ROR1 antibody immunoconjugates
Inventors
Lannutti, Brian • Jessen, Katti • Vo, Thanh-Trang • Watkins, Jeffry Dean
Assignees
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Publication Number
US-10335496-B2
Publication Date
2019-07-02
Expiration Date
Abstract
Provided herein are immunoconjugates comprising an anti-ROR1 antibody or an antigen-fragment fragment thereof and a drug moiety. These immunoconjugates are useful for treating ROR1 expressing cancers.
Core Innovation
The invention relates to immunoconjugates and antibody-drug conjugates as immunoconjugates in which an antibody or antigen-binding fragment is conjugated to a cytotoxic drug moiety. The antibody comprises V_H and V_L sequences including SEQ ID NOs: 5 and 6, and the disclosed immunoconjugates include ADC-A, ADC-E, ADC-H, ADC-J, ADC-K, ADC-L, ADC-M, ADC-N, ADC-O, ADC-P, ADC-Q, and ADC-R having an ADC structure in which Ab is the antibody.
The immunoconjugates include selected cytotoxic drug moieties and linker-related components, including cleavable and non-cleavable linker types, an optional spacer, and linker/drug attachment variables such as X, p, q, n, u, and v. The disclosed payload classes include monomethyl auristatin E (MMAE), DM1, azonafide, Duocarmycin, PNU-159682, PBD, and α-amanitin, with different ADC embodiments varying the cytotoxic payload D while maintaining the overall ADC structure.
The invention is directed to treating ROR1-expressing cancers, including CLL, MCL, DLBCL, NHL, Richter’s transformation, and solid tumors. The disclosure also presents pharmaceutical compositions comprising the immunoconjugate with a pharmaceutically acceptable excipient, combination therapy with additional therapeutic agents such as BTK inhibitors, Bcl-2 inhibitors, mTOR inhibitors, or PI3K inhibitors, and therapeutic administration to patients in need.
Claims Coverage
The independent claims are directed to ROR1-targeted antibody-cytotoxic drug immunoconjugates defined by antibody variable region sequences SEQ ID NOs: 5 and 6 and ADC structure definitions. Across the independent claims, the coverage includes a cytotoxic drug moiety to antibody ratio of 1 to 7, pharmaceutical compositions with a pharmaceutically acceptable excipient, combination therapy features, treating ROR1-expressing cancer, and making methods.
Antibody variable regions defined by SEQ ID NOs 5 and 6
An immunoconjugate comprising an antibody conjugated to a cytotoxic drug moiety, wherein the V_H and V_L of the antibody comprise the amino acid sequences of SEQ ID NOs: 5 and 6, respectively, and the immunoconjugate is ADC-A, ADC-E, ADC-H, ADC-J, ADC-K, ADC-L, ADC-M, ADC-N, ADC-O, ADC-P, ADC-Q, or ADC-R.
ADC immunoconjugate structure definition
The immunoconjugate is defined as ADC-A, ADC-E, ADC-H, ADC-J, ADC-K, ADC-L, ADC-M, ADC-N, ADC-O, ADC-P, ADC-Q, or ADC-R having the structure wherein Ab in the structure is the antibody.
Cytotoxic drug moiety to antibody ratio constraint
The immunoconjugate is defined where the cytotoxic drug moiety to antibody ratio is 1 to 7.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition includes the immunoconjugate together with a pharmaceutically acceptable excipient.
Combination therapy with additional therapeutic agents
A pharmaceutical composition or related composition includes an additional therapeutic agent selected from BTK inhibitors, Bcl-2 inhibitors, mTOR inhibitors, or PI3K inhibitors.
Treating ROR1-expressing cancer
A method for treating a ROR1-expressing cancer by administering a therapeutically effective amount of the immunoconjugate to a patient in need thereof.
Method of making by conjugating a payload to an ROR1-binding antibody
A method for making an immunoconjugate by providing an antibody that specifically binds to ROR1 and conjugating a cytotoxic payload to the antibody, with payload-conjugation embodiments including MMAE, azonafide, Duocarmycin, PBD, PNU-159682, or related named payloads.
The claims collectively define ROR1-targeted antibody-cytotoxic drug immunoconjugates with antibody variable region sequences SEQ ID NOs: 5 and 6 and ADC structure definitions. They further cover a cytotoxic drug moiety to antibody ratio of 1 to 7, pharmaceutical compositions with a pharmaceutically acceptable excipient, combination with BTK/Bcl-2/mTOR/PI3K inhibitors, treating ROR1-expressing cancer, and making methods using ROR1-binding antibodies and named cytotoxic payloads.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment of ROR1-expressing cancer by administering a therapeutically effective amount of the immunoconjugate to a patient in need thereof.
Pharmaceutical compositions comprising the immunoconjugate together with a pharmaceutically acceptable excipient, optionally with additional therapeutic agents selected from BTK inhibitors, Bcl-2 inhibitors, mTOR inhibitors, or PI3K inhibitors.
Methods for producing immunoconjugates by providing an antibody that specifically binds to ROR1 and conjugating named cytotoxic drug moieties to the antibody.
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