WO2011131746A2 - Heterodimeric antibody fc-containing proteins and methods for production thereof - Google Patents

Heterodimeric antibody fc-containing proteins and methods for production thereof Download PDF

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Publication number
WO2011131746A2
WO2011131746A2 PCT/EP2011/056388 EP2011056388W WO2011131746A2 WO 2011131746 A2 WO2011131746 A2 WO 2011131746A2 EP 2011056388 W EP2011056388 W EP 2011056388W WO 2011131746 A2 WO2011131746 A2 WO 2011131746A2
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WIPO (PCT)
Prior art keywords
iggl
homodimeric
protein
antibodies
vitro method
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PCT/EP2011/056388
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English (en)
French (fr)
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WO2011131746A3 (en
Inventor
Aran Frank Labrijn
Joyce Meesters
Ewald Van Den Bremer
Joost J. Neijssen
Patrick Van Berkel
Bart De Goeij
Tom Vink
Jan Van De Winkel
Janine Schuurman
Paul Parren
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Genmab AS
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Genmab AS
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Priority to EP11716882.3A priority Critical patent/EP2560993B1/en
Priority to EA201201435A priority patent/EA201201435A1/ru
Priority to MX2012012019A priority patent/MX353144B/es
Priority to RS20241034A priority patent/RS65965B1/sr
Priority to UAA201213258A priority patent/UA113146C2/uk
Priority to BR112012026766-3A priority patent/BR112012026766B1/pt
Priority to DK11716882.3T priority patent/DK2560993T3/da
Priority to BR122021015749-9A priority patent/BR122021015749B1/pt
Priority to CA2796181A priority patent/CA2796181C/en
Priority to US13/642,253 priority patent/US9150663B2/en
Priority to LTEPPCT/EP2011/056388T priority patent/LT2560993T/lt
Priority to PL11716882.3T priority patent/PL2560993T3/pl
Priority to SG2012073524A priority patent/SG184427A1/en
Priority to KR1020127030223A priority patent/KR101930964B1/ko
Priority to MX2017016805A priority patent/MX391041B/es
Priority to AU2011244282A priority patent/AU2011244282A1/en
Priority to SI201132116T priority patent/SI2560993T1/sl
Priority to ES11716882T priority patent/ES2989108T3/es
Priority to HRP20241208TT priority patent/HRP20241208T1/hr
Priority to JP2013505485A priority patent/JP6040148B2/ja
Priority to CN201180030540.9A priority patent/CN103097417B/zh
Priority to FIEP11716882.3T priority patent/FI2560993T3/fi
Priority to EP24183460.5A priority patent/EP4477668A3/en
Priority to KR1020187036131A priority patent/KR102152109B1/ko
Priority to ES11722423T priority patent/ES2733921T3/es
Priority to CA2800785A priority patent/CA2800785C/en
Priority to NZ60400311A priority patent/NZ604003A/en
Priority to NZ717883A priority patent/NZ717883A/en
Priority to AU2011257121A priority patent/AU2011257121A1/en
Priority to CN202210148377.6A priority patent/CN114805583A/zh
Priority to IL299365A priority patent/IL299365A/en
Priority to CN201180036934.5A priority patent/CN103154035B/zh
Priority to CA3051311A priority patent/CA3051311A1/en
Priority to CN201710259581.4A priority patent/CN107253992B/zh
Priority to PCT/EP2011/058779 priority patent/WO2011147986A1/en
Priority to EP19168254.1A priority patent/EP3539988A3/en
Priority to EP11722423.8A priority patent/EP2576621B1/en
Priority to US13/700,341 priority patent/US9862769B2/en
Priority to JP2013511703A priority patent/JP6320753B2/ja
Publication of WO2011131746A2 publication Critical patent/WO2011131746A2/en
Publication of WO2011131746A3 publication Critical patent/WO2011131746A3/en
Priority to EP24214055.6A priority patent/EP4520771A3/en
Priority to EP12718626.0A priority patent/EP2699262A2/en
Priority to JP2014505654A priority patent/JP6177231B2/ja
Priority to CA2832389A priority patent/CA2832389A1/en
Priority to EP12715407.8A priority patent/EP2699260B1/en
Priority to AU2012245116A priority patent/AU2012245116A1/en
Priority to PCT/EP2012/057307 priority patent/WO2012143524A2/en
Priority to CA2832387A priority patent/CA2832387A1/en
Priority to CN201280030668.XA priority patent/CN103796677B/zh
Priority to US14/112,848 priority patent/US20140170148A1/en
Priority to JP2014505655A priority patent/JP2014514314A/ja
Priority to CN201280030714.6A priority patent/CN103796678B/zh
Priority to US14/112,859 priority patent/US20140170149A1/en
Priority to PCT/EP2012/057303 priority patent/WO2012143523A1/en
Priority to IL222507A priority patent/IL222507B/en
Anticipated expiration legal-status Critical
Priority to IL223162A priority patent/IL223162A0/en
Priority to IL228802A priority patent/IL228802A0/en
Priority to US14/830,336 priority patent/US20160046727A1/en
Priority to AU2016201676A priority patent/AU2016201676B2/en
Priority to IL245275A priority patent/IL245275B/en
Priority to JP2016176459A priority patent/JP6341963B2/ja
Priority to US15/414,122 priority patent/US10597464B2/en
Priority to JP2017047043A priority patent/JP6560703B2/ja
Priority to US15/599,393 priority patent/US20170369590A1/en
Priority to US15/599,395 priority patent/US20170369594A1/en
Priority to AU2017204346A priority patent/AU2017204346A1/en
Priority to US15/832,337 priority patent/US11091553B2/en
Priority to US15/832,366 priority patent/US11046771B2/en
Priority to US15/832,421 priority patent/US20180179286A1/en
Priority to AU2017276192A priority patent/AU2017276192A1/en
Priority to IL266073A priority patent/IL266073B/en
Priority to IL267022A priority patent/IL267022B2/en
Priority to AU2019204527A priority patent/AU2019204527B2/en
Priority to AU2019222926A priority patent/AU2019222926A1/en
Priority to US16/667,369 priority patent/US11578141B2/en
Priority to US16/777,053 priority patent/US11866514B2/en
Priority to US17/149,019 priority patent/US20210324105A1/en
Priority to US17/369,542 priority patent/US20220169738A1/en
Priority to AU2021261868A priority patent/AU2021261868B2/en
Priority to US18/507,869 priority patent/US20240209117A1/en
Priority to US18/596,319 priority patent/US20250066506A1/en
Ceased legal-status Critical Current

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Definitions

  • the present invention relates to novel heterodimeric antibody-Fc-containing proteins, such as bispecific antibodies, and novel methods for producing such proteins.
  • Monoclonal antibodies have in recent years become successful therapeutic molecules, in particular for the treatment of cancer. Unfortunately, however, monoclonal antibodies are often unable to cure diseases when used as monotherapy. Bispecific antibodies can potentially overcome some of the limitations of monoclonal antibody therapy, e.g. they could be used as mediators to target a drug or toxic compound to target cells, as mediators to retarget effector mechanisms to disease-associated sites or as mediators to increase specificity for tumor cells, for example by binding to a combination of targets molecules that is exclusively found on tumor cells.
  • bispecific antibodies Different formats and uses of bispecific antibodies have recently been reviewed by Chames and Baty (2009) Curr Opin Drug Disc Dev 12: 276.
  • One of the major obstacles in the development of bispecific antibodies has been the difficulty of producing the material in sufficient quality and quantity by traditional technologies, such as the hybrid hybridoma and chemical conjugation methods (Marvin and Zhu (2005) Acta Pharmacol Sin 26: 649).
  • Protuberances are constructed by replacing small amino- acid side-chains from the interface of the first polypeptide with larger side chains. Compensatory “cavities” of identical or similar size to the protuberances are created in the interface of the second polypeptide by replacing large amino-acid side-chains with smaller ones (US patent 5,731,168).
  • EP1870459 (Chugai) and WO 2009089004 (Amgen) describe other strategies for favoring heterodimer formation upon co- expression of different antibody domains in a host cell. In these methods, one or more residues that make up the CH3-CH3 interface in both CH3 domains are replaced with a charged amino acid such that homodimer formation is electrostatically unfavorable and heterodimerization is electrostatically favorable.
  • WO2007110205 Merck describe yet another strategy, wherein differences between IgA and IgG CH3 domains are exploited to promote heterodimerization.
  • WO 2008119353 describes an in vitro method for producing bispecific antibodies wherein a bispecific antibody is formed by "Fab-arm” or "half- molecule” exchange (swapping of a heavy chain and attached light chain) between two monospecific IgG4- or IgG4-like antibodies upon incubation under reducing conditions.
  • This Fab-arm exchange reaction is the result of a disulfide-bond isomerization reaction and dissociation-association of CH3 domains wherein heavy- chain disulfide bonds in the hinge regions of the parent (originally monospecific) antibodies are reduced and the resulting free cysteines form an inter heavy-chain disulfide bond with cysteine residues of another parent antibody molecule (originally with a different specificity), and simultaneously CH3 domains of the parent antibodies release and reform by dissociation-association.
  • the resulting product is a bispecific antibody having two Fab arms which potentially are compased different sequences. It should be noted that the process is random however and Fab-arm exchange can also occur between two molecules with identical sequence or two bispecific molecules can engage in Fab-arm exchange to regenerate antibodies comprising the original monospecific parent antibody specificity.
  • the present invention provides an efficient in vitro method for the production of highly stable heterodimeric Fc-containing proteins on the basis of stable homodimeric Fc-containing starting materials.
  • a highly stable bispecific antibody can be formed with high yield and purity on the basis of two stable monospecific antibodies as starting material.
  • the invention relates to an in vitro method for generating a heterodimeric protein, said method comprising the following steps: a) providing a first homodimeric protein comprising an Fc region of an immunoglobulin, said Fc region comprising a first CH3 region,
  • sequences of said first and second CH3 regions are different and are such that the heterodimeric interaction between said first and second CH3 regions is stronger than each of the homodimeric interactions of said first and second CH3 regions
  • the method can for example be used for in vitro production of heterodimeric proteins, such as bispecific antibodies, for various uses, such as therapeutic or diagnostic uses.
  • An advantage of this in vitro method is that heavy-chain/light-chain pairing stays intact during the reaction, so no undesired combinations of heavy chain and light chains are obtained in the product. This in contrast to some of the co- expression methods described in the prior art (see above) where a common light chain which can form a functional antibody with both heavy chain needs to be found in order to avoid the formation of non-functional heavy-chain/light-chain products, because of random heavy-chain/light-chain pairing in the cell.
  • the in vitro process can be performed in the laboratory which allows greater control, flexibility and yield of the heterodimeric protein than is allowed by co-expression.
  • the in vitro method of the invention can also be used to create compound libraries of larger size, e.g . in a screening method to identify advantageous combinations of specificities.
  • a bispecific antibody having a desired property e.g . optimal target binding or cell killing, may be identified by :
  • sequences of said first and second CH3 regions are different and are such that the heterodimeric interaction between said first and second CH3 regions is stronger than each of the homodimeric interactions of said first and second CH3 regions
  • the present invention relates to heterodimeric proteins obtained or obtainable by the method of the invention and to methods for producing heterodimeric proteins of the invention by co-expression in a suitable host cell.
  • FIG. 1 Generation of bispecific antibodies by interspecies Fab-arm exchange.
  • the generation of bispecific antibodies after GSH-induced in vitro Fab- arm exchange between the indicated EGFR (2F8) and CD20 (7D8) IgG4 antibodies was determined by an ELISA.
  • a concentration series (total antibody) of 0- 1 ⁇ g/mL was analyzed in the ELISA.
  • Bispecific binding was higher after Fab-arm exchange between rhesus (Rh) and human (Hu) IgG4 antibodies than between two antibodies of the same species.
  • Figure 2 Alignment of the amino acid sequences of the core hinge (i.e. the CPPC sequence in human IgGl which includes the two cysteine residues that potentially form the interheavy chain disulphide bonds and corresponding residues in other human isotypes or other species) and CH3- CH3 interface of the human and rhesus antibody isotypes.
  • core hinge i.e. the CPPC sequence in human IgGl which includes the two cysteine residues that potentially form the interheavy chain disulphide bonds and corresponding residues in other human isotypes or other species
  • FIG. 3 Generation of bispecific antibodies using mutant human IgGl engaged for Fab-arm exchange.
  • the generation of bispecific antibodies after GSH-induced in vitro Fab-arm exchange between human CD20 (7D8) IgG4 antibody and the indicated human EGFR (2F8) IgG l antibodies was determined by an ELISA.
  • the presented graph shows average numbers of three independent Fab-arm exchange experiments, in which a total antibody concentration of 1 ⁇ g/mL was used for ELISA.
  • Bispecific binding was higher after Fab-arm exchange between IgGl-2F8- CPSC-ITL and IgG4-7D8 than between two IgG4 antibodies. Combining IgG4-7D8 with either IgG l-2F8-CPSC or IgGl-2F8-ITL did not result in bispecific antibodies under the conditions used .
  • FIG. 4 Generation of bispecific antibodies by in vivo Fab-arm exchange of human IgG4 and mutant IgGl antibodies.
  • the generation of bispecific antibodies after in vivo Fab-arm exchange in immunodeficient mice between human CD20 (7D8) IgG4 and the indicated human EGFR (2F8) IgGl and IgG4 mutant antibodies was determined by an ELISA.
  • Bispecific reactivity is presented as the concentration bispecific antibodies relative to the total IgG concentration (percentage) .
  • Human IgG4 with a stabilized hinge (CPPC) or R409K mutation in the CH3 domain is not able to participate in Fab-arm exchange.
  • CPPC stabilized hinge
  • R409K mutation in the CH3 domain is not able to participate in Fab-arm exchange.
  • IgGl with both a CPSC sequence in the hinge and a K409R mutation in the CH3 domain is engaged for Fab-arm exchange.
  • Bispecific binding for the mixtures containing either IgGl-2F8, IgG4-2F8-CPPC or IgG4-2F8-R409K was below the detection limit and therefore arbitrarily set to zero.
  • FIG. 5 Generation of bispecific antibodies using 2-mercapto- ethylamine*HCI- (2-MEA-) induced Fab-arm exchange between human IgGl and IgG4 antibodies.
  • the generation of bispecific antibodies after 2-M EA-induced in vitro Fab-arm exchange between the indicated human EGFR (2F8) and CD20 (7D8) antibodies was determined by an ELISA.
  • a concentration series of 0-40 mM 2- MEA was tested .
  • the presented graph shows the result of the ELISA in which a total antibody concentration of 20 ⁇ / ⁇ -. was used .
  • 2-MEA efficiently induced Fab-arm exchange, also between antibodies containing a stabilized hinge (CPPC) .
  • CPPC stabilized hinge
  • Figure 6 Generation of bispecific antibodies using 2-MEA-induced Fab-arm exchange between human IgGl and IgG4 antibodies.
  • Figure 7 Stability analysis of heterodimeric bispecific antibodies obtained by 2-MEA-induced Fab-arm exchange.
  • the stability of bispecific samples generated by 2-MEA induced Fab-arm exchange by combining either IgG l-2F8-ITL x IgG4-7D8-CPPC (A), or IgG4-2F8 x IgG4-7D8 (B) was tested by measuring EGFR/CD20 bispecific binding in an ELISA after a GSH-induced Fab-arm exchange reaction in the presence of the indicated concentrations irrelevant IgG4. Bispecific binding is presented relative to the bispecific binding of the starting material (control), which was set to 100%.
  • FIG. 8 Plasma clearance rate of a heterodimeric bispecific antibody generated by 2-MEA-induced Fab-arm exchange.
  • Three groups of mice (3 mice per group) were injected with the indicated antibodies : ( 1) 100 ⁇ g bispecific antibody, generated by in vitro 2-M EA-induced Fab-arm exchange between IgGl- 2F8-ITL x IgG4-7D8-CPPC; (2) 100 ⁇ g bispecific antibody + 1,000 ⁇ g irrelevant IgG4; (3) 50 ⁇ IgGl-2F8-ITL + 50 ⁇ IgG4-7D8-CPPC.
  • A Total antibody concentrations over time, determined by ELISA. The curves of the total antibody plasma concentrations were the same for all antibodies.
  • Figure 9 Purity of bispecific antibody generated by Fab-arm exchange between human IgGl-2F8 and IgG4-7D8-CPPC.
  • A Reducing SDS-PAGE
  • a shows bands of the heavy and light chains for both the bispecific sample and the IgGl control sample.
  • Non-reducing SDS-PAGE (b) .
  • B The peak results from the H P- SEC analysis shows that >98% of the bispecific sample is homogenous, and practically no antibody aggregates were detectable.
  • C Mass spectrometry shows that Fab-arm exchange resulted in approximately 100% bispecific product.
  • FIG. 10 Comparison between triple mutant (ITL), double mutants (IT, IL, TL) and single mutant (L) human IgGl-2F8 in the generation of bispecific antibodies by Fab-arm exchange with human IgG4-7D8.
  • Combinations with the single mutant IgG l-2F8-F405L result in bispecific EGFR/CD20 binding .
  • FIG 11 Generation of bispecific antibodies using 2-MEA-induced Fab-arm exchange at different temperatures.
  • the generation of bispecific antibodies by combining the indicated human EGFR (2F8) and CD20 (7D8) antibodies in 2-M EA- induced in vitro Fab-arm exchange reactions at 0°C, 20°C and 37°C was followed in time by an ELISA. Bispecific binding was most efficient at 37°C, and slower at 20°C. At 0°C, no generation of bispecific binding was measured .
  • Figure 12 Generation of bispecific antibodies by in vitro Fab-arm exchange induced by different reducing agents.
  • FIG. 13 2-MEA-induced Fab-arm exchange between IgGl-2F8-ITL and IgGl-7D8-K409X mutants.
  • the generation of bispecific antibodies after 2-MEA- induced in vitro Fab-arm exchange between IgGl-2F8-ITL and the indicated IgGl- 7D8-K409X mutants was determined by an ELISA.
  • a concentration series (total antibody) of 0-20 ⁇ g/mL was analyzed .
  • the positive control is a purified batch of bispecific antibody, derived from IgGl-2F8-ITL x IgG4-7D8-CPPC.
  • FIG. 14 Antibody deglycosylation does not affect the generation of bispecific antibodies by 2-MEA-induced Fab-arm exchange.
  • the generation of bispecific antibodies after 2-MEA-induced in vitro Fab-arm exchange between the indicated EGFR (2F8) and CD20 (7D8) antibodies was determined by an ELISA. Exchange with the 7D8 antibodies was compared with their enzymatically deglycosylated variants. A concentration series (total antibody) of 0-20 ⁇ g/mL was analyzed in the ELISA.
  • Fab-arm exchange reactions involving deglycosylated (deglyc) antibodies showed identical bispecific bind ing curves as the glycosylated variants from which they were derived .
  • Figure 15 The ability to engage in Fab-arm exchange is correlated to the CH3-CH3 interaction strength.
  • D and E Relation between apparent K D (Table 2) and bispecific antibody generation after 24 hrs ( Figures 15A/B/C) for IgGl-based (D) or IgG4-based (E) molecules .
  • Figure 16 Sequence alignment of anti-EGFr antibody 2F8 in an IgGl, IgG4 and (partial) IgG3 backbone. Amino acid numbering according to Kabat and according to the EU-index are depicted (both described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed . Public Health Service, National Institutes of Health, Bethesda, MD. ( 1991)) .
  • FIG. 17 Generation of bispecific antibodies by in vitro Fab-arm-exchange induced by different reducing agents.
  • An ELISA was used to measure the generation of bispecific antibodies by combining human IgGl-2F8-F405L and IgG l- 7D8-K409R in a reduction reaction with concentration series of the indicated reducing agents. Measured OD values were normalized to the signal of a bispecific control sample derived from 2-MEA-induced Fab-arm-exchange between IgG l-2F8- ITL x IgG4-7D8-CPPC, which was set to 100%.
  • Figure 19 Purity of bispecific antibody generated by Fab-arm-exchange between human IgGl-2F8-F405L x IgGl-7D8-K409R. Mass spectrometry shows that Fab-arm-exchange resulted in approximately 100% bispecific product.
  • Figure 20 Plasma clearance of a bispecific antibody generated by 2-MEA- induced Fab-arm-exchange. Two groups of mice (3 mice per group) were injected with the indicated antibodies : ( 1) 100 ⁇ bispecific antibody, generated by in vitro 2- MEA-induced Fab-arm-exchange between IgGl-2F8-F405L x IgGl-7D8-K409R; (2) 100 ⁇ g bispecific antibody + 1,000 ⁇ g irrelevant IgG4.
  • FIG. 21 CDC-mediated cell kill of CD20-expressing cells by a bispecific antibody generated by 2-MEA-induced Fab-arm-exchange between IgGl- 2F8-F405L x IgGl-7D8-K409R.
  • Concentration series of the indicated antibodies were used to test their capacity to mediate CDC on Daudi (A) and Raji (B) cells. Both cell lines express CD20 but not EGFR. Introduction of the K409R in IgGl-7D8 did not influence its capacity to induce CDC.
  • the bispecific antibody derived from 2- MEA-induced Fab-arm-exchange between IgGl-2F8-F405L x IgGl-7D8-K409R was still capable to induce CDC.
  • FIG. 22 ADCC-mediated cell kill of EGFR-expressing cells by a bispecific antibody generated by 2-MEA-induced Fab-arm-exchange between IgGl- 2F8-F405L x IgGl-7D8-K409R. Concentration series of the indicated antibodies were used to test their capacity to mediate ADCC on A431 cells. IgGl-7D8 can not bind the CD20-negative A431 cells and consequently did not induce ADCC. ADCC was induced by the EGFR antibody IgG l-2F8, also after introduction of the F405L mutations in the CH3 domain.
  • the ADCC effector function of IgGl-2F8-F405L was retained in the bispecific format obtained by Fab-arm-exchange between IgG l-2F8- F405L x IgGl-7D8-K409R.
  • FIG. 23 2-MEA-induced Fab-arm-exchange between IgGl-2F8-F405X mutants and IgGl-7D8-K409R.
  • the generation of bispecific antibodies after 2- MEA-induced in vitro Fab-arm-exchange between the indicated IgG l-2F8-F405X mutants and IgGl-7D8-K409R was determined by an ELISA.
  • a concentration series (total antibody) of 0-20 ⁇ g/mL was analyzed in the ELISA.
  • the positive control is a purified batch of bispecific antibody, derived from IgGl-2F8-F405L x IgGl-7D8- K409R.
  • FIG. 24 2-MEA-induced Fab-arm-exchange between IgGl-2F8-Y407X mutants and IgGl-7D8-K409R.
  • the generation of bispecific antibodies after 2- MEA-induced in vitro Fab-arm-exchange between the indicated IgGl-2F8-Y407X mutants and IgGl-7D8-K409R was determined by an ELISA.
  • a concentration series (total antibody) of 0-20 ⁇ g/mL was analyzed in the ELISA.
  • the positive control is a purified batch of bispecific antibody, derived from IgGl-2F8-F405L x IgGl-7D8- K409R.
  • Figure 25 Analysis of bispecific antibody generated by 2-MEA-induced Fab-arm exchange by SDS-PAGE under non-reducing ( Figure 25(A)) and reducing ( Figure 25(B)) conditions.
  • Figure 26 HP-SEC profiles of the homodimer starting material IgGl-2F8-F405L ( Figure 26(B)), the homodimer starting material IgGl-7D8-K409R ( Figure 26(A)), the mixture ( 1 : 1) of both homodimers ( Figure 26(C)), and the bispecific product generated by 2-M EA-induced Fab-arm exchange between IgG l-2F8-F405L x IgG l- 7D8-K409R ( Figure 26(D)) .
  • Figure 27 Mass spectrometry (ESI-MS) of the homodimer starting material IgGl- 2F8-F405L ( Figure 27(B)), the homodimer starting material IgGl-7D8-K409R ( Figure 27(A)), the mixture ( 1 : 1) of both homodimers ( Figure 27(C)), and the bispecific product generated by 2-M EA-induced Fab-arm exchange between IgGl-2F8-F405L x IgGl-7D8-K409R ( Figure 27(D)) .
  • ESI-MS Mass spectrometry
  • Figure 28 Capillary isoelectrofocussing (cIEF) profiles of the homodimer starting material IgG l-2F8-F405L ( Figure 28(A)), the homodimer starting material IgGl-7D8- K409R ( Figure 28(B)), the mixture ( 1 : 1) of both homodimers ( Figure 28(C)), and the bispecific product generated by 2-MEA-induced Fab-arm exchange between IgG l- 2F8-F405L x IgGl-7D8-K409R ( Figure 28(D)) .
  • cIEF Capillary isoelectrofocussing
  • Figure 29 HPLC-CIEX profiles of the homodimer starting material IgGl-2F8-F405L (Figure 29(A)), the homodimer starting material IgGl-7D8-K409R ( Figure 29(B)), the mixture ( 1 : 1) of both homodimers ( Figure 29(C)), and the bispecific product generated by 2-M EA-induced Fab-arm exchange between IgG l-2F8-F405L x IgGl- 7D8-K409R ( Figure 29(D)) .
  • FIG. 30 Electrospray ionization mass spec analysis of IgG obtained by co- transfection of the expression vectors encoding the heavy and light chain of IgGl- 7D8-K409R or IgGl-2F8-F405. Heterodimer peaks are indicated with an * .
  • FIG. 31 Exchange reaction of the homodimers IgGl-2F8-F405L and IgG l-7D8- K409R as monitored by High Pressure Liquid Chromatography Cation Exchange (H PLC-CIEX) after injection at different intervals.
  • H PLC-CIEX High Pressure Liquid Chromatography Cation Exchange
  • Figure 32 Residual homodimers of the exchange reaction as shown in Figure 32 as detected with the CIEX method (indicated by arrows) .
  • Figure 33 Generation of bispecific antibodies at various IgG concentrations, 2-MEA concentrations, incubation temperatures and times as determined by an ELISA.
  • Figure 34 Generation of bispecific antibodies at various IgG concentrations, 2-MEA concentrations, incubation temperatures and times as determined by an ELISA and compared to control which was arbitrarily set to 100%.
  • FIG. 35 Generation of bispecific antibodies at various IgG concentrations, 2-MEA concentrations, incubation temperatures and times as analysed by HPLC-CIEX.
  • Figure 36 Generation of bispecific antibodies after 2-M EA-induced in vitro Fab-arm exchange between the indicated IgGl-2F8-L368X mutants and IgG l-7D8-K409R was determined by an ELISA using a concentration series (total antibody) of 0-20 ⁇ g/mL ( Figure 37(A)) .
  • the positive control is a purified batch of bispecific antibody, derived from IgGl-2F8-F405L x IgGl-7D8-K409R.
  • Figure 37(B) shows the bispecific binding at 20 ⁇ g/mL relative to the positive control (black bar) .
  • Figure 37 Generation of bispecific antibodies after 2-MEA-induced in vitro Fab-arm exchange between the indicated IgGl-2F8-K370X mutants and IgGl-7D8-K409R was determined by an ELISA using a concentration series (total antibody) of 0-20 ⁇ g/mL ( Figure 37(A)) .
  • the positive control is a purified batch of bispecific antibody, derived from IgGl-2F8-F405L x IgGl-7D8-K409R.
  • Figure 37(B) shows the bispecific binding at 20 ⁇ g/mL relative to the positive control (black bar) .
  • Dark grey bars represents the bispecific binding between the IgG4 control (IgG4-7D8 x IgG4-2F8) and the negative control (IgGl-2F8 x IgGl-7D8-K409R) .
  • Light grey bars represent results from simultaneously performed Fab-arm-exchange reactions between the indicated IgGl-2F8-D370X mutants and IgGl-7D8-K409R.
  • Figure 38 Generation of bispecific antibodies after 2-M EA-induced in vitro Fab-arm exchange between the indicated IgGl-2F8-D399X mutants and IgGl-7D8-K409R was determined by an ELISA using a concentration series (total antibody) of 0-20 ⁇ g/mL (Figure 38(A)) .
  • Figure 38(B) shows the bispecific binding at 20 ⁇ g/mL antibody concentration relative to the positive control (black bar) .
  • Dark grey bars represents the bispecific binding between the IgG4 control (IgG4-7D8 x IgG4-2F8) and the negative control (IgG l-2F8 x IgGl-7D8-K409R) .
  • Light grey bars represent results from simultaneously performed Fab-arm-exchange reactions between the indicated IgGl-2F8-D399X mutants and IgGl-7D8-K409R.
  • Figure 39 2-M EA-induced Fab-arm exchange between four different IgGl mutant combinations at 15°C after 0, 30, 60, 105 and 200 min incubations as determined by sandwich ELISA.
  • Figure 40 2-MEA-induced Fab-arm exchange between different IgGl mutant combinations after antibody incubation at 15°C for 90 min as determined by sandwich ELISA.
  • Figure 41 Phosphorylation of c-Met by c-Met specific antibodies.
  • A549 cells are incubated for 15 min with HGF or a panel of different antibodies. Proteins are separated by SDS-page gel electrophoresis and and transferred to membranes by western blotting .
  • Phosphorylated c-Met, total c-Met and ⁇ -actin are detected by antibodies against phosphorylated c-Met, total c-Met or ⁇ -actin .
  • Figure 42 Proliferation assay with NCI-H441 cells. NCI-H441 cells were incubated for seven days with monovalent bispecific IgG l 069/bl2, control antibodies (IgGl-
  • FIG 43 CDC-mediated cell kill of CD20 expressing cells by bispecific antibodies generated by 2-MEA-induced Fab-arm-exchange between IgGl-7D8-F405L or IgG l- 2F8-F405L and IgG l-7D8-K409R. Concentration series of the indicated antibodies were used to test their capacity to mediate CDC on Daudi (A) and Raji (B) cells. Both cell lines express CD20 but not EGFR.
  • the bispecific antibody generated by 2-M EA- induced Fab-arm-exchange between IgG l-7D8-F405L x IgGl-7D8-K409R was as effective as IgGl-7D8 in induction of CDC mediated cell kill.
  • the bispecific antibody derived from 2-MEA-induced Fab-arm-exchange between IgG2-2F8-F405L x IgG l- 7D8-K409R results in a monovalent CD20 binding bispecific antibody, which slightly affected the induction of CDC mediated cell kill with slightly.
  • Figure 44 Killing of A431 cells induced by anti-kappa-ETA' pre-incubated HER2 x HER2 bispecific antibodies.
  • Figure 45 HER2 x HER2 bispecific molecules induced downmodulation of HER2 receptor. Relative percentage of HER2 expression levels in AU565 cell lysates after 3 days incubation with 10 ⁇ g/mL mAb. The amount of HER2 was quantified using a HER2-specific capture ELISA and depicted as percentage inhibition compared to untreated cells. Data shown is the mean of two experiments plus standard deviation.
  • Figure 46 Colocalization analysis of HER2 x HER2 bispecific antibodies (FITC) with lysosomal marker LAMP1 (Cy5).
  • FITC pixel intensity overlapping with Cy5 for various monospecific HER2 antibodies and HER2 x HER2 bispecific antibodies ( Figure 46(B)) FITC pixel intensity in LAMP1/Cy5 positive pixels of three different images is plotted for each antibody tested. Monospecifics show lower FITC pixel intensities in the LAMP1/Cy5 positive pixels compared to bispecifics. Figure 46(B) represents the mean value of FITC pixel intensity per LAMP1/Cy5 positive pixel calculated from the three different images. Together these results indicate that after internalization higher levels of bispecific antibodies, compared to monospecifics antibodies, localize to Lampl/Cy5 positive vesicles.
  • Figure 47 Inhibition of proliferation by HER-2 mono and bispecific antibodies.
  • AU565 cells were seeded in the presence of 10 ⁇ g/mL HER2 antibody or HER2 x HER2 bispecific antibody in serum-free cell culture medium. After three days, the amount of viable cells was quantified with Alamarblue and cell viability was presented as a percentage relative to untreated cells. An isotype control antibody was used as negative control. Data shown are percentage viable AU565 cells compared to untreated cells measured in five-fold ⁇ the standard deviation. * indicates only one data point was depicted.
  • Figure 48 Binding of mono and bispecific IgGl and hinge-deleted IgGl antibodies to human and mouse FcRn at different pH. Plates with human and mouse FcRn were incubated with different mono- and bispecific IgGl antibodies or hinge-deleted IgGl molecules. Binding to FcRn was analyzed by ELISA at 405 nm.
  • the bispecific molecule harboring the H435A mutation in only one Fab-arm is still able to bind mouse FcRn.
  • Hinge-deleted IgGl (Uni-Gl) molecules bind mouse FcRn with intermediate efficiency and the hinge-deleted IgGl (Uni-Gl) bispecific molecule harboring the H435A mutation in only one Fab-arm is slightly less efficient.
  • Figure 49 T cell mediated cytotoxicity of AU565 cells by Her2 x CD3 bispecific antibodies as well as by N297Q mutants of Her2 x CD3 bispecific antibodies.
  • immunoglobulin refers to a class of structurally related glycoproteins consisting of two pairs of polypeptide chains, one pair of light (L) low molecular weight chains and one pair of heavy (H) chains, all four inter-connected by disulfide bonds.
  • L light
  • H heavy
  • each heavy chain typically is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region.
  • VH heavy chain variable region
  • the heavy chain constant region typically is comprised of three domains, CH I, CH2, and CH3.
  • Each light chain typically is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region.
  • the light chain constant region typically is comprised of one domain, CL.
  • the numbering of amino acid residues in the constant region is performed according to the EU-index as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991).
  • Figure 16 gives an overview of the EU and Kabat numbering for different isotype forms of antibody 2F8 (WO 02/100348).
  • the VH and VL regions may be further subdivided into regions of hypervariability (or hypervariable regions which may be hypervariable in sequence and/or form of structurally defined loops), also termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs).
  • CDRs complementarity determining regions
  • FRs framework regions
  • Each VH and VL is typically composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FRl, CDRl, FR2, CDR2, FR3, CDR3, FR4 (see also Chothia and Lesk J. Mol. Biol. 196, 901 917 (1987)).
  • Fab-arm refers to one heavy chain-light chain pair.
  • Fc region refers to an antibody region comprising at least the hinge region, a CH2 domain and a CH3 domain.
  • antibody in the context of the present invention refers to an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or a derivative of either thereof, which has the ability to specifically bind to an antigen under typical physiological conditions with a half life of significant periods of time, such as at least about 30 min, at least about 45 min, at least about one hour, at least about two hours, at least about four hours, at least about 8 hours, at least about 12 hours (h), about 24 hours or more, about 48 hours or more, about 3, 4, 5, 6, 7 or more days, etc., or any other relevant functionally-defined period (such as a time sufficient to induce, promote, enhance, and/or modulate a physiological response associated with antibody binding to the antigen and/or time sufficient for the antibody to recruit an effector activity).
  • variable regions of the heavy and light chains of the immunoglobulin molecule contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (such as effector cells) and components of the complement system such as Clq, the first component in the classical pathway of complement activation.
  • An antibody may also be a bispecific antibody, diabody, or similar molecule.
  • bispecific antibody refers to antibody having specificities for at least two different epitopes, typically non-overlapping epitopes.
  • the term antibody herein unless otherwise stated or clearly contradicted by the context, includes fragments of an antibody that retain the ability to specifically bind to the antigen.
  • Such fragments may be provided by any known technique, such as enzymatic cleavage, peptide synthesis and recombinant expression techniques. It has been shown that the antigen-binding function of an antibody may be performed by fragments of a full-length antibody, e.g. a F(ab')2 fragment. It also should be understood that the term antibody, unless specified otherwise, also includes polyclonal antibodies, monoclonal antibodies (mAbs), antibody-like polypeptides, such as chimeric antibodies and humanized antibodies. An antibody as generated can possess any isotype.
  • full-length antibody when used herein, refers to an antibody which contains all heavy and light chain constant and variable domains that are normally found in an antibody of that isotype.
  • isotype refers to the immunoglobulin class (for instance IgGl, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM) that is encoded by heavy chain constant region genes.
  • human antibody is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences.
  • the human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
  • human antibody is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • heavy chain antibody or “heavy-chain antibody” refers to an antibody which consists only of two heavy chains and lacks the two light chains usually found in antibodies. Heavy chain antibodies, which naturally occur in e.g. camelids, can bind antigens despite having only VH domains.
  • epitope means a protein determinant capable of specific binding to an antibody.
  • Epitopes usually consist of surface groupings of molecules such as amino acids or sugar side chains and usually have specific three dimensional structural characteristics, as well as specific charge characteristics. Conformational and nonconformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.
  • the epitope may comprise amino acid residues directly involved in the binding (also called immunodominant component of the epitope) and other amino acid residues, which are not directly involved in the binding, such as amino acid residues which are effectively blocked by the specifically antigen binding peptide (in other words, the amino acid residue is within the footprint of the specifically antigen binding peptide).
  • binding in the context of the binding of an antibody to a predetermined antigen typically is a binding with an affinity corresponding to a K D of about 10 "6 M or less, e.g. 10 "7 M or less, such as about 10 "8 M or less, such as about 10 "9 M or less, about 10 10 M or less, or about 10 11 M or even less when determined by for instance surface plasmon resonance (SPR) technology in a BIAcore 3000 instrument using the antigen as the ligand and the antibody as the analyte, and binds to the predetermined antigen with an affinity corresponding to a K D that is at least ten-fold lower, such as at least 100 fold lower, for instance at least 1,000 fold lower, such as at least 10,000 fold lower, for instance at least 100,000 fold lower than its affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely-related antigen.
  • a non-specific antigen e.g., BSA, case
  • the amount with which the affinity is lower is dependent on the K D of the antibody, so that when the K D of the antibody is very low (that is, the antibody is highly specific), then the amount with which the affinity for the antigen is lower than the affinity for a non-specific antigen may be at least 10,000 fold.
  • K D (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody-antigen interaction.
  • heterodimeric interaction between the first and second CH3 regions refers to the interaction between the first CH3 region and the second CH3 region in a first-CH3/second-CH3 heterodimeric protein.
  • homodimeric interactions of the first and second CH3 regions refers to the interaction between a first CH3 region and another first CH3 region in a first-CH3/first-CH3 homodimeric protein and the interaction between a second CH3 region and another second CH3 region in a second-CH3/second-CH3 homodimeric protein.
  • an “isolated antibody,” as used herein, denotes that the material has been removed from its original environment (e.g., the natural environment if it is naturally occurring or the host cell if it is recombinantly expressed). It is also advantageous that the antibodies be in purified form.
  • purified does not require absolute purity; rather, it is intended as a relative definition, indicating an increase of the antibody concentration relative to the concentration of contaminants in a composition as compared to the starting material.
  • host cell is intended to refer to a cell into which an expression vector has been introduced, e.g. an expression vector encoding an antibody of the invention.
  • Recombinant host cells include, for example, transfectomas, such as CHO cells, HEK293 cells, NS/0 cells, and lymphocytic cells.
  • co-expression of two or more nucleic acid constructs refers to expression of the two constructs in a single host cell.
  • tumor cell protein refers to a protein located on the cell surface of a tumor cell.
  • effector cell refers to an immune cell which is involved in the effector phase of an immune response, as opposed to the cognitive and activation phases of an immune response.
  • exemplary immune cells include a cell of a myeloid or lymphoid origin, for instance lymphocytes (such as B cells and T cells including cytolytic T cells (CTLs)), killer cells, natural killer cells, macrophages, monocytes, eosinophils, polymorphonuclear cells, such as neutrophils, granulocytes, mast cells, and basophils.
  • lymphocytes such as B cells and T cells including cytolytic T cells (CTLs)
  • killer cells such as B cells and T cells including cytolytic T cells (CTLs)
  • killer cells such as B cells and T cells including cytolytic T cells (CTLs)
  • killer cells such as B cells and T cells including cytolytic T cells (CTLs)
  • killer cells such as B cells and T cells including cytolytic T cells (CTLs)
  • killer cells such as B
  • an effector cell is capable of inducing antibody-dependent cellular cytotoxicity (ADCC), such as a natural killer cell, capable of inducing ADCC.
  • ADCC antibody-dependent cellular cytotoxicity
  • an effector cell may phagocytose a target antigen or target cell.
  • reducing conditions or “reducing environment” refers to a condition or an environment in which a substrate, here a cysteine residue in the hinge region of an antibody, is more likely to become reduced than oxidized.
  • disulfide bond isomerization refers to an exchange of disulfide bonds between different cysteines, i.e., the shuffling of disulfide bonds.
  • the invention relates to an in vitro method for generating a heterodimeric protein, said method comprising the following steps:
  • the bispecific format may be used in many ways to generate desired combinations of bispecific antibodies. In addition to being able of combining antibodies targeting different antigens in a very selective way it can be used to change a desired property, e.g. to increase CDC, by combining two different antibodies targeting the same antigen. Furthermore, it can be used to remove partial agonistic activity of an antagonistic antibody or convert an agonistic antibody into an antagonistic antbody by making a bispecific antibody thereof with an irrelevant (inactive) antibody.
  • the homodimeric proteins are selected from the group consisting of (i) an Fc region, (ii) an antibody, (iii) a fusion protein comprising an Fc region, such as anFc region fused to a receptor, cytokine or hormone, and (iv) a Fc region conjugated to a prodrug, peptide, drug or a toxin.
  • said first and/or second homodimeric protein comprise, in addition to the Fc region, one or more or all of the other regions of an antibody, i.e. a CH I region, a VH region, a CL region and/or a VL region.
  • said first homodimeric protein is a full-length antibody.
  • said second homodimeric protein is a full-length antibody.
  • said first and second homodimeric proteins are both antibodies, preferably full-length antibodies, and bind different epitopes.
  • the heterodimeric protein that is generated is a bispecific antibody. Said epitopes may be located on different antigens or on the same antigen.
  • both of the homodimeric proteins is a full-length antibody and the other homodimeric protein is not a full-length antibody, e.g. an Fc region without a variable region, expressed in conjunction to another protein or peptide sequence like a receptor, cytokine or hormone, or conjugated to a prodrug, peptide, a drug or a toxin.
  • neither of the homodimeric proteins is a full-length antibody.
  • both homodimeric proteins may be Fc regions that are fused to another protein or peptide sequence like a receptor, cytokine or hormone, or conjugated to a prodrug, peptide, a drug or a toxin.
  • the Fc region of the first homodimeric protein is of an isotype selected from the group consisting of IgGl, IgG2, IgG3 and IgG4 and the Fc region of the second homodimeric protein is of an isotype selected from the group consisting of IgGl, IgG2, IgG3 and IgG4.
  • the Fc regions of both said first and said second homodimeric protein are of the IgGl isotype.
  • one of the Fc regions of said homodimeric proteins is of the IgGl isotype and the other of the IgG4 isotype.
  • the resulting heterodimeric comprises an Fc region of an IgGl and an Fc region of IgG4 and may thus have interesting intermediate properties with respect to activation of effector functions.
  • a similar product can be obtained if said first and/or said second homodimeric protein comprises a mutation removing the acceptor site for Asn-linked glycosylation or is otherwise manipulated to change the glycosylation properties.
  • one or both of the homodimeric proteins is glyco- engineered to reduce fucose and thus enhance ADCC, e.g. by addition of compounds to the culture media during antibody production as described in US2009317869 or as described in van Berkel et al. (2010) Biotechnol. Bioeng. 105 : 350 or by using FUT8 knockout cells, e.g. as described in Yamane-Ohnuki et al (2004) Biotechnol. Bioeng 87 :614.
  • ADCC may alternatively be optimized using the method described by Umaha et al. (1999) Nature Biotech 17: 176.
  • one or both of the homodimeric proteins has been engineered to enhance complement activation, e.g. as described in Natsume et al. (2009) Cancer Sci. 100 : 2411.
  • one or both of the homodimeric proteins has been engineered to reduce or increase the binding to the neonatal Fc receptor (FcRn) in order to manipulate the serum half-life of the heterodimeric protein.
  • FcRn neonatal Fc receptor
  • one of the homodimeric starting proteins has been engineered to not bind Protein A, thus allowing to separate the heterodimeric protein from said homodimeric starting protein by passing the product over a protein A column.
  • This may in particular be useful for embodiments wherein an excess of one homodimeric protein is used relative to the other homodimeric protein as starting material. In such embodiments, it may be useful to engineer the homodimeric protein that is in excess so that is looses its ability to bind protein A. Following the heterodimerization reaction, the heterodimeric protein may then be separated from a surplus of unexchanged homodimeric protein by passage over a protein A column.
  • one of the homodimeric proteins is an Fc region or a full-length antibody recognizing a non-relevant epitope or a full-length antibody containing germline-derived sequences that have not undergone somatic hypermutation and do not bind self-antigens.
  • the heterodimeric protein functions as a monovalent antibody.
  • both homodimeric proteins comprises the same heavy chain, but only one of the homodimeric proteins contains a light chain which forms a functional antigen-binding site with said heavy chain, whereas the other homodimeric protein contains a nonfunctional light chain, which does not bind any antigen in combination with said heavy chain.
  • the heterodimeric protein functions as a monovalent antibody.
  • a non-functional light chain can e.g. be a germline- derived sequence that has not undergone somatic hypermutation and does not bind self-antigens.
  • Antibodies to be used as homodimeric starting material of the present invention may e.g. be produced by the hybridoma method first described by Kohler et al., Nature 256, 495 (1975), or may be produced by recombinant DNA methods. Monoclonal antibodies may also be isolated from phage antibody libraries using the techniques described in, for example, Clackson et al., Nature 352, 624 628 (1991) and Marks et al., J. Mol. Biol. 222, 581 597 (1991). Monoclonal antibodies may be obtained from any suitable source.
  • monoclonal antibodies may be obtained from hybridomas prepared from murine splenic B cells obtained from mice immunized with an antigen of interest, for instance in form of cells expressing the antigen on the surface, or a nucleic acid encoding an antigen of interest.
  • Monoclonal antibodies may also be obtained from hybridomas derived from antibody-expressing cells of immunized humans or non-human mammals such as rats, dogs, primates, etc.
  • Antibodies to be used as homodimeric starting material of the present invention may e.g. chimeric or humanized antibodies.
  • one or both of the homodimeric starting proteins, except for any specified mutations is a human antibody.
  • Human monoclonal antibodies may be generated using transgenic or transchromosomal mice, e.g. HuMAb mice, carrying parts of the human immune system rather than the mouse system.
  • the HuMAb mouse contains a human immunoglobulin gene miniloci that encodes unrearranged human heavy ( ⁇ and ⁇ ) and K light chain immunoglobulin sequences, together with targeted mutations that inactivate the endogenous ⁇ and ⁇ chain loci (Lonberg, N. et al., Nature 368, 856 859 (1994)).
  • mice exhibit reduced expression of mouse IgM or ⁇ and in response to immunization, the introduced human heavy and light chain transgenes, undergo class switching and somatic mutation to generate high affinity human IgG, K monoclonal antibodies (Lonberg, N. et al. (1994), supra; reviewed in Lonberg, N. Handbook of Experimental Pharmacology 113, 49 101 (1994) , Lonberg, N. and Huszar, D., Intern. Rev. Immunol. Vol. 13 65 93 (1995) and Harding, F. and Lonberg, N. Ann. N.Y. Acad. Sci 764 536 546 (1995)).
  • the preparation of HuMAb mice is described in detail in Taylor, L.
  • human antibodies of the present invention or antibodies of the present invention from other species may be identified through display-type technologies, including, without limitation, phage display, retroviral display, ribosomal display, mammalian display, and other techniques, using techniques well known in the art and the resulting molecules may be subjected to additional maturation, such as affinity maturation, as such techniques are well known in the art.
  • the antibody or a part thereof e.g. one or more CDRs
  • the antibody or a part thereof is of a species in the family Camelidae, see WO2010001251, or a species of cartilaginous fish, such as the nurse shark or heavy-chain or domain antibodies.
  • said first and second homodimeric proteins provided in step a) and b) are purified.
  • the first and/or second homodimeric protein is conjugated to a drug, a prodrug or a toxin or contains an acceptor group for the same.
  • acceptor group may e.g. be an unnatural amino acid.
  • sequences of the first and second CH3 regions of the homodimeric starting proteins are different and are such that the heterodimeric interaction between said first and second CH3 regions is stronger than each of the homodimeric interactions of said first and second CH3 regions.
  • the increased strength of the heterodimeric interaction as compared to each of the homodimeric interactions is due to CH3 modifications other than the introduction of covalent bonds, cysteine residues or charged residues.
  • the product of the invention is highly stable and does not undergo Fab-arm exchange under mildly reducing conditions in vitro or, importantly, in vivo upon administration to a human being.
  • the heterodimeric interaction between said first and second proteins in the resulting heterodimeric protein is such that no Fab-arm exchange can occur at 0.5 mM GSH under the conditions described in Example 13.
  • heterodimeric interaction between said first and second proteins in the resulting heterodimeric protein is such that no Fab-arm exchange occurs in vivo in mice under the conditions described in Example 14.
  • the heterodimeric interaction between said first and second proteins in the resulting heterodimeric protein is more than two times stronger, such as more than three times stronger, e.g. more than five times stronger than the strongest of the two homodimeric interactions, e.g. when determined as described in Example 30.
  • sequences of said first and second CH3 regions are such that the dissociation constants of the heterodimeric interaction between said first and second proteins in the resulting heterodimeric protein is below 0.05 micromolar when assayed as described in Example 30.
  • the sequences of said first and second CH3 regions are such that the dissociation constants of both homodimeric interactions are above 0.01 micromolar, such as above 0.05 micromolar preferably between 0.01 and 10 micromolar, such as between 0.05 and 10 micromolar, more preferably between 0.01 and 5, such as between 0.05 and 5 micromolar, even more preferably between 0.01 and 1 micromolar, such as between 0.05 and 1 micromolar, between 0.01 and 0.5 or between 0.01 and 0.1 when assayed as described in Example 21.
  • Embodiments wherein the homodimeric starting proteins are relatively stable can have the advantage that it is easier to produce a large quantity of starting protein and e.g. avoid aggregation or misfolding.
  • a stable heterodimeric protein can be obtained at high yield using the method of the invention on the basis of two homodimeric starting proteins containing only a few, fairly conservative, asymmetrical mutations in the CH3 regions.
  • sequences of said first and second CH3 regions contain amino acid substitutions at non-identical positions.
  • the amino acid substituents may be natural amino acids or unnatural amino acids.
  • unnatural amino acids are e.g. disclosed in Xie J and Schultz P. G., Current Opinion in Chemical Biology (2005), 9: 548-554, and Wang Q. et al., Chemistry & Biology (2009), 16: 323-336.
  • the amino acids are natural amino acids.
  • said first homodimeric protein has no more than one amino acid substitution in the CH3 region
  • the second homodimeric protein has no more than one amino acid substitution in the CH3 region relative to the wild-type CH3 regions.
  • the first homodimeric protein has an amino acid substitution at a position selected from the group consisting of: 366, 368, 370, 399, 405, 407 and 409
  • said second homodimeric protein has an amino acid substitution at a position selected from the group consisting of: 366, 368, 370, 399, 405, 407 and 409, and wherein said first homodimeric protein and said second homodimeric protein is not substituted in the same positions.
  • the first homodimeric protein has an amino acid substitution at position 366
  • said second homodimeric protein has an amino acid substitution at a position selected from the group consisting of: 368, 370, 399, 405, 407 and 409.
  • the amino acid at position 366 is selected from Arg, Lys, Asn, Gin, Tyr, Glu and Gly.
  • the first homodimeric protein has an amino acid substitution at position 368
  • said second homodimeric protein has an amino acid substitution at a position selected from the group consisting of: 366, 370, 399, 405, 407 and 409.
  • the first homodimeric protein has an amino acid substitution at position 370
  • said second homodimeric protein has an amino acid substitution at a position selected from the group consisting of: 366, 368, 399, 405, 407 and 409.
  • the first homodimeric protein has an amino acid substitution at position 399
  • said second homodimeric protein has an amino acid substitution at a position selected from the group consisting of: 366, 368, 370, 405, 407 and 409.
  • the first homodimeric protein has an amino acid substitution at position 405, and said second homodimeric protein has an amino acid substitution at a position selected from the group consisting of: 366, 368, 370, 399, 407 and 409.
  • the first homodimeric protein has an amino acid substitution at position 407
  • said second homodimeric protein has an amino acid substitution at a position selected from the group consisting of: 366, 368, 370, 399, 405, and 409.
  • the first homodimeric protein has an amino acid substitution at position 409
  • said second homodimeric protein has an amino acid substitution at a position selected from the group consisting of: 366, 368, 370, 399, 405, and 407.
  • the sequences of said first and second CH3 regions contain asymmetrical mutations, i.e. mutations at different positions in the two CH3 regions, e.g. a mutation at position 405 in one of the CH3 regions and a mutation at position 409 in the other CH3 region.
  • the first homodimeric protein has an amino acid other than Lys, Leu or Met at position 409 and said second homodimeric protein has an amino-acid substitution at a position selected from the group consisting of: 366, 368, 370, 399, 405 and 407.
  • said first homodimeric protein has an amino acid other than Lys, Leu or Met at position 409 and said second homodimeric protein has an amino acid other than Phe at position 405.
  • said first homodimeric protein has an amino acid other than Lys, Leu or Met at position 409 and said second homodimeric protein has an amino acid other than Phe, Arg or Gly at position 405.
  • said first homodimeric protein comprises a Phe at position 405 and an amino acid other than Lys, Leu or Met at position 409 and said second homodimeric protein comprises an amino acid other than Phe at position 405 and a Lys at position 409.
  • said first homodimeric protein comprises a Phe at position 405 and an amino acid other than Lys, Leu or Met at position 409 and said second homodimeric protein comprises an amino acid other than Phe, Arg or Gly at position 405 and a Lys at position 409.
  • said first homodimeric protein comprises a Phe at position 405 and an amino acid other than Lys, Leu or Met at position 409 and said second homodimeric protein comprises a Leu at position 405 and a Lys at position 409.
  • said first homodimeric protein comprises a Phe at position 405 and an Arg at position 409 and said second homodimeric protein comprises an amino acid other than Phe, Arg or Gly at position 405 and a Lys at position 409.
  • said first homodimeric protein comprises Phe at position 405 and an Arg at position 409 and said second homodimeric protein comprises a Leu at position 405 and a Lys at position 409.
  • said first homodimeric protein comprises an amino acid other than Lys, Leu or Met at position 409 and said second homodimeric protein comprises a Lys at position 409, a Thr at position 370 and a Leu at position 405.
  • said first homodimeric protein comprises an Arg at position 409 and said second homodimeric protein comprises a Lys at position 409, a Thr at position 370 and a Leu at position 405.
  • said first homodimeric protein comprises a Lys at position 370, a Phe at position 405 and an Arg at position 409 and said second homodimeric protein comprises a Lys at position 409, a Thr at position 370 and a Leu at position 405.
  • said first homodimeric protein comprises an amino acid other than Lys, Leu or Met at position 409 and said second homodimeric protein comprises a Lys at position 409 and : a) an He at position 350 and a Leu at position 405, or b) a Thr at position 370 and a Leu at position 405.
  • said first homodimeric protein comprises an Arg at position 409 and said second homodimeric protein comprises a Lys at position 409 and : a) an He at position 350 and a Leu at position 405, or b) a Thr at position 370 and a Leu at position 405.
  • said first homodimeric protein comprises a Thr at position 350, a Lys at position 370, a Phe at position 405 and an Arg at position 409
  • said second homodimeric protein comprises a Lys at position 409 and : a) an He at position 350 and a Leu at position 405, or b) a Thr at position 370 and a Leu at position 405.
  • said first homodimeric protein comprises a Thr at position 350, a Lys at position 370, a Phe at position 405 and an Arg at position 409 and said second homodimeric protein comprises an He at position 350, a Thr at position 370, a Leu at position 405 and a Lys at position 409.
  • said first homodimeric protein has an amino acid other than Lys, Leu or Met at position 409 and said second homodimeric protein has an amino acid other than Tyr, Asp, Glu, Phe, Lys, Gin, Arg, Ser or Thr at position 407.
  • said first homodimeric protein has an amino acid other than Lys, Leu or Met at position 409 and said second homodimeric protein has an Ala, Gly, His, He, Leu, Met, Asn, Val or Trp at position 407.
  • said first homodimeric protein has an amino acid other than Lys, Leu or Met at position 409 and said second homodimeric protein has a Gly, Leu, Met, Asn or Trp at position 407.
  • said first homodimeric protein has a Tyr at position
  • said second homodimeric protein has an amino acid other than Tyr, Asp, Glu, Phe, Lys, Gin, Arg, Ser or Thr at position 407 and a Lys at position 409.
  • said first homodimeric protein has a Tyr at position 407 and an amino acid other than Lys, Leu or Met at position 409 and said second homodimeric protein has an Ala, Gly, His, He, Leu, Met, Asn, Val or Trp at position 407 and a Lys at position 409.
  • said first homodimeric protein has a Tyr at position 407 and an amino acid other than Lys, Leu or Met at position 409 and said second homodimeric protein has a Gly, Leu, Met, Asn or Trp at position 407 and a Lys at position 409.
  • said first homodimeric protein has a Tyr at position 407 and an Arg at position 409 and said second homodimeric protein has an amino acid other than Tyr, Asp, Glu, Phe, Lys, Gin, Arg, Ser or Thr at position 407 and a Lys at position 409.
  • said first homodimeric protein has a Tyr at position 407 and an Arg at position 409 and said second homodimeric protein has an Ala, Gly, His, He, Leu, Met, Asn, Val or Trp at position 407 and a Lys at position 409.
  • said first homodimeric protein has a Tyr at position 407 and an Arg at position 409 and said second homodimeric protein has a Gly, Leu, Met, Asn or Trp at position 407 and a Lys at position 409.
  • the first homodimeric protein has an amino acid other than Lys, Leu or Met at position 409, and the second homodimeric protein has
  • the first homodimeric protein has an Arg, Ala, His or Gly at position 409, and the second homodimeric protein has
  • the first homodimeric protein has an Arg at position 409, and the second homodimeric protein has
  • said first and second homodimeric protein may contain further amino-acid substitutions, deletion or insertions relative to wild-type Fc sequences.
  • said first and second CH3 regions, except for the specified mutations comprise the sequence set forth in SEQ ID NO : l (IgGlm(a)) :
  • said first and second CH3 regions comprise the sequence set forth in SEQ ID NO : 2 (IgGlm(f)) :
  • said first and second CH3 regions comprise the sequence set forth in SEQ ID NO : 3 (IgGlm(ax)) :
  • the homodimeric proteins provided may be a rat antibody and a mouse antibody, who show preferential pairing, as described by Lindhofer et al. (1995) J Immunol 155 : 219 (see above), or so-called knob-in-hole variant antibodies, as described in US patent 5,731,168 (see above).
  • the latter homodimeric starting proteins may be more difficult to produce, because of too weak homodimeric CH3-CH3 interactions.
  • the herein described variants having mutations at positions 350, 370, 405 and 409 may be preferred.
  • the sequence of the hinge region of the homodimeric starting proteins may vary. However, the resulting heterodimeric protein may be more stable under some circumstances if the hinge region is not IgG4-like, and, preferably is IgGl-like.
  • neither said first nor said second homodimeric protein comprises a Cys-Pro-Ser-Cys sequence in the (core) hinge region.
  • both said first and said second homodimeric protein comprise a Cys-Pro-Pro-Cys sequence in the (core) hinge region.
  • first and said second homodimeric proteins are antibodies
  • said antibodies further comprise a light chain.
  • said light chains may be different, i.e. differ in sequence and each form a functional antigen-binding domain with only one of the heavy chains.
  • said first and second homodimeric proteins are heavy-chain antibodies, which do not need a light chain for antigen binding, see e.g. Hamers-Casterman (1993) Nature 363 :446.
  • step c) of the method of the invention comprises incubating said first protein together with said second protein under reducing conditions sufficient to allow the cysteines in the hinge region to undergo disulfide- bond isomerisation.
  • suitable conditions are given herein.
  • the minimal requirements for the cysteines in the hinge region for undergoing disulfide-bond isomerisation may differ depending on the homodimeric starting proteins, in particular depending on the exact sequence in the hinge region. It is important that the respective homodimeric interactions of said first and second CH3 regions are sufficiently weak to allow cysteines in the hinge region to undergo disulfide-bond isomerisation under the given conditions.
  • the reducing conditions in step c) comprise the addition of a reducing agent, e.g. a reducing agent selected from the group consisting of: 2- mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cysteine and beta-mercapto- ethanol, preferably a reducing agent selected from the group consisting of: 2- mercaptoethylamine, dithiothreitol and tris(2-carboxyethyl)phosphine.
  • a reducing agent selected from the group consisting of: 2- mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cy
  • the reducing conditions enabling controlled Fab-arm exchange are described in terms of the required redox potential.
  • the tripeptide glutathione (GSH) is the major low-molecular weight thiol in cells and controls thiol- disulphide redox state which is essential for normal redox signaling in vivo.
  • the dynamics of cellular redox balance are achieved by maintenance of the thiol-to- disulphide status of reduced GSH and its oxidized form GSSG.
  • the values for the reduction potential can be measured as in Rost and Rapoport, Nature 201 : 185 (1964) and Aslund et al., J. Biol. Chem. 272: 30780-30786 (1997).
  • E h The redox potential E h , which takes into consideration the stoichiometry of two GSH oxidized per GSSG is a quantitative measure for the redox state.
  • Eo is the standard potential for the redox couple at defined pH, R is the gas constant, T is the absolute temperature, F is Faraday's constant and n is the number of electrons transferred.
  • In vivo estimates for Eh for the GSH/GSSG couple are in the range of -260 to -200 mV (Aw, T., News Physiol. Sci. 18 : 201-204 (2003)). Terminally differentiated cells thereby maintain an Eh in the order of -200 mV, whereas actively proliferating cells maintain a more reduced Eh of approximately -260 mV.
  • TCEP has been shown to reduce DTT in solution and therefore has a more negative redox potential than DTT. The precise value however has not been reported. Reducing conditions allowing controlled Fab-arm exchange conditions can therefore be described in terms of a required redox potential Eh, which is optimally below the value that is achieved under normal plasma conditions in vivo and that is above the redox potential which reduces antibody disulphide bonds outside those located in the hinge region and involved in inter-heavy chain disulphide bond formation.
  • step c) is performed under reducing conditions with a redox potential ranging below -50 mV, such as below -150 mV, preferably between -150 and -600 mV, such as between -200 and -500 mV, more preferably between -250 and -450 mV, such as between -250 and -400 mV, even more preferably between -260 and -300 mV.
  • a redox potential ranging below -50 mV, such as below -150 mV, preferably between -150 and -600 mV, such as between -200 and -500 mV, more preferably between -250 and -450 mV, such as between -250 and -400 mV, even more preferably between -260 and -300 mV.
  • step c) comprises incubation for at least 90 min at a temperature of at least 20°C in the presence of at least 25 mM 2- mercaptoethylamine or in the presence of at least 0.5 mM dithiothreitol.
  • the incubation may be performed at a pH of from 5 to 8, such as at pH 7.0 or at pH 7.4.
  • step d) comprises restoring the conditions to become non-reducing or less reducing, for example by removal of a reducing agent, e.g. by desalting.
  • the method of the invention yields an antibody product wherein more than 80%, such as more than 90%, e.g. more than 95%, such as more than 99% of the antibody molecules are the desired bispecific antibodies.
  • the post-production is more flexible and easier to control compared to the prior art methods based on co-expression.
  • bispecific antibodies by Fab-exchange under reducing conditions makes it a highly suitable strategy for (high-throughput) screening of multiple combinations of specificities for bispecific antibody discovery.
  • the in vitro process can be performed in the laboratory which allows greater control, flexibility and yield of the heterodimeric protein than is allowed by co-expression.
  • An additional advantage of this strategy is that the screening can be done in the final therapeutic format, precluding the need for engineering upon lead selection.
  • the method of the invention may be used for "matrix" screening, i.e. for generating a large number of different combinations of binding specificities on the basis of two sets of antibodies, one set having identical first CH3 regions and the other set having identical second CH3 regions, wherein the sequences of said first and second CH3 regions are different and are such that the heterodimeric interaction between said first and second CH3 regions is stronger than each of the homodimeric interactions of said first and second CH3 regions.
  • the invention relates to a method for the selection of a heterodimeric protein having a desired property, said method comprising the steps of: a) providing a first set of homodimeric proteins comprising an Fc region wherein the homodimeric proteins have identical first CH3 regions, b) providing a second set of homodimeric proteins comprising an Fc region wherein the homodimeric proteins have identical second CH3 regions, wherein the sequences of said first and second CH3 regions are different and are such that the heterodimeric interaction between said first and second CH3 regions is stronger than each of the homodimeric interactions of said first and second CH3 regions, c) incubating combinations of the homodimeric proteins of said first set and of said second set under reducing conditions sufficient to allow the cysteines in the hinge region to undergo disulfide-bond isomerization, thus generating a set of bispecific antibodies, d) optionally restoring the conditions to non-reducing, e) assaying the resulting set of heterodimeric proteins for
  • the invention relates to a method for the selection of a bispecific antibody having a desired property, said method comprising the steps of: a) a) providing a first set of homodimeric antibodies comprising antibodies with different variable regions, wherein said antibodies of said first set comprise identical first CH3 regions, b) providing a second set of homodimeric antibodies comprising antibodies with different variable regions or identical variable regions, wherein said antibodies of said second set comprise identical second CH3 regions, wherein the sequences of said first and second CH3 regions are different and are such that the heterodimeric interaction between said first and second CH3 regions is stronger than each of the homodimeric interactions of said first and second CH3 regions, c) incubating combinations of antibodies of said first set and of said second set under reducing conditions sufficient to allow the cysteines in the hinge region to undergo disulfide-bond isomerization, thus generating a set of bispecific antibodies, d) optionally restoring the conditions to non-reducing, e) assaying the resulting set of bispecific antibodies for
  • the homodimeric antibodies of the second set have different variable regions. In one embodiment, the homodimeric antibodies of the second set have identical variable regions, but have different different amino acid or structural variations outside of the antigen binding region.
  • the two sets can be composed in many different ways as desired.
  • the two sets may target the same epitope or different epitopes on the same antigen.
  • the two sets may also target different antigens, and each set may contain antibodies binding to the same epitope or different epitopes on the antigen in question.
  • one of the sets or both sets may each contain antibodies targeting different antigens.
  • said desired property is cell killing, cell lysis, inhibition of cell proliferation, or binding to cells expressing both antigen targets.
  • the screening strategy includes two panels of antibody vectors containing a range of specificities, where one panel is cloned into a backbone that is able to engage in Fab-arm exchange under reducing conditions (such as by addition of 2- MEA) with the backbone of the second panel.
  • a backbone that is able to engage in Fab-arm exchange under reducing conditions (such as by addition of 2- MEA) with the backbone of the second panel.
  • the first panel is cloned into an IgGl-F405L backbone and the second panel is cloned into a IgGl-K409R backbone (for other possible backbone combination see also Examples 19, 28, 29, 30, 35, 36, 37, 38, and 39).
  • Each member of the two panels of antibody vectors is then expressed individually at small scale.
  • all antibody vectors are transfected transiently in HEK293 cells and expressed in 2.3 ml_ cultures in 24-well plates.
  • suitable (small-scale) production systems known in the art may be used.
  • the expressed antibodies of the two panels of antibodies are then mixed pair- wise in a matrix-like fashion at equimolar ratios.
  • all individual antibodies are purified by small-scale protein A chromatography and antibody concentration are measured by absorbance at a wavelength of 280 nm.
  • Other suitable (small-scale) purification methods or methods for determining protein concentration known in the art may alternatively be used.
  • the purification step may be left out if down-stream applications are not affected by the expression medium. Thereafter, the antibody concentrations are normalized so that a suitable volume contains equimolar amounts of both antibodies.
  • a panel of 8 antibodies in the F405L backbone is individually mixed with 8 antibodies in the K409R backbone so that 64 mixtures of 100 ⁇ contain 80 ⁇ g/mL of antibody A (F405L) and 80 g/mL of antibody B (K409R).
  • the strategy contains a bispecific antibody-specific purification step down-stream, the step to normalize antibody amounts may be left out.
  • a suitable amount of reducing agent is added and incubated for a suitable period of time at a permissive temperature. For example, to 100 ⁇ containing 80 ⁇ g/mL of antibody A (F405L) and 80 ⁇ g/mL of antibody B (K409R), 25 ⁇ of 125 mM 2-MEA is added (final concentration 25 mM 2- MEA) and incubated overnight at 25°C.
  • the reducing agent is thereupon removed from the mixtures (now containing bispecific antibodies) to promote oxidation of the disulfide bonds and to avoid interference of the reducing agent in the screening assays.
  • 2-MEA is removed by performing a buffer exchange of the 64 mixtures using Zeba Spin 96- well desalting plates (Pierce Biotechnology, #89807).
  • Other suitable methods to remove the reducing agent known in the art may be used
  • the bispecific antibodies are then characterized biochemically or functionally to identify the lead candidates. For example, the 64 bispecific antibodies are assessed for proliferation inhibition of suitable cell-lines or binding to suitable cell- lines. Identified lead candidates will then be produced at larger scale and characterized in more detail. Production by co-expression
  • heterodimeric proteins of the invention may also be obtained by co-expression of constructs encoding the first and second polypeptides in a single cell.
  • the invention relates to a method for producing a heterodimeric protein, said method comprising the following steps: a) providing a first nucleic-acid construct encoding a first polypeptide comprising a first Fc region of an immunoglobulin, said first Fc region comprising a first CH3 region, b) providing a second nucleic-acid construct encoding a second polypeptide comprising a second Fc region of an immunoglobulin, said second Fc region comprising a first CH3 region, wherein the sequences of said first and second CH3 regions are different and are such that the heterodimeric interaction between said first and second CH3 regions is stronger than each of the homodimeric interactions of said first and second CH3 regions, and wherein said first homodimeric protein has an amino acid other than Lys, Leu or Met at position 409 and said second homodimeric protein has an amino- acid substitution at a position selected from the group consisting of: 366, 368, 370, 399
  • sequences of said first and second CH3 regions are such that the dissociation constants of homodimeric interactions of each of the CH3 regions are between 0.01 and 10 micromolar, such as between 0.05 and 10 micromolar, more preferably between 0.01 and 5, such as between 0.05 and 5 micromolar, even more preferably between 0.01 and 1 micromolar, such as between 0.05 and 1 micromolar, between 0.01 and 0.5 or between 0.01 and 0.1 when assayed as described in Example 21.
  • Suitable expression vectors including promoters, enhancers, etc., and suitable host cells for the production of antibodies are well-known in the art.
  • suitable host cells include yeast, bacterial and mammalian cells, such as CHO or HEK cells.
  • said first CH3 region has an amino acid other than Lys, Leu or Met at position 409 and said second CH3 region has an amino acid other than Phe at position 405.
  • the sequences of said first and second CH3 regions are such that the dissociation constants of homodimeric interactions of each of the CH3 regions are between 0.01 and 10 micromolar, such as between 0.05 and 10 micromolar, more preferably between 0.01 and 5, such as between 0.05 and 5 micromolar, even more preferably between 0.01 and 1 micromolar, such as between 0.05 and 1 micromolar, between 0.01 and 0.5 or between 0.01 and 0.1 when assayed as described in Example 21.
  • this method is another embodiment of this method :
  • said first CH3 region has an amino acid other than Lys, Leu or Met at position 409 and said second CH3 region has an amino acid other than Phe at position 405, such as other than Phe, Arg or Gly at position 405
  • said first CH3 region has an amino acid other than Lys, Leu or Met at position
  • said second CH3 region has an amino acid other than Tyr, Asp, Glu, Phe, Lys, Gin, Arg, Ser or Thr at position 407.
  • said first and second polypeptides are full-length heavy chains of two antibodies that bind different epitopes (i.e. said first and second nucleic-acid constructs encode full-length heavy chains of two antibodies that bind different epitopes), and thus the heterodimeric protein is a bispecific antibody.
  • This bispecific antibody can be a heavy-chain antibody, or said host cell may further express one or more nucleic-acid constructs encoding a light-chain. If only one light- chain construct is co-expressed with the heavy chain constructs, then a functional bispecific antibody is only formed if the light chain sequence is such that it can form a functional antigen-binding domain with each of the heavy chains. If two or more different light-chain constructs are co-expressed with the heavy chain, multiple products will be formed.
  • the co-expression method according to the invention comprises any of the further features described under the in vitro method above.
  • the invention relates to an expression vector comprising the first and second nucleic-acid constructs specified herein above.
  • the invention relates to a host cell comprising the first and second nucleic-acid constructs specified herein above.
  • the invention relates to a heterodimeric protein obtained or obtainable by the method of the invention.
  • the method of the invention enables the formation of asymmetrical molecules, molecules with different characteristics on each of the Fab- arms or on each of the CH3 domains or molecules with distinct modifications thoroughout the molecules, e.g. molecules with unnatural amino acid substitution(s) for conjugation.
  • asymmetrical molecules can be generated in any suitable combinatons. This is illustrated further below by some non-limiting examples.
  • Bispecific antibodies can be used to pretarget a target cell of interest, including but not limited to, a tumor cell. Pretargeting of a target cell could be used for imaging studies or for immunotherapeutic purposes.
  • the first Fab-arm of the bispecific molecule binds to a tumor cell, such as a tumor cell surface protein or tumor cell surface carbohydrate, such as one of the tumor cell surface proteins listed herein and the second Fab-arm recognizes a radioactive effector molecule including but not limited to, a radiolabel coupled or linked (via a chelator) to a peptide or hapten.
  • a radioactive effector molecule including but not limited to, a radiolabel coupled or linked (via a chelator) to a peptide or hapten.
  • radiolabeled peptide is indium-labelled
  • hapten-labelled colloidal particles such as liposomes, nanoparticles of polymeric micelles carrying
  • radionuclides such as for example technetium-99 (Jestin et al. Q J Nucl Med Mol Imaging 2007; 51 : 51-60).
  • a hapten-coupled alternative cytostatic molecule such as a toxin is used.
  • the first Fab-arm of the bispecific molecule is glycosylated at position N297 (EU numbering) and the second Fab-arm of the bispecific molecules is aglycosylated (nonglycosylated for instance by mutating N297 to Q or A or E mutation (Bolt S et al., Eur J Immunol 1993, 23 :403-411)).
  • Asymmetrical glycosylation in the Fc-region impacts the interaction to Fcy-receptors and has impact on antibody-dependent cell cytotoxicity effect of the antibody (Ha et al., Glycobiology 2011, April 5) as well as interaction with other effector function molecules such as Clq.
  • the first Fab-arm of the bispecific molecule interacts with FcRn, the neonatal Fc receptor (Roopenian DC, et al. Nat. Rev. Immunol. 2007, 7: 715-725) and the second Fab-arm is impaired in binding to FcRn by mutation of the FcRn interaction site on the molecules for instance by making a H435A mutation (Shields, R.L., et al, J Biol Chem, 2001, Firan, M., et al, Int Immunol, 2001).
  • the first Fab-arm of the bispecific molecule interacts with staphylococcal protein A (protein A,
  • the binding to either Fcy-receptors or FcRn is improved or decreased on one of the two Fab-arms of the bispecific molecule.
  • the binding to Clq is improved or decreased on one of the two Fab-arms of the bispecific molecule.
  • the protein has been engineered to enhance complement activation on one or both of the two Fab-arms of the molecule.
  • each of the Fab-arms present in the bispecific molecule is derived from a different IgG subclass.
  • each of the Fab-arms present in the bispecific molecule carry different allotypic mutations (Jefferis & Lefranc, 2009, MABs 1 : 332- 8).
  • another category of asymmetric immunotherapeutic molecules is generated by replacement of the Fab of one of the Fab-arms of the bispecific molecule by an immuno active, stimulating or inhibiting cytokine.
  • cytokines are IL-2, IFN-a, IFN- ⁇ , IFN-y, TNF-a, G-CSF, GM- CSF, IL-10, IL-4, IL-6, IL-13.
  • a (growth) factor or hormone stimulating or inhibition agent is included in the molecules.
  • a Fab of one of the Fab-arms is replaced by a lytic peptide, i. e. peptides that are able to lyse tumor cells, bacteria, fungi etc, including but not limited to antimicrobial peptides like magainin, mellitin, cecropin, KLAKKLAK and variants thereof (Schweizer et al. Eur. J. Pharmacology 2009; 625: 190-194, Javadpour, J. Med. Chem. , 1996, 39: 3107-3113, Marks et al, Cancer Res 2005; 65 :2373-2377, Rege et al, Cancer Res.
  • a lytic peptide i. e. peptides that are able to lyse tumor cells, bacteria, fungi etc, including but not limited to antimicrobial peptides like magainin, mellitin, cecropin, KLAKKLAK and variants thereof
  • one or both of the Fabs on the Fab arms is replaced by receptors for cytokines and/or growth factors, creating socalled decoy receptors, of which Enbrel® (etanercept) targeting TNF-a and VEGF-trap, targeting VEGF, are well-known examples. Combining these two decoy receptors into one molecule showed superior activity over the single decoy receptors (Jung, J.Biol. Chem. 201 1 ; 286: 14410-14418).
  • another category of asymmetric immunotherapeutic molecules is generated by fusion of immuno-active, -stimulating or inhibiting cytokines to the N-terminus or C-terminus of one, or both, of the Fab-arms present in the bispecific molecules. This may positively impact anti-tumor activity of the bispecific molecule.
  • IL-2 Frnier et al., 2011, Int. J. Oncology, doi : 10.3892/ijo.2011.976
  • IFN-a, IFN- ⁇ or IFN- ⁇ Huan et al., 2007; J. lmmunol.
  • N-terminal or C-terminal fusion of cytokines such as for example G-CSF, GM-CSF, IL-10, IL-4, IL-6, or IL-13 may positively impact the bispecific antibody molecule effector function.
  • cytokines such as for example G-CSF, GM-CSF, IL-10, IL-4, IL-6, or IL-13
  • a growth factor or hormone stimulating or inhibition agent is included in the molecules on the N-terminus or C-terminus.
  • N-terminal or C-terminal fusion of a lytic peptide such as for example antimicrobial peptides like magainin, mellitin, cecropin,
  • KLAKKLAK and variants thereof (Schweizer et al. Eur. J. Pharmacology 2009; 625 : 190-194, Javadpour, J. Med. Chem., 1996, 39: 3107-3113, Marks et al, Cancer Res 2005; 65: 2373-2377, Rege et al, Cancer Res. 2007; 67: 6368-6375) or cationic lytic peptides (CLYP technology, US2009/0269341) on one or both of the Fab-ams may enhance the activity of the molecule.
  • another category of asymmetric immunotherapeutic molecules is monovalent antibodies, molecules which interact with one Fab-arm to the target of choice.
  • one of the Fab-arms present in the bispecific molecule is directed against the target molecule of choice, the second Fab-arm of the molecule does not carry a Fab or has a non-binding/non-functional Fab such as decribed for MetMab (Genentech; WO 96/38557).
  • monomeric Fc-fusion proteins such as those described for Factor VIII and IX (Peters et al., Blood 2010; 115: 2057-2064) may be generated.
  • the invention relates to a heterodimeric protein comprising a first polypeptide comprising a first Fc region of an immunoglobulin, said first Fc region comprising a first CH3 region, and a second polypeptide comprising a second Fc region of an immunoglobulin, said second Fc region comprising a second CH3 region, wherein the sequences of said first and second CH3 regions are different and are such that the heterodimeric interaction between said first and second CH3 regions is stronger than each of the homodimeric interactions of said first and second CH3 regions, and wherein said first homodimeric protein has an amino acid other than Lys, Leu or Met at position 409 and said second homodimeric protein has an amino- acid substitution at a position selected from the group consisting of: 366, 368, 370, 399, 405 and 407 and/or wherein the sequences of said first and second CH3 regions
  • said first CH3 region has an amino acid other than Lys, Leu or Met at position 409 and said second CH3 region has an amino acid other than Phe at position 405
  • the sequences of said first and second CH3 regions are such that the dissociation constants of homodimeric interactions of each of the CH3 regions are between 0.01 and 10 micromolar, such as between 0.05 and 10 micromolar, more preferably between 0.01 and 5, such as between 0.05 and 5 micromolar, even more preferably between 0.01 and 1 micromolar, such as between 0.05 and 1 micromolar, between 0.01 and 0.5 or between 0.01 and 0.1 when assayed as described in Example 21.
  • the heterodimeric protein such as between 0.05 and 10 micromolar, more preferably between 0.01 and 5, such as between 0.05 and 5 micromolar, even more preferably between 0.01 and 1 micromolar, such as between 0.05 and 1 micromolar, between 0.01 and 0.5 or between 0.01 and 0.1 when assayed as described in Example 21.
  • said first CH3 region has an amino acid other than Lys, Leu or Met at position 409 and said second CH3 region has an amino acid other than Phe at position 405, such as other than Phe, Arg or Gly, at position 405
  • said first CH3 region has an amino acid other than Lys, Leu or Met at position 409 and said second CH3 region has an amino acid other than Tyr, Asp, Glu, Phe, Lys, Gin, Arg, Ser or Thr at position 407.
  • heterodimeric protein according to the invention comprises any of the further features described above for the methods of production.
  • said first polypeptide is a full-length heavy chain of an antibody, preferably a human antibody.
  • said second polypeptide is a full-length heavy chain of an antibody, preferably a human antibody.
  • said first and second polypeptides are both full-length heavy chains of two antibodies, preferably both human antibodies that bind different epitopes, and thus the resulting heterodimeric protein is a bispecific antibody.
  • This bispecific antibody can be a heavy-chain antibody, or an antibody which in addition to the heavy chains comprises two full-length light chains, which may be identical or different.
  • the Fc region of the first polypeptide is of an isotype selected from the group consisting of IgGl, IgG2, IgG3 and IgG4 (except for the specified mutations) and the Fc region of the second polypeptide is of an isotype selected from the group consisting of IgGl, IgG2, IgG3 and IgG4 (except for the specified mutations).
  • the Fc regions of both said first and said second polypeptides are of the IgGl isotype.
  • one of the Fc regions of said polypeptides is of the IgGl isotype and the other of the IgG4 isotype.
  • the increased strength of the heterodimeric interaction as compared to each of the homodimeric interactions is due to CH3 modifications other than the introduction of covalent bonds, cysteine residues or charged residues.
  • the heterodimeric interaction between said first and second polypeptides in the heterodimeric protein is such that no Fab-arm exchange can occur at 0.5 mM GSH under the conditions described in Example 13.
  • heterodimeric interaction between said first and second polypeptides in the resulting heterodimeric protein is such that no Fab-arm exchange occurs in vivo in mice under the conditions described in Example 14.
  • said first CH3 region comprises a Phe at position 405 and an amino acid other than Lys, Leu or Met at position 409 and said second CH3 region comprises an amino acid other than Phe at position 405 and a Lys at position 409.
  • said first CH3 region comprises a Phe at position 405 and an amino acid other than Lys, Leu or Met at position 409 and said second CH3 region comprises a Leu at position 405 and a Lys at position 409.
  • said first CH3 region comprises Phe at position 405 and an Arg at position 409 and said second CH3 region comprises a Leu at position 405 and a Lys at position 409.
  • said first CH3 region comprises an amino acid other than Lys, Leu or Met at position 409 and said second CH3 region comprises a Lys at position 409 and : a) an He at position 350 and a Leu at position 405, or b) a Thr at position 370 and a Leu at position 405.
  • said first CH3 region comprises an Arg at position 409 and said second CH3 region comprises a Lys at position 409 and : a) an He at position 350 and a Leu at position 405, or b) a Thr at position 370 and a Leu at position 405.
  • said first CH3 region comprises a Thr at position 350, a Lys at position 370, a Phe at position 405 and an Arg at position 409 and said second CH3 region comprises a Lys at position 409 and : a) an He at position 350 and a Leu at position 405, or b) a Thr at position 370 and a Leu at position 405.
  • said first CH3 region comprises a Thr at position 350, a Lys at position 370, a Phe at position 405 and an Arg at position 409 and said second CH3 region comprises an He at position 350, a Thr at position 370, a Leu at position 405 and a Lys at position 409.
  • neither said first nor said second polypeptide comprises a Cys-Pro-Ser-Cys sequence in the hinge region.
  • both said first and said second polypeptide comprise a Cys-Pro-Pro-Cys sequence in the hinge region.
  • said first and/or said second polypeptide comprises a mutation removing the acceptor site for Asn-linked glycosylation.
  • the heterodimeric protein is a bispecific antibody comprising two variable regions that differ in binding specificity, i.e. bind different epitopes.
  • bispecific antibodies can potentially be used to overcome some of the limitations of monospecific antibodies.
  • One possible limitation of a monospecific antibody is a lack of specificity for the desired target cells due to expression of the target antigen on other cell types towards which no antibody binding is desired.
  • a target antigen overexpressed on tumor cells may also be expressed in healthy tissues which could result in undesired side-effects upon treatment with an antibody directed against that antigen.
  • a bispecific antibody having a further specificity against a protein which is exclusively expressed on the target cell type could potentially improve specific binding to tumor cells.
  • said first and second epitopes are located on the same cell, e.g. a tumor cell.
  • Suitable targets on tumor cells include, but are not limited to, the following : erbBl (EGFR), erbB2 (HER2), erbB3, erbB4, MUC-1, CD19, CD20, CD4, CD38, CD138, CXCR5, c-Met, HERV-envelop protein, periostin, Bigh3, SPARC, BCR, CD79, CD37, EGFrvIII, Ll-CAM, AXL, Tissue Factor (TF), CD74, EpCAM and MRP3.
  • EGFR erbBl
  • HER2 erbB2
  • erbB3, erbB4 MUC-1
  • tumor cell targets include, but are not limited to : erbBl + erbB2, erbB2 + erbB3, erbBl + erbB3, CD19 + CD20, CD38 + CD34, CD4 + CXCR5, CD38 + RANKL, CD38 + CXCR4, CD20 + CXCR4, CD20 + CCR7, CD20 + CXCR5, CD20 + RANKL, erbB2 + AXL, erbBl + cMet, erbB2 + c-Met, erbB2 + EpCAM, c-Met + AXL, c-Met + TF, CD38 + CD20, CD38 + CD138.
  • said first and second epitopes may be located on the same target antigen, wherein the location of the two epitopes on the target antigen is such that binding of an antibody to one epitope does not interfere with antibody binding to the other epitope.
  • said first and second homodimeric proteins are antibodies that bind to two different epitopes located on the same target antigen, but have a different mode-of-action for killing the target cell, e.g. a tumor cell.
  • the target antigen is erbB2 (HER2) and the bispecific antibody combines the pertuzumab and trastuzumab antigen-binding sites.
  • the target antigen is erbBl (EGFr) and the bispecific antibody combines the zalutumumab and nimotuzumab antigen-binding sites.
  • Bispecific antibodies can also be used as mediators to retarget effector mechanisms to disease-associated tissues, e.g. tumors.
  • said first or said second epitope is located on a tumor cell, such as a tumor cell protein or tumor cell carbohydrate, and the other epitope is located on an effector cell.
  • the effector cell is a T cell.
  • FcgammaRI (CD64) : expressed on monocytes and macrophages and activated neutrophils
  • FcgammaRIII (CD16) expressed on natural killer and macrophages
  • CD3 expressed on circulating T cells
  • CD89 expressed on PMN (polymorphonuclear neutrophils), eosinophils, monocytes and macrophages
  • CD32a expressed on macrophages, neutrophils, eosinophils
  • FcsRI expressed on basophils and mast cells.
  • the epitope is located on CD3 expressed on T cells.
  • the first antibody has binding specificity for a pathogenic microorganism and the second antibody has binding specificity for an effector cell protein, such as CD3, CD4, CD8, CD40, CD25, CD28, CD16, CD89, CD32, CD64, FcsRI or CD1.
  • bispecific antibodies can be used to target a chemotherapeutic agent more specifically to the cells on which the agent should act.
  • one of the homodimeric proteins is an antibody which recognizes a small molecule or peptide, or is able to form a covalent bond with such a molecule, e.g. according to the principle described in Rader et al, (2003) PNAS 100: 5396.
  • the first antibody has binding specificity for (i.e. binds to an epitope on) a tumor cell or tumor cell surface protein, such as erbBl, erbB2, erbB3, erbB4, EGFR3vIII, CEA, MUC-1, CD19, CD20, CD4, CD38, EPCAM, c-Met, AXL, Ll-CAM, Tissue Factor, CD74 or CXCR5 and the second antibody has a binding specificity for a chemotherapeutic agent, such as a toxin (including a radiolabeled peptide), a drug or a prodrug.
  • a chemotherapeutic agent such as a toxin (including a radiolabeled peptide), a drug or a prodrug.
  • Bispecific antibodies may also be used to target a vesicle, e.g. an electron dense vesicles, or minicell containing a toxin, drug or prodrug to a tumor.
  • a vesicle e.g. an electron dense vesicles, or minicell containing a toxin, drug or prodrug to a tumor.
  • Minicells are achromosomal cells that are products of aberrant cell division which do not contain chromosomal DNA.
  • said first or said second epitope is located on a tumor cell, such as a tumor cell protein or tumor cell carbohydrate, and the other epitope is located on an electron dense vesicle or minicell.
  • serum half-life of an antibody may be altered by including in a bispecific antibody a binding specificity for a serum protein.
  • serum half- life may be prolonged by including in a bispecific antibody, a binding specificity for serum albumin.
  • the first antibody has binding specificity for a tumor cell or tumor cell protein, such as erbBl (EGFR), erbB2 (HER2), erbB3, erbB4, MUC-1, CD19, CD20, CD4, CD38, CD138, CXCR5, c-Met, HERV-envelope protein, periostin, Bigh3, SPARC, BCR, CD79, CD37, EGFrvIII, Ll-CAM, AXL, Tissue Factor (TF), CD74, EpCAM or MRP3, CEA and the second antibody has a binding specificity for a blood protein, such as serum albumin.
  • a tumor cell or tumor cell protein such as erbBl (EGFR), erbB2 (HER2), erbB3, er
  • a second binding specificity can also be used to target an antibody to a specific tissue, such as the central nervous system or brain (across the blood brain barrier).
  • the first antibody has binding specificity for a brain-specific target, such as amyloid-beta (e.g. for treatment of Alzheimer's disease), Her-2 (e.g. for treatment of breast cancer metastases in brain), EGFr (e.g. for treatment of primary brain cancer), Nogo A (e.g. for treatment of brain injury), TRAIL (e.g. for treatment of HIV), alpha-synuclein (e.g. for treatment of Parkinson), Htt (e.g. for treatment of Huntington), a prion (e.g.
  • amyloid-beta e.g. for treatment of Alzheimer's disease
  • Her-2 e.g. for treatment of breast cancer metastases in brain
  • EGFr e.g. for treatment of primary brain cancer
  • Nogo A e.g. for treatment of brain injury
  • TRAIL
  • TfR transferrin receptor
  • MTFR melanotransferrin receptor
  • LfR lactoferrin receptor
  • ApoER2 Apolipoprotein E receptor 2
  • LRP1 and LRP2 LDL-receptor- related protein 1 and 2
  • RAGE receptor for advanced glycosylation end-products
  • a binding specificity for a blood brain barrier protein can also be used to target another, non-antibody, molecule, to a specific tissue, such as the central nervous system or brain (across the blood brain barrier).
  • VIP vasoactive intestinal peptide
  • BDNF brain-derived neurotrophic factor
  • FGF fibroblast growth factor
  • EGF epidermal growth factor
  • PNA peptide nucleic acid
  • NGF Neve growth factor
  • a second binding specificity can be used to target blood clotting factors to a particular desired site of action.
  • a bispecific antibody having a first binding specificity for a tumor cell and a second binding specificity for a blood clotting factor could direct blood clotting to a tumor, and thus stop tumor growth.
  • the first antibody has binding specificity for a tumor cell or tumor cell protein, such as erbBl, erbB2, erbB3, erbB4, MUC-1, CD19, CD20, CD4 or CXCR5 and the second antibody has a binding specificity for a protein involved in blood clotting, such as tissue factor.
  • binding specificity combinations include: CD3 + HER2, CD3 + CD20, IL-12 + IL18, IL-la + IL-lb, VEGF + EGFR, EpCAM + CD3, GD2 + CD3, GD3 + CD3, HER2 + CD64, EGFR + CD64, CD30 + CD16, NG2 + CD28, HER2 + HER3, CD20 + CD28, HER2 + CD16, Bcl2 + CD3, CD19 + CD3, CEA + CD3, EGFR + CD3, IgE + CD3, EphA2 + CD3, CD33 + CD3, MCSP + CD3, PSMA + CD3, TF + CD3, CD3, CD19 + CD16, CD19 + CD16a, CD30 + CD16a, CEA + HSG, CD20 + HSG, MUC1 + HSG, CD20 + CD22, HLA-DR + CD79, PDGFR + VEGF, IL17a + IL23, CD32b + CD25, CD20 + CD38, HER2
  • the bispecific antibodies according to the invention may be used to clear pathogens, pathogenic autoantibodies or harmful compounds such as venoms and toxins from the circulation by targeting to erythrocytes essentially as described in Taylor et al. J. Immunol. 158: 842-850 (1997) and Taylor and Ferguson, J. Hematother. 4: 357-362, 1995.
  • Said first epitope is located on an erythrocyte (red blood cell) protein including, but not limited to, the erythrocyte complement receptor 1 and said second epitope is located on the compound or organism to be targeted for clearance.
  • the second Fab-arm comprises a fusion protein representing an autoantigen or a conjugation site to attach an autoantigen such as dsDNA.
  • a fusion protein representing an autoantigen or a conjugation site to attach an autoantigen such as dsDNA.
  • the first and/or second homodimeric protein is linked to a compound selected from the group consisting of: a toxin (including a radioisotope) a prodrug or a drug.
  • a compound selected from the group consisting of: a toxin (including a radioisotope) a prodrug or a drug.
  • a toxin including a radioisotope
  • a prodrug or a drug e.g. in cancer therapy.
  • the resulting heterodimeric protein is thus an immunoconjugate.
  • the compound may alternatively be coupled to the resulting heterodimeric protein, i.e. after the Fab-arm exchange has taken place.
  • Suitable compounds for forming immunoconjugates of the present invention include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydro- testosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin, antimetabolites (such as methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, fludarabin, 5-fluorouracil, decarbazine, hydroxyurea, asparaginase, gemcitabine, cladribine), alkylating agents (such as mechlorethamine, thioepa,
  • conjugated molecules include ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, diphtherin toxin, Pseudomonas endotoxin, Maytansinoids, Auristatins (MMAE, MMAF), Calicheamicins and Duocarmycin analogs (Ducry and Stump, Bioconjugate Chem. 2010, 21 : 5-13), Dolostatin-10, Dolostatin-15, Irinotecan or its active metabolite SN38, pyrrolobenzodiazepines (PBD's).
  • RNase ribonuclease
  • DNase I DNase I
  • Staphylococcal enterotoxin-A Staphylococcal enterotoxin-A
  • pokeweed antiviral protein diphtherin toxin
  • Pseudomonas endotoxin Maytansinoids
  • Auristatins MMAE
  • the first and/or second homodimeric protein is linked to an alpha emitter, including but not limited to Thorium-227, Radium-223, Bismuth-212, and Actinium-225.
  • the first and/or second homodimeric protein is linked to a beta emitting radionuclide, including but not limited to Iodium-313, Yttrium-90, Fluorine-18, Rhenium-186, Gallium-68, Technetium-99, Indium-I l l, and Lutetium-177.
  • the compound to be conjugated comprises a nucleic acid or nucleic acid-associated molecule.
  • the conjugated nucleic acid is a cytotoxic ribonuclease, an antisense nucleic acid, an inhibitory RNA molecule (e.g., a siRNA molecule) or an immunostimulatory nucleic acid (e.g., an immunostimulatory CpG motif-containing DNA molecule).
  • Conjugates may be produced by chemically conjugating the other moiety to the N-terminal side or C-terminal side of the protein (see, e.g., Antibody Engineering Handbook, edited by Osamu Kanemitsu, published by Chijin Shokan (1994)). Such conjugated antibody derivatives may also be generated by conjugation at internal residues or sugars, where appropriate.
  • the agents may be coupled either directly or indirectly to a protein of the present invention.
  • One example of indirect coupling of a second agent is coupling by a spacer moiety.
  • Linking technologies for drug-conjugates have recently been summarized by Ducry and Stump (2010) Bioconjugate Chem. 21 : 5.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a heterodimeric protein according to the invention as described herein and a pharmaceutically-acceptable carrier.
  • compositions may be formulated in accordance with conventional techniques such as those disclosed in Remington : The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • a pharmaceutical composition of the present invention may e.g. include diluents, fillers, salts, buffers, detergents (e. g., a nonionic detergent, such as Tween-20 or Tween-80), stabilizers (e. g., sugars or protein-free amino acids), preservatives, tissue fixatives, solubilizers, and/or other materials suitable for inclusion in a pharmaceutical composition.
  • detergents e. g., a nonionic detergent, such as Tween-20 or Tween-80
  • stabilizers e. g., sugars or protein-free amino acids
  • preservatives e. g., tissue fixatives, solubilizers, and/or other materials suitable for inclusion in a pharmaceutical composition.
  • Pharmaceutically acceptable carriers include any and all suitable solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity agents, antioxidants and absorption delaying agents, and the like that are physiologically compatible with a compound of the present invention.
  • suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the present invention include water, saline, phosphate buffered saline, ethanol, dextrose, polyols (such as glycerol, propylene glycol, polyethylene glycol).
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions of the present invention may also comprise pharmaceutically acceptable antioxidants for instance (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, lec
  • compositions of the present invention may also comprise isotonicity agents, such as sugars, polyalcohols, such as mannitol, sorbitol, glycerol or sodium chloride in the compositions.
  • isotonicity agents such as sugars, polyalcohols, such as mannitol, sorbitol, glycerol or sodium chloride in the compositions.
  • compositions of the present invention may also contain one or more adjuvants appropriate for the chosen route of administration such as preservatives, wetting agents, emulsifying agents, dispersing agents, preservatives or buffers, which may enhance the shelf life or effectiveness of the pharmaceutical composition.
  • adjuvants appropriate for the chosen route of administration such as preservatives, wetting agents, emulsifying agents, dispersing agents, preservatives or buffers, which may enhance the shelf life or effectiveness of the pharmaceutical composition.
  • the compounds of the present invention may be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • Such carriers may include gelatin, glyceryl monostearate, glyceryl distearate, biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid alone or with a wax, or other materials well known in the art. Methods for the preparation of such formulations are generally known to those skilled in the art.
  • Sterile injectable solutions may be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients e.g. as enumerated above, as required, followed by sterilization microfiltration.
  • the actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • the pharmaceutical composition may be administered by any suitable route and mode.
  • a pharmaceutical composition of the present invention is administered parenterally.
  • administered parenterally means modes of administration other than enteral and topical administration, usually by injection, and include epidermal, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural and intrasternal injection and infusion.
  • composition is administered by intravenous or subcutaneous injection or infusion.
  • the invention relates to a heterodimeric protein according to the invention, such as a bispecific antibody according to the invention, for use as a medicament.
  • the heterodimeric protein of the invention may be used for a number of purposes.
  • the heterodimeric proteins of the invention may be used for the treatment of various forms of cancer, including metastatic cancer and refractory cancer.
  • the invention relates to a method for inhibiting growth and/or proliferation of and/or for killing of a tumor cell comprising administration of a heterodimeric protein according to the invention as described herein to an individual in need thereof.
  • heterodimeric proteins of the invention are used for the treatment of immune and autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, CNS and musculoskeletal diseases.
  • Dosage regimens in the above methods of treatment and uses are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • An exemplary, non-limiting range for a therapeutically effective amount of a bispecific antibody of the present invention is about 0.1-100 mg/kg, such as about 0.1-50 mg/kg, for example about 0.1-20 mg/kg, such as about 0.1-10 mg/kg, for instance about 0.5, about such as 0.3, about 1, about 3, about 5, or about 8 mg/kg.
  • a physician or veterinarian having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the heterodimeric protein employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a composition of the present invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect.
  • Administration may e.g. be parenteral, such as intravenous, intramuscular or subcutaneous.
  • a heterodimeric protein of the invention may also be administered prophylactically in order to reduce the risk of developing disease, such as cancer, delay the onset of the occurrence of an event in disease progression, and/or reduce the risk of recurrence when a disease, such as cancer is in remission.
  • Heterodimeric proteins, such as bispecific antibodies, of the present invention may also be administered in combination therapy, i.e., combined with other therapeutic agents relevant for the disease or condition to be treated.
  • the Heterodimeric-protein-containing medicament is for combination with one or more further therapeutic agents, such as a cytotoxic, chemotherapeutic or anti-angiogenic agents.
  • Such combined administration may be simultaneous, separate or sequential.
  • the present invention provides a method for treating or preventing disease, such as cancer, which method comprises administration to a subject in need thereof of a therapeutically effective amount of a heterodimeric protein, such as a bispecific antibody of the present invention, in combination with radiotherapy and/or surgery.
  • Heterodimeric proteins, such as bispecific antibodies, of the present invention may also be used for diagnostic purposes.
  • Example 1 Expression vectors for the expression of human IgGl-2F8 and IgGl-7D8
  • VH and VL coding regions of HuMab 2F8 were cloned in the expression vector pConGlf (containing the genomic sequence of the human IgGlf allotype constant region (Lonza Biologies)) for the production of the human IgGl heavy chain and pConKappa (containing the human kappa light chain constant region, Lonza Biologies) for the production of the kappa light chain.
  • pConGlf containing the genomic sequence of the human IgGlf allotype constant region (Lonza Biologies)
  • pConKappa containing the human kappa light chain constant region, Lonza Biologies
  • vectors were used containing the fully codon-optimized coding regions of the heavy chain (IgGl or IgG4) in the pEE12.4 vector or the human kappa light chain of HuMab 2F8 or HuMab 7D8 in the pEE6.4 vector (Lonza Biologies).
  • Example 2 Expression vectors for the expression hinge-deleted-IgGl-2F8, and human IgGl and IgG4 CH2-CH3 fragments containing specific mutations
  • constructs encoding the CH2 and CH3 fragments were constructed either by PCR or synthesized fully codon optimized. These constructs had an N-terminal signal peptide and a 6 amino acid His tag and contained amino acids 341-447 of the human IgGl/4 constant region. The constructs were cloned in pEE12.4.
  • hinge-deleted-IgGl (Uni-Gl) molecules
  • a synthetic DNA construct were was made encoding the Uni-Gl format for human IgGl isotypes with EGFR specificity.
  • the natural hinge region (as defined by the hinge exon) was deleted.
  • An extra Ser to Cys mutation at position 158 was made in the IgGl construct to salvage the Cys bond between the HC and LC chains in this subtype.
  • the protein sequence is shown below. The construct was inserted in the pEE6.4 vector and named pHGl-2F8.
  • Example 3 Expression vectors for the expression of rhesus IgG4-2F8 and IgG4-7D8
  • the Rhesus light chain constant region (CL) sequence used was:
  • Example 4 Antibody production by transient expression in HEK-293F cells
  • Antibodies were produced, under serum-free conditions, by cotransfecting relevant heavy and light chain expression vectors in HEK-293F cells (Invitrogen), using 293fectin (Invitrogen), according to the manufacturer's instructions.
  • IgGl and IgG4 antibodies were purified by protein A affinity chromatography.
  • the cell culture supernatants were filtered over a 0.20 ⁇ dead-end filter, followed by loading on a 5 ml_ Protein A column (rProtein A FF, GE Healthcare, Uppsala, Sweden) and elution of the IgG with 0.1 M citric acid-NaOH, pH 3.
  • the eluate was immediately neutralized with 2 M Tris-HCI, pH 9 and dialyzed overnight to 12.6 mM sodium phosphate, 140 mM NaCI, pH 7.4 (B. Braun, Oss, The Netherlands).
  • samples were sterile filtered over a 0.20 ⁇ dead-end filter. Concentration of the purified IgGs was determined by nephelometry and absorbance at 280 nm. Purified proteins were analyzed by SDS-PAGE, IEF, mass spectrometry and glycoanalysis.
  • the His-tagged CH2-CH3 proteins were purified by immobilized metal ion
  • WO 2008119353 describes an in vitro method for producing bispecific antibodies wherein a bispecific antibody is formed by "Fab-arm" or "half-molecule” exchange (swapping of a heavy chain and attached light chain) between two monospecific IgG4- or IgG4-like antibodies upon incubation under reducing conditions.
  • This Fab-arm exchange reaction is the result of a disulfide-bond isomerization reaction wherein the inter heavy-chain disulfide bonds in the hinge regions of monospecific antibodies are reduced and the resulting free cysteines form a new inter heavy-chain disulfide bond with cysteine residues of another antibody molecule with a different specificity.
  • the resulting product is a bispecific antibody having two Fab arms with different sequences.
  • ELISA sandwich enzyme-linked immunosorbent assay
  • Figure 1 shows that a combination of human and rhesus IgG4 resulted in more bispecific binding (a higher OD 405 nm) compared with each of the combinations of IgG4 molecules of the same species.
  • Fab-arm exchange occurs between human IgG4 and rhesus IgG4.
  • the higher bispecific binding suggests that human IgG4 half molecules show preferential dimerisation to rhesus IgG4 half molecules (heterodimerization), resulting in an equilibrium of the Fab-arm exchange reaction that is shifted towards the bispecific heterodimer instead of a stochastic exchange with 50% heterodimer and 50% homodimers.
  • Example 8 Sequence analysis of human and rhesus IgG4
  • Fab-arm exchange was found to be an inherent feature of IgG4, characterized by an arginine (R) at position 409 in the CH3 domain and a permissive hinge (226-CPSC- 229) (see WO 2008145142 (Genmab)).
  • R arginine
  • TrC- 229 a permissive hinge
  • human IgGl which does not engage in Fab-arm exchange, has a Lysine (K) at position 409 and a stable (i.e. non- permissive) hinge (226-CPPC-229) (EU numbering, see also Figure 16).
  • rhesus IgG4 is characterized by three more amino acid substitutions in the CH3-CH3 interface as compared to human IgG4: isoleucine (I) at position 350 in rhesus versus threonine (T) in human; threonine (T) at position 370 in rhesus versus lysine (K) in human; and leucine (L) at position 405 in rhesus versus phenylalanine (F) in human.
  • I isoleucine
  • T threonine
  • K threonine
  • L leucine
  • Example 9 Generation of bispecific antibodies using GSH-induced Fab-arm exchange between human IgG4 and human IgGl containing rhesus IgG4 CH3 sequences
  • the antibody mixtures containing each antibody at a final concentration of 4 ⁇ g/mL in 0.5 mL PBS with 0.5 mM GSH, were incubated at 37°C for 0-3-6-24h .
  • 0.5 mL PBS/0.05 % Tween 20 (PBST) was added to the reaction mixture. Measurements of bispecific binding in an ELISA were performed as described in Example 7.
  • Figure 3 confirms that introduction of a CPSC hinge alone does not engage human IgGl-2F8 for GSH-induced Fab-arm exchange when combined with human IgG4-7D8. Also the introduction of the rhesus IgG4-specific CH3 interface amino acids (ITL) into human IgG l-2F8, while preserving the wild type IgGl hinge, did not result in engagement for Fab-arm exchange when combined with human IgG4-7D8 under these conditions.
  • ITL rhesus IgG4-specific CH3 interface amino acids
  • a variant human IgGl-2F8 backbone sequence that harbors both a CPSC sequence in the hinge and the rhesus IgG4-specific CH3 interface amino acids showed increased bispecific binding after GSH-induced Fab-arm exchange with human IgG4-7D8 compared to two human IgG4 antibodies.
  • Example 10 Generation of bispecific antibodies by in vivo Fab-arm exchange between human IgG4 and IgGl or IgG4 mutants
  • human IgG4 and IgGl variants were analyzed in vivo.
  • Four female SCID mice (Charles River, Maastricht, The Netherlands) per group were i .v. injected with antibody mixtures, containing 600 ⁇ g antibody (500 ⁇ g 7D8 + 100 ⁇ g 2F8) in a total volume of 300 ⁇ _.
  • Blood samples were drawn from the saphenal vein at 3, 24, 48 and 72 hours after injection. Blood was collected in heparin-containing vials and centrifuged at 10,000 g for 5 min to separate plasma from cells.
  • bispecific antibodies were followed by assessing CD20 and EGFR bispecific reactivity in an ELISA using serial diluted plasma samples in PBSTB as described in Example 7.
  • Bispecific antibodies in plasma samples were quantified by non-linear regression curve-fitting (GraphPad Software, San Diego, CA) using an in vitro exchanged antibody mixture as reference.
  • Figure 4 shows that human IgG4-2F8, in which either the hinge or the CH3 sequence is converted to the corresponding human IgGl sequence (CPPC or R409K, respectively), does not engage in Fab-arm exchange anymore in vivo.
  • human IgGl in which both the hinge region and the CH3 interface sequences are converted to the corresponding human IgG4 sequences (CPSC and K409R), is able to participate in Fab-arm exchange in vivo.
  • Example 11 Generation of bispecific antibodies by 2-MEA-induced Fab-arm exchange: bypass/disruption of a stabilized hinge
  • 2-Mercaptoethylamine- HCI (2-MEA) is a mild reducing agent that has been described to selectively cleave disulphide bonds in the hinge region of antibodies, while preserving the disulphide bonds between the heavy and light chains. Therefore, a concentration series of 2-MEA was tested for its ability to induce the generation of bispecific antibodies by Fab-arm exchange between two antibodies containing CPSC or CPPC hinge regions.
  • the reducing agent 2-M EA was removed by desalting the samples using spin columns (Microcon centrifugal filters, 30k, M illipore) according to the manufacturer's recommendations. Bispecific binding was measured in an ELISA as described in Example 7.
  • 2-MEA-induced Fab-arm exchange was tested for the combination IgG4-2F8 x IgG4-7D8, containing CPSC hinge regions and known to participate in GSH-induced Fab-arm exchange, and for the combination IgGl-2F8-ITL x IgG4-7D8-CPPC, not participating in GSH-induced Fab-arm exchange due to the stabilized hinge regions (described in Example 9, Figure 3) .
  • 2-MEA was found to induce separation of light chains from heavy chains as determined by non-reducing SDS- PAGE (data not shown) . Nonetheless, functional bispecific antibodies were generated as shown in Figure 5.
  • Example 11 The generation of bispecific antibodies by 2-M EA-induced Fab-arm exchange is described in Example 11, where bispecific binding was shown by an ELISA ( Figure 5) .
  • the samples were analyzed by electrospray ionization mass spectrometry (ESI-MS) to determine the molecular weights.
  • ESI-MS electrospray ionization mass spectrometry
  • Figure 6A shows three representative mass spectrometry profiles of the Fab-arm exchange reaction between IgG l-2F8-ITL and IgG4-7D8-CPPC with 0 mM 2-MEA (two peaks corresponding to the parental antibodies), 7 mM 2-MEA (three peaks corresponding to the parental and the bispecific antibodies), and 40 mM 2-MEA (one peak corresponding to the bispecific antibody) .
  • the homogenous peak of the bispecific product indicates that no light chain mispairing occurred, which would have resulted in subdivided peaks.
  • the quantified data are presented in Figure 6B and show that Fab-arm exchange between IgG l-2F8-ITL and IgG4-7D8-CPPC resulted in nearly 100% bispecific antibody.
  • bispecific antibodies generated by 2-MEA-induced in vitro Fab- arm exchange was tested . Therefore, 2 pg of a bispecific sample generated from IgGl-2F8-ITL and IgG4-7D8-CPPC with 7.0 mM 2-M EA (as described in Example 11, Figure 5) was used in a GSH-induced Fab-arm exchange reaction in the presence of a concentration series (0, 2, 20, 100 ⁇ ) irrelevant IgG4 (IgG4-MG against acetylcholine receptor), representing a 0, 1, 10, 50x excess of IgG4-MG compared to the 2 ⁇ g bispecific test sample. Fab-arm exchange in this reaction would result in loss of bispecific EGFR/CD20 binding .
  • Figure 7A shows that for the IgG l-2F8-ITL x IgG4-7D8-CPPC derived bispecific sample, EGFR/CD20 bispecific binding is not significantly changed after GSH-induced Fab-arm exchange in the presence of irrelevant IgG4. This indicates that the bispecific product is stable, i.e. does not participate in GSH-induced Fab-arm exchange.
  • Figure 7B shows that an IgG4-2F8 x IgG4-7D8 derived sample shows diminished EGFR/CD20 bispecific binding after GSH-induced Fab-arm exchange in the presence of irrelevant IgG4, indicating that this product is not stable.
  • Example 14 I n vivo analysis of the pharmacokinetics and stability of bispecific antibodies generated by 2-MEA-induced Fab-arm exchange
  • the bispecific antibody generated by in vitro 2-MEA-induced Fab-arm exchange between IgGl-2F8-ITL x IgG4-7D8-CPPC was injected in SCID mice to analyze its stability (in vivo Fab-arm exchange) and pharmacokinetic properties (plasma clearance rate) in comparison to the parental antibodies IgG l-2F8-ITL and IgG4-7D8-CPPC.
  • mice Three groups of mice (3 mice per group) were injected intravenously in the tail vein with 200 ⁇ _ purified antibody : (1) 100 ⁇ g bispecific antibody; (2) 100 ⁇ g bispecific antibody + 1,000 ⁇ g irrelevant IgG4 (natalizumab, anti-a4-integrin); (3) 50 ⁇ g IgG l-2F8-ITL + 50 ⁇ g IgG4-7D8-CPPC.
  • Blood samples 50- 100 ⁇ _
  • Blood samples were collected by cheek puncture at pre-determined time intervals after antibody administration ( 10 min, 3h, 1, 2, 7, 14, 21 days) . Blood was collected into heparin containing vials and centrifuged for 10 min at 14,000 g . Plasma was stored at -20°C before further analysis.
  • Total IgG concentrations in the plasma samples were assayed by ELISA.
  • the assay conditions of the succeeding steps were the same as for the ELISA described in Example 7.
  • Specific compounds used for total IgG measurement were the following : coat with 2 ⁇ g/mL mouse anti-human IgG (clone MH 16- 1 ; CLB; cat. no. M 1268) ; serum samples dilutions ( 1 : 500 and 1 : 2,500 for groups 1 and 3) and (1 : 2,500 and 1 : 10,000 for group 2) ; conjugate : H RP-conjugated goat anti-human IgG (clone 11 H ; Jackson; cat. no. 109-035-098; 1 : 10,000) .
  • the presence of bispecific antibodies in the plasma samples was assayed and quantified by CD20 and EGFR bispecific reactivity in an ELISA as described in Example 10.
  • Figure 8A shows total antibody plasma concentrations.
  • the shape of the plasma clearance curves was identical in all groups, indicating that the plasma clearance of the bispecific antibody was the same as for the parental antibodies IgGl-2F8-ITL and IgG4-7D8-CPPC over the analyzed time interval.
  • Figure 8B shows the plasma concentrations of bispecific antibodies over time. The addition of a 10- fold excess irrelevant IgG4 to the bispecific antibody did not affect bispecific antibody concentrations, indicating that no Fab-arm exchange occurred in vivo. After injection of the parental antibodies (IgGl-2F8-ITL + IgG4-7D8-CPPC), no bispecific antibodies were detectable in the plasma, confirming that these antibodies do not participate in Fab-arm exchange in vivo.
  • HP-SEC fractionation was performed using a Waters Alliance 2695 separation unit (Waters, Etten-Leur, The Netherlands) connected to a TSK HP-SEC column (G3000SW X i; Toso Biosciences, via Omnilabo, Breda, The Netherlands) and a Waters 2487 dual ⁇ absorbance detector (Waters) .
  • the samples were run at 1 mL/min.
  • Results were processed using Empower software version 2002 and expressed per peak as percentage of total peak height.
  • Figure 9B shows that >98% of the sample consists of intact IgG, with practically no aggregates formed .
  • FIG. 9C shows the mass spectrometry profiles of the starting materials IgG l-2F8-ITL and IgG4-7D8-CPPC and the bispecific product generated by Fab-arm exchange between IgGl-2F8-ITL x IgG4-7D8-CPPC.
  • the bispecific antibody product showed a homogenous peak, indicating that no light chain mispairing occurred, which would have resulted in subdivided peaks.
  • These data show that Fab-arm exchange resulted in 100% bispecific antibody.
  • the small peaks detected in addition to the main peak (K0) of the IgG4-7D8-CPPC and bispecific sample can be attributed to the presence of one (Kl) or two (K2) C- terminal lysines.
  • IgGl containing the triple mutation T350I-K370T-F405L (ITL) was compared to the double mutants T350I-K370T (IT), T350I-F405L (IL) and K370T-F405L (TL) . Also the single mutant F405L (L) was tested .
  • 2-MEA was used as a reductant to induce in vitro Fab-arm exchange (50 ⁇ g of each antibody in 100 ⁇ _ PBS/25 mM 2-MEA for 90 min at 37°C).
  • IgGl-2F8 The triple (ITL), double mutations (IT, IL and TL) and single mutation (L) were introduced in IgGl-2F8. These mutants were combined with IgG4-7D8, containing a CPSC hinge (wild type) or a stabilized hinge (IgG4-7D8-CPPC), for Fab- arm exchange using 25 mM 2-MEA for 90 min at 37°C.
  • Figure 10A-B shows that the IgGl-2F8-IL and -TL mutants showed Fab-arm exchange to the same level as the triple mutant ITL, irrespective of the combined IgG4-7D8 (CPSC or CPPC hinge). In contrast, no bispecific binding was found for the combination with the IgGl-2F8-IT mutant.
  • Figure IOC shows that also the IgGl-2F8-F405L mutant showed Fab-arm exchange, irrespective of the combined IgG4-7D8 (CPSC or CPPC hinge). These data indicate that the F405L mutation is sufficient to engage human IgGl for Fab-arm exchange under the conditions mentioned above.
  • Example 17 Generation of bispecific antibodies by 2-MEA-induced Fab-arm exchange at different temperatures
  • the ability of 2-MEA to induce the generation of bispecific antibodies by Fab- arm exchange between two different antibodies was tested at different temperatures.
  • the Fab-arm exchange reactions were started by incubating 160 ⁇ g human IgGl-2F8-ITL with 160 ⁇ g IgG4-7D8-CPPC in 320 ⁇ PBS/25 mM 2-MEA (final concentration of 0.5 mg/mL for each antibody) at either 0°C, 20°C (RT) or 37°C. From these reactions, 20 ⁇ L ⁇ samples were taken at different time points (0, 2.5, 5, 10, 15, 30, 45, 60, 75, 90, 120, 150, 180 and 240 min).
  • FIG. 11 shows that the generation of bispecific antibodies by 2-MEA-induced Fab-arm exchange between human IgGl-2F8-ITL and IgG4-7D8-CPPC was found to be most efficient at 37°C, with maximal bispecific binding reached after 45 min. At room temperature, the generation of bispecific antibodies was slower, reaching maximal bispecific binding after 240 min . At 0°C, no generation of bispecific binding was observed during the analyzed time course.
  • Example 18 Analysis of different reducing agents for their ability to induce the generation of bispecific antibodies by in vitro Fab-arm exchange
  • Figure 12 confirms that 2-MEA induces maximal bispecific binding at a concentration of 25 mM 2-MEA.
  • DTT was found to be very effective in the generation of bispecific antibodies with maximal bispecific binding reached at 2.5 mM DTT.
  • GSH concentrations in the range 0-5 mM were not able to induce the generation of bispecific antibodies by Fab-arm exchange between the IgGl-ITL and IgG4-CPPC antibodies, both containing stabilized hinge regions.
  • H igher GSH concentrations (12.5-50 mM) resulted in the formation of antibody aggregates, as was determined by non-reducing SDS-PAGE (data not shown). Therefore, these samples were excluded from the analysis.
  • Example 19 Determinants at the IgGl 409 position for engagement in 2- MEA-induced Fab-arm exchange in combination with IgGl-ITL
  • 2-MEA can induce Fab-arm exchange between human IgGl-ITL and IgG4- CPPC, as described in Example 11 ( Figure 5).
  • the CH3 interface residues of human IgGl and IgG4 differ at position 409 only: lysine (K) in IgGl and arginine (R) in IgG4 (described in Example 8, Figure 2). Therefore, it was tested whether substitution of lysine at position 409 by arginine or any other amino acid (K409X) could enable IgGl to engage in 2-MEA-induced Fab-arm exchange with IgGl-ITL.
  • FIG. 13A shows the results of bispecific binding upon 2-MEA induced Fab- arm exchange between IgGl-2F8-ITL x IgGl-7D8-K409X.
  • Figure 13B the exchange is presented as bispecific binding relative to a purified batch of bispecific antibody derived from a 2-MEA-induced Fab-arm-exchange between IgGl-2F8-ITL and IgG4-7D8-CPPC, which was set to 100%.
  • These data were also scored as (-) no Fab-arm exchange, (+/-) low, (+) intermediate or (++) high Fab-arm exchange, as presented in Table 1.
  • Fab-arm exchange was found to be intermediate (+) when the 409 position in IgGl-7D8 was F, I, N or Y and high (++) when the 409 position in IgGl-7D8 was A, D, E, G, H, Q, R, S, T, V or W.
  • Table 1 2-MEA-induced Fab-arm exchange between IgGl-2F8-ITL and IgGl-7D8-K409X mutants.
  • Example 20 Antibody deglycosylation does not influence the generation of bispecific antibodies by 2-MEA-induced Fab-arm exchange
  • IgG4-7D8 and IgG4-7D8-CPPC samples were deglycosylated by incubating 200 ⁇ g antibody overnight at 37°C with 0.005 U N-Glycanase (cat. no. GKE-5006D; Prozyme) in 180 ⁇ _ PBS. These samples were used directly in a Fab-arm exchange reaction. Fab-arm exchange was performed by incubating 50 ⁇ g of each antibody in 100 ⁇ PBS/25 mM 2-M EA (final concentration of 0.5 mg/mL for each antibody) for 90 min at 37°C. The reducing agent 2-MEA was removed by desalting the samples using spin columns as described in Example 11. Dilution series of the antibody samples (total antibody concentration 0-20 ⁇ g/mL in 3-fold dilutions) were used in a sandwich ELISA to measure bispecific binding as described in Example 7.
  • the strength of the interactions at the CH3 interface should be such that it is possible that both heavy chains in the parental antibodies dissociate in the Fab-arm exchange reaction and that they subsequently associate in the heterodimerization reaction. Therefore, the correlation between the ability to participate in Fab-arm exchange and the strength of the non-covalent CH3-CH3 interaction (dissociation constant, K D ) was analyzed .
  • GSH-induced Fab-arm exchange was performed as described in Example 9 (0.5 mM GSH at 37°C) for the following combinations of human antibodies:
  • IgG l-2F8-CPSC-ITL IgGl-7D8-CPSC-ITL
  • IgG l-2F8-CPSC-K409R x IgGl-7D8-CPSC-K409R
  • IgG4-2F8-R409A x IgG4-7D8-R409A
  • IgG4-2F8-R409L x IgG4-7D8-R409L
  • IgG4-2F8-R409T x IgG4-7D8-R409T
  • IgG4-2F8-F405A x IgG4-7D8-F405A
  • IgG4-2F8-F405L x IgG4-7D8-F405L
  • IgG4-2F8-E357T x IgG4-7D8-E357T
  • IgG4-2F8-K370E x IgG4-7D8-K370E The generation of bispecific antibodies was measured by determination of bispecific binding in a sandwich ELISA as described in Example 7.
  • Figures 15A/B/C show the results of the bispecific binding after the Fab-arm exchange reaction.
  • fragments composed of only the CH2-CH3 domains were made.
  • the lack of a hinge region in these fragments prevented covalent inter-heavy chain disulfide bonds.
  • the fragments were analyzed by native mass spectrometry. Samples were buffer-exchanged to 100 mM ammonium acetate pH 7, using 10 kDa MWCO spin-filter columns. Aliquots ( ⁇ 1 ⁇ _) of serial diluted samples (20 ⁇ - 25 nM; monomer equivalent) were loaded into gold-plated borosilicate capillaries for analysis on a LCT mass spectrometer (Waters).
  • the concentration of monomer at equilibrium, [M] eq was defined as M S . [M] 0 where [M] 0 is the overall protein concentration in terms of monomer.
  • the dimer concentration at equilibrium, [D] eq was defined as ([M] 0 -[M] eq )/2.
  • the K D was then extracted from the gradient of a plot of [D] eq versus [M] eq 2 .
  • the K D of the non-covalent CH3-CH3 interactions is presented in Table 2.
  • Figures 15D/E show the percentage bispecific binding after Fab-arm exchange plotted against the measured K D of the corresponding CH2-CH3 fragment ( Figure 15D for IgGl; Figure 15E for IgG4).
  • G4-F405A 1.9 x 10 "5 0.0025
  • Example 22 Analysis of different reductantia for their ability to induce the generation of bispecific antibodies by in vitro Fab-arm-exchange between IgGl-2F8-F405L and IgGl-7D8-K409R
  • 2-MEA and DTT were found to induce in vitro Fab-arm-exchange between human IgG l-ITL and IgG4-CPPC ( Figure 12) . It was tested whether these reductantia can also induce in vitro Fab-arm-exchange between human IgGl-2F8- F405L and IgGl-7D8-K409R.
  • Concentration series of 2-MEA, DTT, GSH and TCEP (tris(2-carboxyethyl)phosphine) were tested .
  • Fab-arm-exchange was performed as described in Example 18. The tested concentration series of the different reducing agents were as follows : 0.0, 0.04, 0. 1, 0.2, 0.5, 1.0, 5.0, 25.0, 50.0 mM 2-MEA, GSH, DTT or TCEP.
  • Figure 17 confirms that 2-MEA induces maximal Fab-arm-exchange at a concentration of 25 mM 2-MEA, which persisted at the higher concentration of 50.0 mM 2-MEA.
  • DTT was found to be very effective in the generation of bispecific antibodies with maximal Fab-arm-exchange reached at 0.5 mM DDT, which also persisted over higher concentrations of DTT ( 1.0-50.0 mM) .
  • TCEP was found to be very effective in the generation of bispecific antibodies with maximal Fab-arm- exchange reached at 0.5 mM . At a concentration > 25.0 mM, Fab-arm-exchange by TCEP was disturbed .
  • Figure 18A shows that 2-MEA induced Fab-arm-exchange between IgGl-2F8-
  • Example 24 Purity of the bispecific antibody generated by 2-MEA-induced Fab-arm-exchange between human IgGl-2F8-F405L x IgGl-7D8-K409R
  • Figure 19 shows the mass spectrometry profiles of the starting materials IgGl-2F8-F405L and IgGl-7D8-K409R and the bispecific product generated by Fab- arm-exchange between IgGl-2F8-F405L x IgGl-7D8-K409R.
  • Example 25 I n vivo analysis of the stability and pharmacokinetics of bispecific antibodies generated from IgGl-2F8-F405L x IgGl-7D8-K409R by 2-MEA-induced Fab-arm-exchange
  • mice The bispecific antibody generated by in vitro 2-M EA-induced Fab-arm- exchange between IgGl-2F8-F405L x IgG l-7D8-K409R was injected in SCID mice to analyze its stability (in vivo Fab-arm-exchange) and pharmacokinetic properties as described in Example 14.
  • Figure 20A shows total antibody plasma concentrations over time. The shape of the plasma clearance curves was identical in both groups.
  • Figure 20B shows the plasma concentrations of bispecific antibody over time. The addition of a 10-fold excess irrelevant IgG4 to the bispecific antibody did not affect bispecific antibody concentrations, indicating that no Fab-arm-exchange occurred in vivo. These data indicate that the bispecific antibody product, generated by in vitro 2-M EA-induced Fab-arm-exchange between IgG l-2F8-F405L x IgGl-7D8-K409R, was stable in vivo (no Fab-arm-exchange).
  • Example 26 CDC-mediated cell kill by bispecific antibody generated by 2- MEA-induced Fab-arm-exchange between human IgGl-2F8-F405L x IgGl- 7D8-K409R
  • the CD20 antibody IgGl-7D8 can efficiently kill CD20-expressing cells by complement-dependent cytotoxicity (CDC) .
  • the EGFR antibody IgG l-2F8 does not mediate CDC on target cells expressing EGFR. It was tested whether the mutant IgGl-7D8-K409R and the bispecific antibody generated by 2-M EA-induced Fab-arm-exchange between IgGl-2F8-F405L x IgG l-7D8-K409R were still able to induce CDC on CD20-expressing cells.
  • Figure 21 shows that CDC-mediated cell kill of CD20-expressing Daudi
  • Example 27 ADCC-mediated cell kill by the bispecific antibody generated by 2-MEA-induced Fab-arm-exchange between human IgGl-2F8-F405L x IgGl- 7D8-K409R
  • the EGFR antibody IgGl-2F8 can kill EGFR-expressing cells, such as A431, by antibody-dependent cellular cytotoxicity (ADCC).
  • A431 cells do not express CD20 and therefore the CD20 antibody IgGl-7D8 does not induce ADCC on these cells. It was tested whether the mutant IgGl-2F8-F405L and the bispecific antibody generated by 2-MEA-induced Fab-arm-exchange between IgGl-2F8-F405L x IgGl-7D8-K409R were still able to induce ADCC on A431 cells.
  • peripheral blood mononuclear cells were isolated from whole blood of a healthy donor using Leucosep ® tubes (Greiner Bio-one, cat.# 227290) according to the manufacturer's recommendations.
  • Target cells were labelled by adding 100 ⁇ 51 Cr to 5xl0 6 A431 cells in 1 mL RPMI medium supplemented with 0.1% BSA and incubating for 60 min in a 37°C shaking water bath. Labelled cells were washed and resuspended in RPMI supplemented with 0.1% BSA.
  • 5xl0 4 labelled target cells in RPMI supplemented with 0.1% BSA were preincubated in 100 ⁇ _ for 15 min with the antibody concentrations series (range 0-10 ⁇ g/mL final concentration in ADCC assay in 3-fold dilutions) at room temperature.
  • the ADCC assay was started by adding 50 ⁇ _ effector cells (5xl0 6 cells) in an E:T ratio 100 : 1. After 4 hours at 37°C, 51 Cr release from triplicate experiments was measured in a scintillation counter as counts per min (cpm).
  • FIG. 22 shows that the CD20-specific antibody IgGl-7D8 did not induce ADCC on the CD20-negative A431 cells.
  • Both IgGl-2F8 and the mutant IgG l-2F8- F405L were able to induce ADCC on A431 cells, indicating that introduction of the F405L mutation in IgG l-2F8 did not affect its ADCC effector function .
  • the bispecific antibody derived from IgG l-2F8-F405L x IgGl-7D8-K409R induced ADCC on A431 cells in a dose-dependent manner, indicating that the ADCC effector function was retained in the bispecific format.
  • Example 28 Determinants at the IgGl 405 position for engagement in 2- MEA-induced Fab-arm-exchange in combination with IgGl-K409R
  • Example 16 it is described that the F405L mutation is sufficient to enable human IgGl to engage in Fab-arm-exchange when combined with IgG4-7D8.
  • Example 16 To further test the determinants at the IgGl 405 position for engagement in 2-MEA- induced Fab-arm-exchange in combination with human IgGl-K409R, all possible IgGl-2F8-F405X mutants (with the exception of C and P) were combined with IgG l- 7D8-K409R. The procedure was performed with purified antibodies as described in Example 19.
  • Fab-arm exchange was found to be high (++) when the 405 position in IgGl-2F8 was A, D, E, H, I, K, L, M, N, Q, S, T, V, W or Y. These data indicate that particular mutations at the IgGl 405 position allow IgGl to engage in 2-M EA-induced Fab-arm-exchange when combined with IgGl-K409R.
  • Table 3 2-MEA-induced Fab-arm-exchange between IgGl-2F8-F405X mutants and IgGl-7D8-K409R.
  • Example 29 Determinants at the IgGl 407 position for engagement in 2- MEA-induced Fab-arm-exchange in combination with IgGl-K409R
  • Example 28 it is described that certain single mutations at position F405 are sufficient to enable human IgGl to engage in Fab-arm-exchange when combined with IgGl-K409R.
  • Fc interface positions in the CH3 domain could also mediate the Fab-arm-exchange mechanism, mutagenesis of the IgGl 407 position was performed and the mutants were tested for engagement in 2-MEA-induced Fab-arm-exchange in combination with human IgGl-K409R. All possible IgGl-2F8-Y407X mutants (with the exception of C and P) were combined with IgGl-7D8-K409R. The procedure was performed with purified antibodies as described in Example 19.
  • Fab-arm exchange was found to be low (+/-) when the 407 position in IgG l-2F8 was D, F, I, S or T and intermediate (+) when the 407 position in IgGl-2F8 was A, H, N or V, and high (++) when the 407 position in IgGl-2F8 was G, L, M or W.
  • Example 21 there is a specific range in the strength of the interaction of the CH3-CH3 homodimers that allows efficient Fab-arm-exchange.
  • the strength of the interactions at the CH3 interface should be such that it is possible that both heavy chains in the parental antibodies (homodimers) dissociate in the Fab-arm-exchange reaction and that they subsequently associate in the heterodimerization reaction.
  • the strength of the heterodimer interaction should be greater than the strength of the homodimer interaction, such that it favors heterodimerization over homodimerization.
  • the strength of the CH3-CH3 interaction in the heterodimers was measured and compared to the strength in the homodimers.
  • the K D of the CH2-CH3 fragments derived from IgGl-K409R, IgGl-F405L and IgGl-ITL homodimers were measured as described in Example 21.
  • CH2-CH3 domain fragments (G1-F405L and Gl-ITL) were mixed with the IgGlAhinge fragment of IgGl-7D8-K409R, which contain all antibody domains except the hinge.
  • the lack of hinge regions in both fragments prevented covalent inter-heavy chain disulfide bonds.
  • the fragments were mixed and analyzed after 24 hours by native mass spectrometry as described in Example 21.
  • Example 31 Biochemical analysis of a bispecific antibody generated by 2- MEA-induced Fab-arm exchange
  • the purity of the bispecific product was analyzed by sodium dodecyl sulfate polyacrylamide gelelectrophoresis (SDS-PAGE), High Performance Size Exclusion Chromatography (HP-SEC), mass spectrometry, HPLC cation exchange chromatography (HPLC-CIEX), capillary isoelectrofocussing (cIEF).
  • FIG(A) show the HP-SEC profiles of the starting materials IgGl-2F8-F405L and IgGl- 7D8-K409R, respectively.
  • the mixture (1 : 1) of both antibodies and the bispecific product generated by 2-MEA induced Fab-arm exchange between IgGl-2F8-F405L x IgGl-7D8-K409R are shown in Figure 26C and Figure 26D, respectively.
  • Figure 26D shows that >99% of the sample consists of intact IgG with practically no aggregates formed.
  • FIG. 27(B) and Figure 27(A) show the mass spectrometry profiles of the starting materials IgGl-2F8-F405L and IgGl-7D8-K409R, respectively.
  • the mixture (1 : 1) of both antibodies and the bispecific product generated by 2-MEA induced Fab-arm exchange between IgGl-2F8-F405L x IgGl-7D8-K409R are shown in Figure 27C and Figure 27D, respectively.
  • the bispecific antibody product showed a homogenous peak, indicating that no light chain mispairing occurred, which would have resulted in subdivided peaks.
  • FIG. 28A and Figure 28B shows cIEF profiles of the starting materials IgGl-2F8-F405L and IgGl-7D8-K409R, respectively.
  • the mixture (1 : 1) of both antibodies and the bispecific product generated by Fab-arm exchange between IgGl-2F8-F405L x IgGl-7D8-K409R are shown in Figure 28C and Figure 28D, respectively. All samples were desalted before use.
  • FIG. 29A and Figure 29B show HPLC-CIEX profiles of the starting materials IgGl-2F8-F405L and IgGl-7D8-K409R, respectively.
  • the mixture (1 : 1) of both antibodies and the bispecific product generated by 2-MEA induced Fab-arm exchange between IgGl- 2F8-F405L x IgGl-7D8-K409R are shown in Figure 29C and Figure 29D, respectively.
  • Samples were diluted to 1 mg/mL in mobile Phase A (10 mM NaP04, pH 7.0) for injection onto the HPLC.
  • the differently charged IgG molecules were separated by using a ProPac® WCX-10, 4 mm x 250 mm, analytical column with a flow rate of 1 mL/min. Elution was performed with a gradient of Mobile Phase A to Mobile Phase B (10 mM NaP0 4 , pH 7.0, 0.25 M NaCI) and detection occurred at 280 nm.
  • Mobile Phase A 10 mM NaP0 4 , pH 7.0, 0.25 M NaCI
  • a bispecific antibody sample was generated by 2-MEA-induced Fab-arm exchange between IgGl-2F8-F405L x IgGl-7D8-K409R. It also shows that cation exchange is a powerful tool to separate residual homodimers from the heterodimer.
  • Another application of cation exchange chromatography is therefore the polishing of a bispecific heterodimer, i.e. to purify away any residual homodimers after exchange.
  • HEK-293F cells were co-transfected with the four expression vectors (see Example 1) encoding the heavy and light chain of IgGl-7D8-K409R and IgGl-2F8-F405 in a 1 : 1 : 1 : 1 ratio.
  • Antibodies were transiently produced under serum-free conditions as described in Example 4.
  • IgG was purified by Protein A chromatography as described in Example 5. Purified IgG was deglycosylated and subsequently analyzed by electrospray ionization mass spectrometry as described in Example 12.
  • Theoretic mass of heavy and light chain of IgGl-7D8-K409R and IgGl- 2F8-F405 are shown in Table 6.
  • Table 6 Theoretical mass of the heavy and light chain of IgGl-7D8-K409R and IgGl-2F8-F405
  • Table 7 Theoretical detection of heavy and light chain of IgGl-7D8-K409R and IgGl-2F8-F40
  • Example 33 Monitoring the kinetics of 2-MEA-induced Fab-arm exchange and quantifying residual homodimers after exchange by using HPLC-CIEX
  • Example 11 The generation of bispecific antibodies by 2-MEA-induced Fab-arm exchange is described in Example 11.
  • the exchange reaction was monitored by conducting High Pressure Liquid Chromatography Cation Exchange (HPLC-CIEX; as described in Example 31) at various time points during the exchange reaction .
  • HPLC-CIEX High Pressure Liquid Chromatography Cation Exchange
  • Homodimers IgG l-2F8-F405L and IgGl-7D8-K409R were mixed in the molar ratio 1 : 1 at a concentration of 1 mg/mL each .
  • the sample was placed in the autosampler of the H PLC, prewarmed at 25°C.
  • the data show that bispecific IgG was formed rather quickly and most of the homodimer was exchanged after 135 min .
  • Example 34 Generation of bispecific antibodies by 2-MEA-induced Fab-arm exchange at high antibody concentrations at various 2-MEA concentrations, temperatures and incubation times
  • the exchange process was performed using the combination of IgGl-7D8-
  • K409R x IgG l-2F8-F405L Both materials were purified with affinity chromatography using protein A. After concentration of the material to > 20 mg/mL, a successive anion exchange step was performed (in flow through mode) using HiPrep Q FF 16/10
  • the bispecific exchange was studied at final IgG concentrations of 20 mg/mL (each homodimer at a final concentration of 10 mg/mL) and 10 mg/mL (each homodimer at a final concentration of 5 mg/mL) in PBS. Separate mixtures were prepared for both IgG concentrations including 2-MEA at final concentrations of 10, 25, 50 and 100 mM . The mixtures were divided into 100 ⁇ aliquots in eppendorf tubes and stored at 15, 25 and 37°C. Separate tubes were used for different incubation times of 90 min, 5 hours and 24 hours at each temperature. The mixture was also prepared without 2-MEA for both IgG concentrations and stored at 4°C as an untreated control.
  • the 90 min and 5 hours samples were collected for desalting to remove the 2-MEA (the 90 min samples were initially put on ice to stop the exchange reaction).
  • the samples were desalted using a Zeba 96-well desalting plate (7k, cat# 89808, Thermo Fisher Scientific). The 24 hours samples were desalted separately after 24 hours incubation.
  • the top OD405 values (as determined for the 10 ⁇ g/mL concentrations in the ELISA) were used to calculate the bispecific binding in comparison to the control, which was arbitrarily set at 100%. This resulted in the percentage of controlled Fab-arm exchange (% cFAE) compared to the control as is shown in Figure 34(A)-(D) for each 2-MEA concentration.
  • HPLC-CIEX Cation Exchange
  • Example 35 Determinants at the IgGl 368 position for engagement in 2- MEA-induced Fab-arm exchange in combination with IgGl-K409R
  • Example 28 and 29 show that certain single mutations at position F405 and
  • Y407 are sufficient to enable human IgGl to engage in Fab-arm exchange when combined with IgGl-K409R.
  • Fc interface positions in the CH3 domain may also mediate the Fab-arm exchange mechanism.
  • mutagenesis of the IgGl 368 position was performed and the mutants were tested for engagement in 2-MEA-induced Fab- arm-exchange in combination with human IgGl-K409R.
  • All possible IgGl-2F8-L368X mutants (with the exception of C and P) were combined with IgGl-7D8-K409R. The procedure was performed with purified antibodies as described in Example 19.
  • Example 36 Determinants at the IgGl 370 position for engagement in 2- MEA-induced Fab-arm exchange in combination with IgGl-K409R
  • Y407 or L368 are sufficient to enable human IgGl to engage in Fab-arm exchange when combined with IgG l-K409R.
  • Fc interface positions in the CH3 domain may also mediate the Fab-arm exchange mechanism .
  • mutagenesis of the IgGl 370 position was performed and the mutants were tested for engagement in 2-MEA-induced Fab- arm-exchange in combination with human IgGl-K409R.
  • All possible IgG l-2F8-K370X mutants (with the exception of C and P) were combined with IgGl-7D8-K409R. The procedure was performed with purified antibodies as described in Example 19.
  • Example 37 Determinants at the IgGl 399 position for engagement in 2- MEA-induced Fab-arm exchange in combination with IgGl-K409R
  • Examples 28, 29, 35 and 36 show that certain sing le mutations at positions F405, Y407, L368 or K370 are sufficient to enable human IgG l to engage in Fab-arm exchange when combined with IgGl-K409R.
  • Fc interface positions in the CH3 domain may also mediate the Fab-arm exchange mechanism .
  • mutagenesis of the IgGl 399 position was performed and the mutants were tested for engagement in 2-MEA- induced Fab-arm-exchange in combination with human IgGl-K409R.
  • All possible IgGl-2F8-D399X mutants (with the exception of C and P) were combined with IgG l- 7D8-K409R. The procedure was performed with purified antibodies as described in Example 19.
  • Example 38 Determination of the condition range in which 2-MEA-induced Fab-arm exchange occurs suboptimally to discriminate between highly efficient IgGl mutants
  • 2-MEA-induced Fab-arm for four different mutant combinations (IgGl- 2F8-F405S x IgGl-7D8-K409A, IgGl-2F8-D399R x IgGl-7D8-K409G, IgGl-2F8- L368R x IgGl-7D8-K409H and IgGl-2F8-F405L x IgGl-7D8-K409R) was studied over time at 15°C and 20°C, respectively. Apart from changes in temperature, time period and antibody dilution (20, 2, 0.2 and 0.02 ⁇ g/mL) the procedure was performed as described in Example 19.
  • Example 39 Analyzing 2-MEA-induced Fab-arm exchange efficiencies of mutants at suboptimal conditions
  • IgGl-2F8 mutants at the L368, D399, F405 and Y407 were selected and subjected to Fab-arm exchange analysis with IgGl-7D8-K409A, G, H or R (based on results reported in Example 19).
  • 2-MEA-induced Fab-arm exchange was performed at 15°C for 90 min (suboptimal conditions).
  • Example 29 and 37 Two IgGl-2F8 mutants Y407Q and D399Q) that showed weak 2-MEA-induced Fab-arm exchange after incubation with IgGl-7D-K409R (Example 29 and 37) were taken along as additional negative controls and used to study whether incubation with another amino acid at the K409 position (G, H, or W) leads to a different result. Apart from a change in temperature and changes in antibody dilution (20, 2, 0.2 and 0.02 ug/mL), the procedure was performed as described in Example 19.
  • Example 40 Using the bispecific format to remove undesired agonistic activity of antagonistic c-Met antibodies converting them into a monovalent, bispecifi format
  • bivalent antibodies developed for monoclonal antibody therapy show undesirable agonistic activity upon binding to their target. This is also the case for most IgGl based antibodies targeting the receptor tyrosine kinase c-Met. These agonistic antibodies induce receptor dimerization followed by activation of several downstream signaling pathways. As a result growth and differentiation of (tumor) cells is induced.
  • monovalent antibody formats can prevent induction of receptor dimerization. Combination of an anti-c-Met antibody Fab-arm with a Fab- arm of an irrelevant antibody results in a bispecific antibody that is functionally monovalent and therefore completely antagonistic.
  • IgGl-069) or a full (IgGl-058) agonistic antibody we combined a partial- (IgGl-069) or a full (IgGl-058) agonistic antibody, with IgGl-bl2 (first described in Burton DR, et al, "Efficient neutralization of primary isolates of HIV-1 by a
  • IgGl-bl2 was regarded as an irrelevant non-binding antibody since it is raised against a viral protein (HIV-gpl20).
  • the anti-c-Met antibodies used in this example are fully human monoclonal antibodies generated in transgenic mice. IgGl-058 and IgGl-069 bind to different epitopes on c-Met.
  • the two anti-c-Met antibodies used are IgGl,K antibodies being modified in their Fc regions as further disclosed. They have the following heavy chain and light chain variable sequences.
  • Monovalent bispecific c-Met antibodies were generated by a Fab-arm exchange reaction with IgGl-058-F405L or IgGl-069-F405L and IgGl-bl2-K409R as described in Example 23 using 25mM 2-MEA. The effect of the bispecific antibody on c-Met phosphorylation was evaluated. Upon dimerization of two adjacent c-Met receptors by either the natural ligand HGF or by agonistic bivalent antibodies, three tyrosine residues (position 1230, 1234 and 1235) in the intracellular domain of c-Met are cross phosphorylated.
  • A549 cells CCL-185 obtained from ATCC, were grown in serum containing DMEM medium until 70% confluency was reached. Cells were trypsinized, washed and plated in a 6 well culture plate at l*10e6 cells/well in serum containing culture medium. After overnight incubation the cells were treated with either HGF (R&D systems; cat. 294-HG) (50 ng/mL) or the panel of antibodies (30 ⁇ g/mL) and incubated for 15 minutes at 37°C. The cells were washed twice with ice cold PBS and lysed with lysis buffer (Cell Signaling; cat. 9803) supplemented with a protease inhibitor cocktail (Roche; cat. 11836170001).
  • Cell lysate samples were stored at - 80°C. Receptor activation was determined by detection of c-Met phosphorylation on Western blot using phospho c-Met specific antibodies.
  • the proteins present in the cell lysate were separated on a 4-12% SDS-PAGE gel and transferred to nitrocellulose membrane that was subsequently stained with an antibody specific for phosphorylated c-Met (Y1234/1235) (Cell Signaling, cat: 3129).
  • Cell Signaling cat: 3129
  • As a control for gel loading total ⁇ -actin and c-Met levels were determined using anti c-Met (Cell Signaling, Cat. No. 3127) and anti ⁇ -actin (Cell Signaling, Cat. No. 4967) antibodies. Results of the Western blots are shown in Figure 41.
  • the monovalent UniBody format as used herein is an IgG4, wherein the hinge region has been deleted and wherein the CH3 region has been mutated at positions 405 and 407.
  • Western blot analysis of cells treated with the positive control HGF or agonistic antibody IgGl-058 showed a clear band at the expected height of the phosphorylated c-Met.
  • Partial agonistic antibody IgGl-069 showed less, but detectable receptor phosphorylation indicating that some cross linking of the receptor takes place.
  • both bispecific IgGl 058/bl2 and bispecific 069/bl2 antibodies did not induce c-Met phosphorylation at all, showing that the agonistic activity associated with the parent antibodies was completely absent ( Figure 41). Effect of c-Met antibodies on NCI-H44 1 proliferation in vitro
  • NCI-H441 ATCC, HTB- 174TM
  • This cell line expresses high levels of c-Met, but does not produce its ligand HGF.
  • NCI-H441 cells were seeded in a 96-wells tissue culture plate (Greiner bio-one, Frickenhausen, Germany) (5,000 cells/well) in RPMI (Lonza) without serum .
  • Anti c-Met antibody was diluted to 66,7 nM in RPMI medium without serum and added to the cells.
  • Example 41 CDC-mediated cell killing by bispecific antibodies generated by 2-MEA-induced Fab-arm-exchange between human IgGl-2F8-F405L or IgGl-7D8-F405L and IgGl-7D8-K409R
  • the CD20 antibody IgGl-7D8 can efficiently kill CD20-expressing cells by complement-dependent cytotoxicity (CDC) .
  • the EGFR antibody IgG l-2F8 does not mediate CDC on target cells expressing EGFR.
  • Both IgGl-7D8-K409R and the bispecific antibody generated by 2-MEA-induced Fab-arm-exchange between IgGl-2F8-F405L x IgGl-7D8-K409R are able to induce CDC on CD20-expressing cells (as is described in Example 26) .
  • HER2 x HER2 bispecific antibodies can deliver a cytotoxic agent into tumor cells after internalization in a generic in vitro cell-based killing assay using kappa-directed pseudomonas-exotoxin A (anti-kappa-ETA') .
  • This assay makes use of a high affinity anti-kappa domain antibody conjugated to a truncated form of the pseudomonas-exotoxin A.
  • Similar fusion proteins of antibody binding proteins IgG-binding motif from Streptococcal protein A or protein G
  • diphtheria toxin or Pseudomonas exotoxin A have previously been (Mazor Y. et al., J. Immunol.
  • anti-HER2 antibodies used in this example and the following Examples 43-45 are fully human monoclonal antibodies generated in transgenic mice. They bind to d ifferent epitopes on HER2. They are all IgGl,K antibodies being modified in their Fc regions as further disclosed. They have the following heavy chain and light chain variable sequences.
  • HER2 x HER2 bispecific antibodies were pre-incubated with the anti-kappa- ETA' before incubation with A431 cells.
  • A431 cells express ⁇ 15,000 HER2 antibodies per cell (determined via Qifi analysis) and are not sensitive to treatment with 'naked' HER2-anti bodies.
  • the optimal concentration of a nti- kappa -ETA' was determined for each cell line, i.e. the maximally tolerated dose that does not lead to induction of nonspecific cell death.
  • A431 cells (2500 cells/well) were seeded in normal cell culture medium in a 96-wells tissue culture plate (Greiner bio-one) and allowed to adhere for at least 4 hours. These cells were incubated with an anti-kappa-ETA' dilution series, 100, 10, 1, 0.1, 0.01, 0.001 and 0 ⁇ / ⁇ . in normal cell culture medium . After 3 days, the amount of viable cells was quantified with Alamarblue (BioSource International, San Francisco, US) according to the manufacturer's instruction.
  • HER2 x HER2 bispecific antibodies and HER2 monospecific antibodies pre-incubated with anti-kappa-ETA' was tested for their ability to induce cell kill .
  • A431 cells were seeded as described above.
  • a dilution series of the HER2 specific antibodies (monospecific and bispecific antibodies) was made and pre- incubated for 30 min with the predetermined concentration of anti-kappa-ETA' before adding them to the cells. After 3 days incubation at 37°C, the amount of viable cells was quantified as described above.
  • the Alamarblue signal of cells treated with anti- kappa-ETA' pre-incubated with the antibodies was plotted compared to cells treated without antibody treatment.
  • Figure 44 shows that all anti-kappa-ETA' pre-incubated H ER2 bispecific antibodies were able to kill A431 cells in a dose-dependent manner. These results demonstrate that most HER2 bispecific antibodies tested were more effective than the monospecific antibody present in the combination in this anti-kappa-ETA' assay.
  • the efficacy of bispecific antibody 005X169, 025X169 and 153X169 showed that the efficacy of a monospecific antibody which lacks activity in this in vitro kappa-directed ETA' killing, H ER2 specific antibody 169, can be increased through bispecific combination with another HER2 specific antibody.
  • Example 43 HER2 receptor downmodulation by incubation with bispecific antibodies targeting different HER2 epitopes
  • HER2 x H ER2 bispecific antibodies may bind two different epitopes on two spatially different HER2 receptors. This may allow other HER2 x H ER2 bispecific antibodies to bind to the remaining epitopes on these receptors. This could result in multivalent receptor cross-linking (compared to dimerization induced by monovalent antibodies) and consequently enhance receptor downmodulation.
  • HER2 x HER2 bispecific antibodies induce enhanced downmodulation of HER2, AU565 cells were incubated with antibodies and bispecific antibodies for three days. Total levels of HER2 and levels of antibody bound HER2 were determined.
  • AU565 cells were seeded in a 24-well tissue culture plate (100.000 cells / well) in normal cell culture medium and cultured for three days at 37°C in the presence of 10 ⁇ g/mL HER2 antibody or HER2 x HER2 bispecific antibodies. After washing with PBS, cells were lysed by incubating them for 30 min at room temperature with 25 ⁇ _ Surefire Lysis buffer (Perkin Elmer, Turku, Finland). Total protein levels were quantified using bicinchoninic acid (BCA) protein assay reagent (Pierce) following manufacturer's protocol. HER2 protein levels in the lysates were analyzed using a HER2-specific sandwich ELISA.
  • BCA bicinchoninic acid
  • HER2 protein levels in the lysates were analyzed using a HER2-specific sandwich ELISA.
  • HER2 intracellular domain antibody (Cell Signaling) was used to capture HER2 and biotinylated goat-anti-human HER2 polyclonal antibody R&D systems, Minneapolis, USA), followed by streptavidin-poly-HRP, were used to detect bound HER2.
  • the reaction was visualized using 2,2'-azino-bis 3-ethylbenzothiazoline-6-sulfonic acid (one ABTS tablet diluted in 50 ml_ ABTS buffer [Roche Diagnostics, Almere, The Netherlands]) and stopped with oxalic acid (Sigma-Aldrich, Zwijndrecht, The Netherlands). Fluorescence at 405 nm was measured on a microtiter plate reader (Biotek Instruments, Winooski, USA) and the amount of HER2 was expressed as a percentage relative to untreated cells.
  • Example 44 Colocalization of HER2 x HER2 bispecific antibodies with lysosomal marker LAMP1 analyzed by confocal microscopy
  • HER2 downmodulation assay as described in Example 43 indicated that HER2 x HER2 bispecific antibodies were able to increase lysosomal degradation of HER2.
  • confocal microscopy technology was applied.
  • AU565 cells were grown glass coverslips (thickness 1.5 micron, Thermo Fisher Scientific, Braunschweig, Germany) in standard tissue culture medium for 3 days at 37 ⁇ . Cells were pre-incubated for 1 hour with leupeptin (Sigma) to block lysosomal activity after which 10 ug/mL HER2 monospecific antibodies or HER2 x HER2 bispecific antibodies were added . The cells were incubated for an additional 3 or 18 hours at 37 °C.
  • TPI Total Pixel Intensity
  • Example 45 Inhibition of proliferation of AU565 cells upon incubation with HER2 monospecific or HER2 X HER2 bispecific antibodies
  • H ER2 bispecific antibodies were tested for their ability to inhibit proliferation of AU565 cells in vitro. Due to the high HER2 expression levels on AU565 cells ( ⁇ 1.000.000 copies per cell as determined with Qifi-kit), H ER2 is constitutively active in these cells and thus not dependent on ligand-induced heterodimerization. In a 96- wells tissue culture plate (Greiner bio-one, Frickenhausen, Germany), 9.000 AU565 cells were seeded per well in the presence of 10 ⁇ g/mL H ER2 antibody or HER2 x H ER2 bispecific antibod ies in serum-free cell culture medium. As a control, cells were seeded in serum-free medium without antibody or bispecific antibodies.
  • the amount of viable cells was quantified with Alamarblue (BioSource International, San Francisco, US) according to the manufacturer's instructions. Fluorescence was monitored using the EnVision 2101 Multilabel reader (PerkinElmer, Turku, Finland) with standard Alamarblue settings. The Alamarblue signal of antibody-treated cells was plotted as a percentage relative to untreated cells.
  • Figure 47 depicts the fluorescent intensity of Alamarblue of AU565 cells after incubation with HER2 antibodies and H ER2XHER2 bispecific antibodies.
  • Herceptin® (trastuzumab) was included as positive control and demonstrated inhibition of proliferation as described by Juntilla TT. et al. , Cancer Cell 2009; 15 : 429-440. All HER2 x HER2 bispecific antibodies were able to inhibit proliferation of AU565 cells.
  • Example 46 I n vitro and in vivo analysis of FcRn binding by bispecific IgGl antibodies and hinge-deleted IgGl bispecific antibodies containing one or two FcRn binding sites in the Fc region.
  • the present example illustrates the generation of asymmetrical bispecific molecules, i.e. molecules with different characteristics in each Fab-arm according to the invention.
  • the neonatal Fc receptor (FcRn) is responsible for the long plasma half-life of IgG by protecting IgG from degradation.
  • FcRn binds to antibody Fc regions in endosomes, where the interaction is stable in the mildly acidic environment (pH 6.0).
  • the environment is neutral (pH 7.4), the interaction is lost and the antibody is released back into the circulation.
  • the Fc region of an antibody contains 2 FcRn binding sites, one in each heavy chain at the CH2-CH3 interfaces.
  • An H435A mutation in the Fc region of the antibody abrogates binding to FcRn (Shields, R.
  • the influence of FcRn binding valency is evaluated by asymmetric bispecific IgGl molecules, containing a single FcRn binding site.
  • the additional contribution of the hinge region is evaluated by asymmetric bispecific hinge-deleted IgGl (Uni-Gl) molecules.
  • FcRn binding of bispecific IgGl or hinge-deleted IgGl (Uni-Gl) molecules containing no, 1 or 2 FcRn binding sites was measured by human and mouse FcRn ELISA.
  • Antibodies IgGl-2F8-ITL, IgGl-7D8-K409R and IgGl-7D8-K409R-H435A monospecific molecules were produced as described in example 2, 3, 4 and 5.
  • Hinge- deleted IgGl molecules Uni-Gl-2F8-ITL, Uni-Gl-7D8-K409R and Uni-Gl-7D8- K409R-H435A monospecific molecules were produced as described in example 11.
  • Bispecific IgGl molecules were generated by 2-MEA induced Fab-arm exchange between IgGl-2F8-ITL and IgGl-7D8-K409R or IgGl-7D8-K409R-H435A molecules.
  • Bispecific hinge-deleted IgGl molecules were produced by incubation of Uni-Gl-2F8- ITL with Uni-Gl-7D8-K409R or Uni-Gl-7D8-K409R-H435A.
  • Figure 48 shows the binding results of monovalent or bivalent IgGl antibodies and hinge-deleted IgGl molecules to human FcRn (A) and mouse FcRn (B) at pH 6.0 and pH 7.4. As expected, all antibodies tested, both (bispecific) IgGl and hinge- deleted IgGl molecules, do not bind efficiently to FcRn (both human and mouse) at pH 7.4.
  • FIG 48(A), pH 6.0, right panel shows the binding to human FcRn of hinge- deleted IgGl molecules (Uni-Gl). All hinge-deleted molecules are impaired in their interaction to human FcRn when compared to the control IgGl molecules (IgGl-2F8) indicating that the hinge is indeed of influence in the interaction with FcRn when evaluated in an FcRn binding ELISA. No clear effect of 2 vs 1 vs 0 FcRn interaction sites can be seen when the binding to human FcRn at pH6.0 is compared of these hinge-deleted molecules.
  • Example 47 Her2 x CD3 bispecific antibodies tested in an in vitro cytotoxicity assay
  • CD3 is a co-receptor in the T cell receptor complex expressed on mature T cells. Combination of a CD3 specific antibody Fab-arm with a tumor antigen specific antibody Fab-arm in a bispecific antibody would result in the specific targeting of T cells to tumor cells, leading to T cell mediated tumor cell lysis. Likewise, CD3 positive T cells could be targeted to other derailed cells in the body, to infected cells or directly to pathogens.
  • Her2 x CD3 bispecific antibodies were generated. Heavy and light chain variable region sequences for the Her2 specific Fab-arm were as indicated for antibody 153 and 169 in Example 42. The following heavy and light chain variable region sequences for the CD3 specific Fab-arm were used :
  • IgGl-Her2-153-K409R and IgGl-Her2-153-N297Q-K409R IgGl-Her2- 169-K409R
  • IgGl-hu-CLB-T3/4-F405L and IgGl-hu-CLB-T3/4-N297Q- F405L IgGl-YTH 12.5-F405L and IgGl-YTH 12.5-N297Q-F405L.
  • Bispecific antibodies from these Her2 and CD3 specific antibodies were generated as described in Example 11 and tested in an in vitro cytotoxicity assay using AU565 cells.
  • AU565 cells were cultured to near confluency. Cells were washed twice with PBS, and trypsinized for 5 minutes at 37°C. 12 ml_ culture medium was added to inactivate trypsin and cells were spun down for 5 min, 800 rpm. Cells were resuspended in 10 ml_ culture medium and a single cell suspension was made by passing the cells through a cellstrainer. 100 ⁇ _ of a 5xl0 5 cells/mL suspension was added to each well of a 96-well culture plate, and cells were incubated at least 3 hrs at 37°C, 5% C02 to allow adherence to the plate.
  • PBMC Peripheral blood mononuclear cells
  • Figure 49 shows that whereas control antibodies (Her2 monospecific IgG l- Herceptin, CD3 monospecific IgGl-YTH 12.5 and monospecific IgGl-huCLB-T3/4, irrelevant antigen monospecific IgGl-bl2, and CD3 x bl2 bispecific antibodies) did not induce T cell mediated cytotoxicity, bispecific (Duo) Her2 x CD3 antibodies huCLB/Her2-153, huCLB/Her2- 169, YTH 12.5/Her2-153 and YTH 12.5/Her2- 169 induced dose dependent T cell med iated cytotoxicity of AU565 cells. Bispecific antibodies containing Her2- 169 were more potent than those containing Her2- 153.

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EP11716882.3A EP2560993B1 (en) 2010-04-20 2011-04-20 Heterodimeric antibody fc-containing proteins and methods for production thereof
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MX2012012019A MX353144B (es) 2010-04-20 2011-04-20 Proteinas que contienen fc de anticuerpos heterodimericos y metodos para produccion de las mismas.
RS20241034A RS65965B1 (sr) 2010-04-20 2011-04-20 Proteini koji sadrže fc heterodimernih antitela i postupci njihove proizvodnje
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BR112012026766-3A BR112012026766B1 (pt) 2010-04-20 2011-04-20 Métodos in vitro para gerar um anticorpo igg heterodimérico, para a seleção de um anticorpo biespecífico, vetor de expressão, anticorpo igg heterodimérico, composição farmacêutica, e, uso de um anticorpo igg heterodimérico
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BR122021015749-9A BR122021015749B1 (pt) 2010-04-20 2011-04-20 Métodos in vitro para gerar uma proteína heterodimérica, para a seleção de um anticorpo biespecífico, método para produzir uma proteína heterodimérica, vetor de expressão, célula hospedeira procariótica, proteína heterodimérica, composição farmacêutica, e, uso de uma proteína heterodimérica
CA2796181A CA2796181C (en) 2010-04-20 2011-04-20 Heterodimeric antibody fc-containing proteins and methods for production thereof
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LTEPPCT/EP2011/056388T LT2560993T (lt) 2010-04-20 2011-04-20 Baltymai, kurių sudėtyje yra heterodimerinio antikūno fc, ir jų gamybos būdai
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FIEP11716882.3T FI2560993T3 (fi) 2010-04-20 2011-04-20 Heterodimeeristä vasta-ainetta FC sisältävät proteiinit ja menetelmät niiden tuottamiseksi
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ES11722423T ES2733921T3 (es) 2010-05-27 2011-05-27 Anticuerpos monoclonales contra HER2
CA2800785A CA2800785C (en) 2010-05-27 2011-05-27 Monoclonal antibodies against her2
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CN202210148377.6A CN114805583A (zh) 2010-05-27 2011-05-27 针对her2的单克隆抗体
IL299365A IL299365A (en) 2010-05-27 2011-05-27 Monoclonal antibodies against 2HER
CN201180036934.5A CN103154035B (zh) 2010-05-27 2011-05-27 针对her2的单克隆抗体
CA3051311A CA3051311A1 (en) 2010-05-27 2011-05-27 Monoclonal antibodies against her2
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PCT/EP2011/058779 WO2011147986A1 (en) 2010-05-27 2011-05-27 Monoclonal antibodies against her2
EP19168254.1A EP3539988A3 (en) 2010-05-27 2011-05-27 Monoclonal antibodies against her2
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US13/700,341 US9862769B2 (en) 2010-05-27 2011-05-27 Monoclonal antibodies against HER2
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EP24214055.6A EP4520771A3 (en) 2011-04-20 2012-04-20 Bispecifc antibodies against her2
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IL223162A IL223162A0 (en) 2010-05-27 2012-11-20 Monoclonal antibodies aganist her2
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