Targeted regulation of platelet and megakaryocyte activation by heteroreceptor co-clustering
AssigneesEtablissement Francais Du Sang, Inserm (Institut National De La Sante Et De La Recherche Medicale), Universite De Strasbourg
InventorsYOTIS SENIS, ALEXANDRA MAZHARIAN, CHRISTIAN GACHET
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Abstract
The present invention relates to multispecific antibodies that specifically bind an ectodomain of human G6B receptor and an ectodomain of a platelet or megakaryocyte immunoreceptor tyrosine-based activation motif (ITAM)-containing receptor, and their use in the treatment of diseases caused or exacerbated by platelet or megakaryocyte activation mediated by said platelet or megakaryocyte ITAM-containing receptor.
Claims21
1-35. (canceled)
A method of treating a disease caused or exacerbated by platelet or megakaryocyte activation mediated by a human platelet or megakaryocyte ITAM (tyrosine-based activation motif)-containing receptor comprising administering a multispecific antibody comprising an antigen binding region that specifically binds an ectodomain of human G6B receptor and an antigen binding region that specifically binds an ectodomain of a human platelet or megakaryocyte ITAM-containing receptor and capable of simultaneous binding to said two ectodomains to a subject having said disease.
A multispecific antibody comprising a first antigen binding region and a second antigen binding region:
- the first antigen binding region comprising:
- a) an antigen binding region that specifically binds an ectodomain of a G6B receptor and which comprises a heavy variable chain comprising one or more of the following CDRs:
- CDR1:
- (SEQ ID NO:
- 2)
- ETYIH or a variant thereof,
- CDR2:
- (SEQ ID NO:
- 3)
- RIDPADVYGRYDPKFQG or a variant thereof,
- and
- CDR3:
- (SEQ ID NO:
- 4)
- SYGSSYGIDY or a variant thereof,
- and/or a light variable chain comprising one or more of the following CDRs:
- CDR1:
- (SEQ ID NO:
- 5)
- RASQDISNYLN or a variant thereof,
- CDR2:
- (SEQ ID NO:
- 6)
- YTSTLHS or a variant thereof,
- and
- CDR3:
- (SEQ ID NO:
- 7)
- QQGYTLPWT or a variant thereof,
- said variants having at least 80% sequence identity to the recited CDR sequences;
- b) the antibody comprises an antigen binding region that specifically binds an ectodomain of a G6B receptor and which comprises a heavy variable chain comprising the following CDRs:
- CDR1:
- (SEQ ID NO:
- 2)
- ETYIH,
- CDR2:
- (SEQ ID NO:
- 3)
- RIDPADVYGRYDPKFQG,
- and
- CDR3:
- (SEQ ID NO:
- 4)
- SYGSSYGIDY,
- and a light variable chain comprising the following CDRs:
- CDR1:
- (SEQ ID NO:
- 5)
- RASQDISNYLN,
- CDR2:
- (SEQ ID NO:
- 6)
- YTSTLHS,
- and
- CDR3:
- (SEQ ID NO:
- 7)
- QQGYTLPWT;
- or
- c) wherein the antibody comprises an antigen binding region that specifically binds an ectodomain of a G6B receptor and which comprises a heavy variable chain comprising the following sequence:
- (SEQ ID NO:
- 8)
- EVQLQQSGAELVKPGASVKLSCTASGFNIKETYIHWVKQRPEQGLEWIGR
- IDPADVYGRYDPKFQGKATITADTSSNSAYLQVSSLTSEDTAVYYCARSY
- GSSYGIDYWGQGTSVTVSS, or a variant thereof;
- and a light variable chain comprising the following sequence:
- (SEQ ID NO:
- 9)
- DIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYY
- TSTLHSGVPSRFSGSGSGTDYSLTISNLEQEDVATYFCQQGYTLPWTFGG
- GTKLEIK, or a variant thereof;
- and
- the second antigen binding region comprising:
- a) an antigen binding region that specifically binds to the D2 ectodomain of human GPVI and comprises a heavy variable chain comprising one or more of the following CDRs:
- CDR1:
- (SEQ ID NO:
- 11)
- GFTFSGYV or a variant thereof,
- CDR2:
- (SEQ ID NO:
- 12)
- ISSGGNYT or a variant thereof,
- and
- CDR3:
- (SEQ ID NO:
- 13)
- ARVAYYGNYDYAMDY or a variant thereof,
- and/or a light variable chain comprising one or more of the following CDRs:
- CDR1:
- (SEQ ID NO:
- 14)
- QDITNY or a variant thereof,
- CDR2:
- YTS or a variant thereof,
- and
- CDR3:
- (SEQ ID NO:
- 15)
- QQGNTLRT or a variant thereof,
- said variants having at least 80% sequence identity to the recited CDR sequences;
- b) the platelet or megakaryocyte ITAM-containing receptor is human GPVI and the antibody comprises an antigen binding region that specifically binds to the D2 ectodomain of human GPVI and comprises a heavy variable chain comprising the following CDRs:
- CDR1:
- (SEQ ID NO:
- 11)
- GFTFSGYV,
- CDR2:
- (SEQ ID NO:
- 12)
- ISSGGNYT,
- and
- CDR3:
- (SEQ ID NO:
- 13)
- ARVAYYGNYDYAMDY,
- and a light variable chain comprising the following CDRs:
- CDR1:
- (SEQ ID NO:
- 14)
- QDITNY,
- CDR2:
- YTS,
- and
- CDR3:
- (SEQ ID NO:
- 15)
- QQGNTLRT;
- c) the platelet or megakaryocyte ITAM-containing receptor is human GPVI and the antibody comprises an antigen binding region that specifically binds to the D2 ectodomain of human GPVI and comprises a heavy variable chain comprising the following sequence
- (SEQ ID NO:
- 16)
- LQQSGGGLVKPGGSLKLSCAASGFTFSGYVMSWVRQSPEKRLEWVAEISS
- GGNYTYYPDTVTGRFTISRDNAKNTLYLEMNSLRSEDTAMYYCARVAYYG
- NYDYAMDYWGQGTSVTVSS, or a variant thereof;
- and a light variable chain comprising the following sequence
- (SEQ ID NO:
- 17)
- DIVLTQTTSSLSASLGDRVTISCRASQDITNYLNWYQQKPDGTLKLLIYY
- TSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLRTFGGG
- TKLEIKRSR, or a variant thereof;
- d) wherein the platelet or megakaryocyte ITAM-containing receptor is human CD32A and the antibody comprises an antigen binding region that specifically binds to the D2 ectodomain of CD32A and comprises a heavy variable chain comprising one or more of the following CDRs:
- CDR1:
- (SEQ ID NO:
- 20)
- GYTFTNYG or a variant thereof,
- CDR2:
- (SEQ ID NO:
- 21)
- LNTYTGES or a variant thereof,
- and
- CDR3:
- (SEQ ID NO:
- 22)
- ARGDYGYDDPLDY or a variant thereof,
- and/or a light variable chain comprising one or more of the following CDRs:
- CDR1:
- (SEQ ID NO:
- 23)
- KSLLHTNGNTY or a variant thereof,
- CDR2:
- RMS or a variant thereof,
- and
- CDR3:
- (SEQ ID NO:
- 24)
- MQHLEYPLT or a variant thereof,
- said variants having at least 80% sequence identity to the recited CDR sequences;
- e) the platelet or megakaryocyte ITAM-containing receptor is human CD32A and the antibody comprises an antigen binding region that specifically binds to the D2 ectodomain of CD32A and comprises a heavy variable chain comprising the following CDRs:
- CDR1:
- (SEQ ID NO:
- 20)
- GYTFTNYG,
- CDR2:
- (SEQ ID NO:
- 21)
- LNTYTGES,
- and
- CDR3:
- (SEQ ID NO:
- 22)
- ARGDYGYDDPLDY,
- and a light variable chain comprising one or more of the following CDRs:
- CDR1:
- (SEQ ID NO:
- 23)
- KSLLHTNGNTY,
- CDR2:
- RMS,
- and
- CDR3:
- (SEQ ID NO:
- 24)
- MQHLEYPLT;
- or
- f) the platelet or megakaryocyte ITAM-containing receptor is human CD32A and the antibody comprises an antigen binding region that specifically binds to the D2 ectodomain of CD32A and comprises a heavy variable chain comprising the following sequence
- (SEQ ID NO:
- 25)
- EIQLQQSGPELKKPGETVKISCKASGYTFTNYGMNWVKQAPGKGLKWMGW
- LNTYTGESIYPDDFKGRFAFSSETSASTAYLQINNLKNEDMATYFCARGD
- YGYDDPLDYWGQGTSVTVSS, or a variant thereof;
- and a light variable chain comprising the following sequence
- (SEQ ID NO:
- 26)
- DVVMTQTPPSVPVTPGESVSISCRSSKSLLHTNGNTYLHWFLQRPGQSPQ
- LLIYRMSVLASGVPDRFSGSGSGTAFTLSISRVEAEDVGVFYCMQHLEYP
- LTFGAGTKLELK, or a variant thereof.
Dependencies are inferred from the claim text.