceutical agent for use in the treatment of cancer, which comprises the antibody, bispecific antibody, chimeric antigen receptor , antibody drug conjugate, or composition according to any one of claims 1 to 14 . Composition .

15. The cancer according to claim 15 , wherein the cancer is lung cancer, ovarian cancer, breast cancer, liver cancer, brain cancer, cervical cancer , renal cancer, testis cancer, prostate cancer or neuroblastoma. Pharmaceutical composition .