US 12,215,157 B2Granted

Multi-specific binding proteins that bind CD33, NKG2D, and CD16, and methods of use

AssigneeDragonfly Therapeutics, Inc.

InventorsGregory P. Chang, Ann F. Cheung, Asya Grinberg, Dhruv Kam Sethi, William Haney, Bianka Prinz, Bradley M. Lunde, Ronnie Wei, Daniel Fallon, Steven O'Neil

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Abstract

Multi-specific binding proteins that bind to and kill human cancer cells expressing CD33 (Siglec-3) are described, as well as pharmaceutical compositions and therapeutic methods useful for the treatment of CD33 expressing cancer. The invention relates to multi-specific binding proteins that bind to human cancer cells expressing CD33 and exhibit high potency and maximum lysis of target cells compared to anti-CD33 monoclonal antibodies. The multi-specific binding proteins comprise a CD33-binding domain, an NKG2D-binding domain and a CD16-binding domain.

Claims40

Dependent claims

A protein comprising:

(a) a first antigen-binding site that binds human NKG2D;
(b) a second antigen-binding site that binds human CD33;
and
(c) an antibody Fc domain that binds human CD16 or a portion thereof that binds human CD16,
wherein the first antigen-binding site that binds human NKG2D comprises a Fab fragment, and
wherein the Fab fragment comprises a light chain complementarity-determining region 1 (CDR1) sequence comprising the amino acid sequence of SEQ ID NO:114, a light chain complementarity-determining region 2 (CDR2) sequence comprising the amino acid sequence of SEQ ID NO:115, a light chain complementarity-determining region 3 (CDR3) sequence comprising the amino acid sequence of SEQ ID NO:
116, a heavy chain complementarity-determining region 1 (CDR1) sequence comprising the amino acid sequence of SEQ ID NO:111, a heavy chain complementarity-determining region 2 (CDR2) sequence comprising the amino acid sequence of SEQ ID NO:112, and a heavy chain complementarity-determining region 3 (CDR3) sequence comprising the amino acid sequence of SEQ ID NO:113;
and wherein the second antigen-binding site that binds human CD33 comprises a single-chain variable fragment (scFv), and wherein the scFv comprises a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO:48, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO:49, a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO:50, a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO:45, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO:46, and a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO:47.

5 more elements

A protein comprising:

(a) a first antigen-binding site that binds human NKG2D;
(b) a second antigen-binding site that binds human CD33;
and
(c) an antibody Fc domain that binds human CD16 or a portion thereof that binds human CD16,
wherein the first antigen-binding site that binds human NKG2D comprises a Fab fragment, and
wherein the Fab fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:87 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:88;
and
wherein the second antigen-binding site that binds human CD33 comprises a single-chain variable fragment (scFv), and wherein the scFv comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:10, wherein the heavy chain variable region of the scFv comprises one amino acid substitution relative to the amino acid sequence of SEQ ID NO:9 located in a framework region of the heavy chain variable region of the scFv, and
wherein the light chain variable region of the scFv comprises one amino acid substitution relative to the amino acid sequence of SEQ ID NO:
10 located in a framework region of the light chain variable region of the scFv;
and
wherein the antibody Fc domain that binds human CD16 or a portion thereof that binds human CD16 comprises an amino acid sequence at least 90% identical to amino acids 234-332 of a human IgG1 antibody according to EU numbering.

9 more elements

A protein comprising:

(a) a first antigen-binding site that binds human NKG2D;
(b) a second antigen-binding site that binds human CD33;
and
(c) an antibody Fc domain that binds human CD16 or a portion thereof that binds human CD16,
wherein the first antigen-binding site that binds human NKG2D comprises a Fab fragment, and
wherein the Fab fragment comprises a light chain complementarity-determining region 1 (CDR1) sequence comprising the amino acid sequence of SEQ ID NO:114, a light chain complementarity-determining region 2 (CDR2) sequence comprising the amino acid sequence of SEQ ID NO:115, a light chain complementarity-determining region 3 (CDR3) sequence comprising the amino acid sequence of SEQ ID NO:116, a heavy chain complementarity-determining region 1 (CDR1) sequence comprising the amino acid sequence of SEQ ID NO:192, a heavy chain complementarity-determining region 2 (CDR2) sequence comprising the amino acid sequence of SEQ ID NO:112, and a heavy chain complementarity-determining region 3 (CDR3) sequence comprising the amino acid sequence of SEQ ID NO:193;
and wherein the second antigen-binding site that binds human CD33 comprises a single-chain variable fragment (scFv), and wherein the scFv comprises a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO:48, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO:49, a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO:50, a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO:181, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO:46, and a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO:
182.

5 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/971,104Filed 20 Feb 2019 · us provisional application
Priority: 20 Feb 2018
Published: US 2021/0101976 A18 Apr 2021
Granted: 4 Feb 2025
Term ends: Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07K 16/2803
Against receptors, cell surface antigens or cell surface determinants: against the immunoglobulin superfamily
C07K 16/283
Against the immunoglobulin superfamily: against Fc-receptors, e.g. CD16, CD32, CD64
A61P 35/00
Antineoplastic agents
C07K 16/2851
Against receptors, cell surface antigens or cell surface determinants: against the lectin superfamily, e.g. CD23, CD72

Family

Application62/632,756Us provisional application · filed 20 Feb 2018
Application62/677,137Us provisional application · filed 28 May 2018
US 2021/0101976 A1Pre-grant publication · published 8 Apr 2021
US 12,215,157 B2This patent

From the US filing history. Foreign family members aren’t listed.

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