WO2016000813A1 - Anti-tnfa antibodies with ph-dependent antigen binding - Google Patents
Anti-tnfa antibodies with ph-dependent antigen binding Download PDFInfo
- Publication number
- WO2016000813A1 WO2016000813A1 PCT/EP2015/001296 EP2015001296W WO2016000813A1 WO 2016000813 A1 WO2016000813 A1 WO 2016000813A1 EP 2015001296 W EP2015001296 W EP 2015001296W WO 2016000813 A1 WO2016000813 A1 WO 2016000813A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- seq
- adalimumab
- antigen binding
- antibody
- mutated
- Prior art date
Links
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- 125000000151 cysteine group Chemical group 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<text dominant-baseline="central" text-anchor="start" x='270.283' y='127.421' style='font-size:8px;font-style:normal;font-weight:normal;fill-opacity:1;stroke:none;font-family:sans-serif;fill:#4284F4' ><tspan>NH</tspan><tspan style='baseline-shift:sub;font-size:6px;'>2</tspan><tspan></tspan></text>
<text dominant-baseline="central" text-anchor="start" x='234.026' y='160.784' style='font-size:8px;font-style:normal;font-weight:normal;fill-opacity:1;stroke:none;font-family:sans-serif;fill:#4284F4' ><tspan>N</tspan></text>
<text dominant-baseline="central" text-anchor="middle" x='206.047' y='218.307' style='font-size:8px;font-style:normal;font-weight:normal;fill-opacity:1;stroke:none;font-family:sans-serif;fill:#4284F4' ><tspan>N</tspan></text>
<text dominant-baseline="central" text-anchor="end" x='96.799' y='205.88' style='font-size:8px;font-style:normal;font-weight:normal;fill-opacity:1;stroke:none;font-family:sans-serif;fill:#E84235' ><tspan>O</tspan></text>
<text dominant-baseline="central" text-anchor="start" x='103.676' y='165.101' style='font-size:8px;font-style:normal;font-weight:normal;fill-opacity:1;stroke:none;font-family:sans-serif;fill:#4284F4' ><tspan>NH</tspan></text>
<text dominant-baseline="central" text-anchor="end" x='27.8853' y='95.1518' style='font-size:8px;font-style:normal;font-weight:normal;fill-opacity:1;stroke:none;font-family:sans-serif;fill:#E84235' ><tspan>HO</tspan></text>
<text dominant-baseline="central" text-anchor="start" x='63.4865' y='85.7009' style='font-size:8px;font-style:normal;font-weight:normal;fill-opacity:1;stroke:none;font-family:sans-serif;fill:#E84235' ><tspan>O</tspan></text>
<text dominant-baseline="central" text-anchor="end" x='44.2547' y='167.259' style='font-size:8px;font-style:normal;font-weight:normal;fill-opacity:1;stroke:none;font-family:sans-serif;fill:#E84235' ><tspan>HO</tspan></text>
<text dominant-baseline="central" text-anchor="start" x='67.2249' y='198.588' style='font-size:8px;font-style:normal;font-weight:normal;fill-opacity:1;stroke:none;font-family:sans-serif;fill:#E84235' ><tspan>O</tspan></text>
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<path class='bond-26' d='M 14.7618,25.7954 L 16.7807,23.9265' style='fill:none;fill-rule:evenodd;stroke:#E84235;stroke-width:2px;stroke-linecap:butt;stroke-linejoin:miter;stroke-opacity:1' />
<path class='bond-28' d='M 17.8553,48.6072 L 15.0635,47.7424' style='fill:none;fill-rule:evenodd;stroke:#3B4143;stroke-width:2px;stroke-linecap:butt;stroke-linejoin:miter;stroke-opacity:1' />
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<path class='bond-31' d='M 39.4136,61.616 L 46.0844,63.6822' style='fill:none;fill-rule:evenodd;stroke:#3B4143;stroke-width:2px;stroke-linecap:butt;stroke-linejoin:miter;stroke-opacity:1' />
<path class='bond-31' d='M 40.8275,60.5917 L 45.497,62.0381' style='fill:none;fill-rule:evenodd;stroke:#3B4143;stroke-width:2px;stroke-linecap:butt;stroke-linejoin:miter;stroke-opacity:1' />
<text dominant-baseline="central" text-anchor="end" x='54.018' y='40.9231' style='font-size:2px;font-style:normal;font-weight:normal;fill-opacity:1;stroke:none;font-family:sans-serif;fill:#4284F4' ><tspan>N</tspan></text>
<text dominant-baseline="central" text-anchor="end" x='57.5968' y='29.369' style='font-size:2px;font-style:normal;font-weight:normal;fill-opacity:1;stroke:none;font-family:sans-serif;fill:#4284F4' ><tspan>N</tspan></text>
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 OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Classifications
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/241—Tumor Necrosis Factors
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6845—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
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- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
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- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
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- C07K2317/72—Increased effector function due to an Fc-modification
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- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
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- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
Abstract
Description
Anti-TNFa antibodies with pH-dependent Antigen Binding
Field of the Invention
The invention relates to anti-TNFa antibodies which are engineered to exhibit a pH-sensitive antigen binding. The invention is preferably directed to anti-TNFa antibody adalimumab (Humira®) or biologically active variants and fragments thereof, wherein the original adalimumab antibody or variant or fragment thereof is engineered by modifications of amino acid sequence within the variable regions. Specifically, the invention relates to adalimumab or biologically active variants or fragments thereof, wherein the CDR domains are modified by replacing one or more amino acid residues by histidine residues.
The resulting modified anti-TNFa antibodies elicit improved pharmacokinetic properties with improved antigen-mediated IgG clearance and extended over-all serum half life.
Background of the Invention
It is believed that therapeutic antibodies (mAbs) at least offer important treatment options for many diseases like inflammatory, autoimmune or oncological disorders. In 2012 there were 40 FDA-approved mAbs on the US market against various targets in oncology and antiinflammatory disorders with ~ 38.5% share within the biologies market. Sales of -$24.6 billion manifest the role of therapeutic antibodies as highest earning category of all biologies (Aggarwal, 2009, Aggarwal, 2014). For therapeutic antibodies different biological outcomes are determined by the interaction profiles with four classes of naturally occurring interaction partners: antigen, neonatal Fc- receptor (FcRn), Fc-receptors (FcyRs), and factors of the complement system (Chan and Carter, 2010). Several strategies have been reported to optimize antibodies that aim for additional or improved functions and specificities. (Beck et al, 2010). Within antibodies there are two structural features that can be addressed for engineering. First, the variable fragment (Fv) that mediates interaction with the antigen, second the constant fragment (Fc) that is involved in antibody recycling or mediates interactions with immune cells.
For different antigens (e.g. cytokines and growth factors) there are multiple mechanisms of action, e.g. blocking of soluble ligands thereby preventing the interaction to its corresponding receptor or blocking of the receptor itself. (Chan and Carter, 2010). A lot of effort has been invested on improving functions towards Fv-engineering that is often valued by increasing specificity and/or binding affinity to respective antigens (Beck et al, 2010). One strategy to elevate antibody efficacy is to enhance the Fv - antigen interaction by affinity maturation approaches. Herein the use of display technologies for screening molecule libraries allows isolation of variants that exhibit superior affinity.
The constant fragment (Fc) and its linked properties can be modulated with altered outcomes for immunity or antibody recycling. Prominent examples for altered Fc-mediated immune functions are enhanced antibody-dependent cellular cytotoxicity (ADCC) and complement- dependent cytotoxicity (CDC) that have been addressed to enhance antibody efficacy and to reduce the dosages.
Further strategies have been explored including direct and indirect arming of antibodies or modulation of specificities within multivalent antibodies (Carter 2011). One important aspect of Fc-function corresponds to its critical role in antibody recycling that determines the long serum half life of human immunoglobulin 1 (lgG1). After cellular absorbtion via fluid phase pinocytosis, the Fc-portion of an lgG1 interacts in a pH-dependent manner with the neonatal Fc-receptor (FcRn) that leads to antibody capture in the acidified endosome (Kuo and Aveson, 2011). From there, antibodies are recycled back to the circulation and therefore can be protected from intracellular catabolism. Different mutational Fc-species with enhanced FcRn binding affinity were generated and tested for increased recycling rates with up to 4-fold extended serum half-life in cynomolgus studies by substituting three amino acids (Dall'Acqua et al, 2006).
Although most antibodies demonstrate highly efficient antigen blocking, there are drawbacks that are not fully addressed in the development process of therapeutic antibodies:
> In many therapeutic antibodies the antigen-binding sites bind to only one antigen molecule during the antibody's lifetime in plasma (Igawa et al, 2010).
> The dosing and frequency of antibody injections depends on the antigen synthesis rate between two injections as antigens are usually produced continuously in vivo (Igawa et al, 2010).
High production costs & administration of large quantities of antibodies:
Tocilicumab therapy: 8 mg/kg/month by i.v. (Maini et al, 2006),
Adalimumab therapy: 40 mg every other week ($19,272 / per person / per year (Schabert et al. 2013).
> When antibodies bind soluble targets "antibody buffering" effects can occur in which the degradation of the antigen is prevented while being bound to the antibody. A pool of free antigen establishes from reversible dissociation of the antigen-antibody complex and therefore prolongs the in vivo persistence (O'Hear and Foote, 2005) / Finkelman et al, 1993)
Considering these drawbacks of therapeutic antibodies, there is a need for more efficient molecules that produce therapeutic responses without high dosing and/or frequent administration (Chapparo-Riggers et al, 2012).
One possibility to achieve these goals is the specific engineering of the variable and optionally the constant region of a new or well established and approved antibody. One approach is to develop antibodies that exhibit pH-sensitive antigen binding. It has been shown that rational or combinatorial incorporation of histidines in the binding interfaces of antibodies and other proteins (Sarkar et al., 2002, Chaparro-Riggers et al., 2012, Ito et al., 1992, Igawa et al., 2010, Igawa et al., 2013, Murtaugh et al., 2011 , Gera et al., 2012) can be commonly used to engineer pH-dependent binding. The basis for the pH-sensitive binding arises from the histidine's sensitivity to get protonated as a result of lowered pH-values in the microenvironment. More in detail, the histidines need to undergo a pKa-change upon binding in order to get protonated in a physiological pH-range (Murtaugh et al., 2011). Protonation of histidine side chains in binding-interfaces can alter electrostatic interactions or may induce conformational changes that lead to pH-dependent differences in binding affinity (Gera et al., 2012). Balanced electrostatic and non-electrostatic components of the binding equilibrium determine the sensitivity of binding (Murtaugh et al., 2011). Incorporation of pH-sensitivity into the antigen binding site can increase the number of antigen-binding cycles. Herein, pH-dependent antibodies bind with similar high or reduced sufficient affinity to their antigens at plasma pH (pH 7.4) and show decreased binding at acidic pH (pH 6) (Chaparro-Riggers et al., 2012, Igawa et al, 2010) resulting in a faster and increased dissociation of the antibody from its antigen binding site within the acidic endosome, thereby enabling recycling back to the plasma and reducing antigen-mediated clearance.
During the FcRn-mediated recycling (Fig.1 a) of conventional antibodies that bind soluble targets, the antibody-antigen complex is recycled back to the extracellular space through the endosomal trafficking pathway (Roopenian and Akilesh, 2007). In contrast, pH-sensitive antibodies (Fig.1 b) release their antigen from the antibody-antigen complex during the endosomal acidification (pH <6.5) (Roopenian and Akilesh, 2007). As a result the free antibody gets recycled to the circulation whereas the antigen enters the degradative pathway (Chaparro-Riggers et al., 2012, Igawa et al, 2010). The pH-sensitive binding therefore enables the antibody to interact with another antigen and allows the neutralization of multiple antigen molecules per antibody molecule. PH-sensitivity can also increase the half-life of antibodies that address membrane associated targets and internalize and degrade upon e.g. receptor binding. Herein pH-sensitivity can lead to increased half-life, when the antibody gets released during the endosomal acidification.
Several different strategies were published that aim for the engineering of pH-switches in proteins. Histidine (His) scanning by which every single amino acid residue (e.g. within the CDR regions) is mutated to His allows the characterization of single substitution variants and identification of effective mutations. Creation of new variants by combining these substitutions can result in enhanced pH-dependent binding (Murtaugh et al., 2011 , Chaparro-Riggers et al., 2012, Igawa et al, 2010). Identification of residues that may contribute to pH-sensitivity upon replacement with histidines by structure-based modeling can help to minimize effort & time that is needed during the histidine scanning approach. Crystal structures are required in order to have a precise idea of residues that are critical for binding and the rational design of pH- switches (Sarkar et al., 2002). Combinatorial histidine scanning library approaches require in vitro screening technologies (e.g. phage display or yeast display) to isolate pH-sensitive variants from a large molecule library. Murtaugh and colleagues designed a llama VHH antibody library by using oligonucleotide-directed mutagenesis thereby allowing every residue within the binding interface to sample both histidine residues and wild-type residues of the parental VHH antibody. Towards screening of a M13-phage display library (diversity ~ 1012) isolated variants showed KDs between 35-91 nM at pH 7.4 and a ~10'fold decrease in binding affinity at pH 5.4 (Murtaugh et al. 2011).
Since the recycled free antibody is capable of binding to another antigen, pH-dependent antigen binding would enable a single antibody molecule to repeatedly bind to multiple antigens, in contrast to the conventional approach in which a single antibody can bind to antigen only once.
Therefore, it is a general need to make available antibodies which are more effective with respect to their plasma and serum concentration, which can be achieved by installing pH sensitivity with respect to different cellular action sites of the therapeutic antibody. Summary of the Invention
The invention provides mutated forms of anti-TNFa antibody adalimumab (Humira®), wherein the mutation consists of one or more substitutions of amino acid residues of the original, non- mutated antibody adalimumab by histidine residues in the complementary determining regions (CDRs) of the heavy and / or light chain variable domains of the antibody. The introduction of histidine residues at defined position in some of the CDRs of adalimumab renders the original antibody much more pH-sensitive or pH-dependent compared to the non- mutated antibody. Interestingly, although the histidine-mutated antibody undergoes a significant loss of binding affinity (up to factor 10 and more of KD) the mutated antibody of the invention is therapeutically significantly more effective compared to its parental non-mutated version, resulting in the possibility to reduce the antibody dosage or the antibody dosing intervals und thus the treatment costs significantly.
It has been shown by the invention that the successful introduction of histidine residues according to the invention by replacement of original amino acid residues in the CDRs of adalimumab or biologically active variants and fragments thereof, does not obey routine rules or mental considerations in view of the desired results regarding degree of pH-sensitivity and binding affinity.
Thus, it was found that histidine-mutated versions of adalimumab are specifically
therapeutically effective, if the pH dependent antigen binding results in an antigen
dissociation rate (KdiS) ratio pH 6 / pH 7 which is 5 - 20 fold higher compared to the respective Kdis rate ratio of non-mutated adalimumab, and the binding affinity of the mutated adalimumab is 1 - 25%, preferably 1 - 15%, more preferably 2 - 12% of the binding affinity of the non- histidine mutated adalimumab. Therefore, the invention provides a human anti-TNFa antibody or an antigen binding fragment thereof with pH dependent antigen binding comprising the light and heavy chain variable regions of human antibody adalimumab or a variant thereof with same or similar biological activity, wherein at least one of the CDR domains of the light and / or the heavy chain variable regions is mutated by replacement of one or more amino acids within said CDR domains by a histidine residue, thus generating a mutated adalimumab or adalimumab variant eliciting a pH dependent antigen binding with an antigen dissociation rate (KdiS) ratio pH 6 / pH 7 measured by Bioayer Interferometrie (Octet Red), or other comparable methods, which is at least 5, 10, 15 or 10 fold higher compared to the respective Kdis rate ratio of non- mutated adalimumab. In a further embodiment, the invention provides a respective mutated adalimumab, wherein the mutated antibody or antigen binding fragment thereof has a reduced antigen binding affinity, which is preferably 1 - 15%, respectively 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13% 14% or 15% of the binding affinity of non-mutated adalimumab. The invention provides human anti-TNFa antibodies deriving from adalimumab, wherein one or more original amino acid residues within the CDRs of parental adalimumab were replaced by histidine residues. Interestingly, the most effective histidine-mutated versions of adalimumab comprise histidine mutations within the variable light chain, especially in the CDR1 and CDR3 domains of the light chain. Preferred histidine-mutated adalimumab versions include further or independently a histidine-mutated CDR3 heavy chain.
Thus the invention provides mutated adalimumab or antigen binding fragment thereof comprising a CDR3 heavy chain sequence selected from the group consisting of:
VSYHSTASSLDY (SEQ ID NO: 12)
VSYLSTAHHLDY (SEQ ID NO: 13)
VSYHSTAHHLDY (SEQ ID NO: 14)
VHYHSTASSLDY (SEQ ID NO: 3D , and
VX1YX2STAX3X4LDY (SEQ ID NO: 40) , wherein Xi
or H, and X4 is S or H, and wherein at least Xi or X2 or X3 or X4 is H. The invention further provides mutated adalimumab or antigen binding fragment thereof comprising a CDR3 light chain sequence selected from the group consisting of:
HHYHRAPYT (SEQ ID NO: 17)
QHYHRAPYH (SEQ ID NO: 18
QRHNRAPYT (SEQ ID NO: 38)
X1HYHRAPYX2 (SEQ ID NO: 19) , wherein Xi
X1X2X3X4RAPYX5 (SEQ ID NO: 41) , wherein Xi
Y or H, X4 is N or H, and X5 is T or H, wherein at least Xi or X2 or X3 or X4 orX5 is H.
The invention further provides mutated adalimumab or antigen binding fragment thereof comprising a CDR1 light chain sequence selected from the group consisting of:
RASQGIRNHLA (SEQ ID NO 15) ,
RASQGIR HHA (SEQ ID NO 16,
RASQGIR X1X2A (SEQ ID NO 42 ) , wherein Xi is Y or H, X2 is L or H, wherein at least Xi or X2 is H.
The invention further provides mutated adalimumab or antigen binding fragment thereof comprising a CDR2 light chain sequence selected from the group consisting of:
AAHTLQS (SEQ ID NO: 32) In an embodiment of the invention, the histidine-mutated adalimumab or antigen binding fragment thereof comprises a CDR3 heavy chain sequence as specified above and in the claims, and a CDR1 light chain sequence as specified above and in the claims.
In a further embodiment of the invention, the histidine-mutated adalimumab or antigen binding fragment thereof comprises a CDR3 heavy chain sequence, and a CDR3 light chain
sequence as specified above and in the claims.
In a further embodiment of the invention, the histidine-mutated adalimumab or antigen binding fragment thereof comprises a CDR3 heavy chain sequence, a CDR2 light chain seguence, and a CDR3 light chain seguence as specified above and in the claims. In another embodiment of the invention, the histidine-mutated adalimumab or antigen binding fragment thereof comprises a CDR3 heavy chain sequence, a CDR1 light chain sequence, and a CDR3 light chain seguence as specified above and in the claims.
It was found by the inventors that preferable versions of histidine-mutated adalimumab comprise one of the following light chain variable regions:
(i)
DIQMTQSPSS LSASVGDRVT ITCRASQGIR NHHAWYQQKP GKAPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQR Y RAPYTFGQ GTKVEIK (SEQ ID NO: 28)
ili)
DIQMTQSPSS LSASVGDRVT ITCRASQGIR NYLAWYQQKP GKAPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCHH YHRAPYTFGQ GTKVEIK (SEQ ID NO: 29) .
m
DIQMTQSPSS LSASVGDRVT ITCRASQGIR NYLAWYQQKP GKAPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQH YHRAPYHFGQ GTKVEIK (SEQ ID NO: 30) .
m
DIQMTQSPSS LSASVGDRVT ITCRASQGIR NYLAWYQQKP GKAPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQH YHRAPYTFGQ GTKVEIK (SEQ ID NO: 33) . DIQMTQSPSS LSASVGDRVT ITCRASQGIR NHLAWYQQKP GKAPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQR YNHAPYTFGQ GTKVEIK ( SEQ ID NO: 34 )
DIQMTQSPSS LSASVGDRVT ITCRASQGIR NHLAWYQQKP GKAPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQR YNRAPYTFGQ GTKVEIK ( SEQ ID NO: 35 )
i iil
DIQMTQSPSS LSASVGDRVT ITCRASQGIR NYLAWYQQKP GKAPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQR HNRAPYTFGQ GTKVEIK ( SEQ ID NO: 36)
i iil)
DIQMTQSPSS LSASVGDRVT ITCRASQGIR NHLAWYQQKP GKAPKLLIYA AHTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQR YNRAPYTFGQ GTKVEIK ( SEQ ID NO: 37 )
DIQMTQSPSS LSASVGDRVT ITCRASQGIR NHXiAWYQQKP GKAPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQR YNRAPYTFGQ GTKVEIK (SEQ ID NO: 20), wherein Xi is L or H,
(x)
DIQMTQSPSS LSASVGDRVT ITCRASQGIR NYLAWYQQKP GKAPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCXiH YHRAPYXIFGQ
GTKVEIK (SEQ ID NO: 21 ) , wherein Xi is Q or H and X2 is T or H (xi)
DIQMTQSPSS LSASVGDRVT ITCRASQGIR NYLAWYQQKP GKAPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCHH YHRAPYXiFGQ
GTKVEIK ( SEQ ID NO: 22 ) , wherein Xi is T or H;
m
DIQMTQSPSS LSASVGDRVT ITCRASQGIR NYLAWYQQKP GKAPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCXiH YHRAPYHFGQ
GTKVEIK (SEQ ID NO: 23 ) , wherein Xi is Q or H; il
DIQMTQSPSS LSASVGDRVT ITCRASQGIR NHXiAWYQQKP GKAPKLLIYA
ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCX2H YHRAPYX3FGQ
GTKVEIK ( SEQ ID NO: 24 ) , wherein X1 is L or H, and X2 is Q or H and X3 is T or H; (xiv)
DIQMTQSPSS LSASVGDRVT ITCRASQGIR NX1X2AWYQQKP GKAPKLLIYA
AX3TLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCX4X5 XeXvRAPYXsFGQ GTKVEIK ( SEQ ID NO: 43), wherein Xi is Y or H, X2 is L or H, X3 is S or H, X4 is Q or H, X5 is R or H, X6 is Y or H, X7 is N or H, X8 is T or H, wherein at least Xi or X2 or X3 or t orX5 or X6 or X70rXs is H.
It was further found by the inventors that preferable versions of histidine-mutated adalimumab comprise one of the following heavy chain variable regions:
(·)
EVQLVESGGG LVQPGRSLRL SCAASGFTFD DYAMHWVRQA PGKGLEWVSA ITW SGHIDY ADSVEGRFTI SRDNAK SLY LQMNSLRAED TAVYYCAKVS YHSTASSLDY WGQGTLVTVS S ( SEQ ID NO: 25) ;
(ii)
EVQLVESGGG LVQPGRSLRL SCAASGFTFD DYAMHWVRQA PGKGLEWVSA ITWNSGHIDY ADSVEGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCAKVS YLSTAHHLDY WGQGTLVTVS S ( SEQ ID NO: 26 ) ;
(•ii)
EVQLVESGGG LVQPGRSLRL SCAASGFTFD DYAMHWVRQA PGKGLEWVSA ITWNSGHIDY ADSVEGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCAKVH YHSTASSLDY WGQGTLVTVS S ( SEQ ID NO: 3 9 ) ,
(iv)
EVQLVESGGG LVQPGRSLRL SCAASGFTFD DYAMHWVRQA PGKGLEWVSA ITWNSGHIDY ADSVEGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCAKVXi
YX2STAX3X4LDY WGQGTLVTVS S ( SEQ ID NO: 44 ) ,
wherein Xi is S or H, X2 is L or H, X3 is S or H, X4 is S or H, wherein at least Xi or X2 or X3 or X4 is H . Preferable histidine-mutated adalimumab according to the invention comprises any of the variable light chains as specified above and any one of the variable heavy chain domains as specified above.
A first preferred embodiment of the invention is a respectively histidine-mutated adalimumab comprising the variable heavy chain sequence :
EVQLVESGGG LVQPGRSLRL SCAASGFTFD DYA HWVRQA PGKGLEWVSA ITW SGHIDY ADSVEGRFTI SRDNA SLY LQMNSLRAED TAVYYCAKVS YHSTASSLDY WGQGTLVTVS S (SEQ ID NO: 25) and
the variable light chain sequence:
DIQMTQSPSS LSASVGDRVT ITCRASQGIR NHHAWYQQKP G APKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQR YNRAPYTFGQ GT VEIK (SEQ ID NO: 27) .
A second preferred embodiment of the invention is a respectively histidine-mutated adalimumab comprising the variable heavy chain sequence :
EVQLVESGGG LVQPGRSLRL SCAASGFTFD DYAMHWVRQA PGKGLEWVSA ITWNSGHIDY ADSVEGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCAKVS YLSTAHHLDY WGQGTLVTVS S (SEQ ID NO: 26) and
the variable light chain sequence:
DIQMTQSPSS LSASVGDRVT ITCRASQGIR NYLAWYQQKP GKAPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCHH YHRAPYTFGQ GTKVEIK (SEQ ID NO: 28.
A third preferred embodiment of the invention is a respectively histidine-mutated adalimumab comprising the variable heavy chain sequence :
EVQLVESGGG LVQPGRSLRL SCAASGFTFD DYAMHWVRQA PGKGLEWVSA ITWNSGHIDY ADSVEGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCAKVS YLSTAHHLDY WGQGTLVTVS S (SEQ ID NO: 26) and
the variable light chain sequence:
DIQMTQSPSS LSASVGDRVT ITCRASQGIR NYLAWYQQKP GKAPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQH YHRAPYHFGQ GTKVEIK (SEQ ID NO: 29) .
The histidine-mutated adalimumab antibodies or variants or fragments thereof can further comprise human heavy and/or light constant regions. In one embodiment they comprise a human IgG, preferably a human lgG1 (such as specified by SEQ ID NO: 11), or lgG2 heavy chain constant region.
In another embodiment of the invention they comprise human kappa light chain constant region. In another embodiment of the invention, the histidine-mutated adalimumab versions of the invention comprise a human heavy chain constant region, preferably lgG1 , wherein the Fc portion is mutated at one or more amino acid positions by replacement of the original amino acid residues by other natural amino acid residues which mediate (increase or decrease) binding of the antibody to FcRn. The histidine-mutated adalimumab antibodies of the invention can be conjugated to other molecules by recombinant fusion with other polypeptides or proteins such as cytokine, or by chemical linkage to chemical, preferably cytotoxic entities, preferably via linker molecules to form antibody-drug-conjugates (ADCs). Techniques and methods to produce such antibody fusion proteins or antibody drug conjugates are well established in the art. The invention also provides pharmaceutical compositions suitable for the treatment of inflammatory, autoimmune or cancer diseases comprising histidine-mutated anti-TNFa antibody adalimumab or a variant or an antigen binding fragment thereof, or a respective antibody-drug conjugate or an antibody cytokine fusion protein together with a
pharmaceutically acceptable carrier, diluent or excipient. The invention finally provides the therapeutic use of such histidine-mutated adalimumab or biologically effective and active variant or fragment thereof, or ADCs or fusion proteins thereof, for the manufacture of a medicament for the treatment of TNFa induced
inflammatory, autoimmune or cancer diseases, as specified in detail below.
The histidine-mutated adalimumab versions of the inventions exhibit the following
advantageous properties and functions:
> Adalimumab binding sites are no longer blocked over a long period of time upon
TNFa-binding.
> Adalimumab shows significantly improved pH-sensitive binding to the target antigen.
> The sTNFa can be released much more efficiently by histidine-mutated adalimumab in the acidified endosome during recycling via FcRn. > Upon binding to the membrane-bound target (mTNFa) initiation of receptor mediated internalization and lysosomal degradation of the mTNFa-adalimumab complex which would lead to elimination of the antibody, can be avoided or reduced.
> Improved pharmacokinetics of the TNFa-binding antibody that exhibit pH-dependent target binding
> pH-sensitive antibody variants are derived from the parental adalimumab sequence by altering the aminoacid sequences within the variable regions of the antibody.
> Incorporation of pH-sensitivity into adalimumab is established by substitutions of aminoacids of the heavy and light chain variable regions with histidines
> The pH-sensitivity of adalimumab variants corresponds to increased ratios between kinetic parameters (KD, kdis) at pH 6 / pH 7.4 in comparison to the ratios of parental adalimumab.
> In this regard the adalimumab antibodies according to the invention are enabled to neutralize the antigen multiple times
> Therefore, the therapeutic effect may be prolonged and may allow less frequent
administrations of the antibody and/or administrations at lower doses.
Details of the Invention
Tumor necrosis factor a (TNFa):
TNFa is a cytokine that plays a key role in immune responses by initiating defense responses to e.g. some bacterial infections. It acts in a complex network in normal inflammation and is also involved in lymhphoid tissue development (Tracey et al., 2008).
Many different cells produce TNFa including macrophages, T cells, mast cells and granulocytes, to name a few. TNFa is a general term that includes soluble (sTNFa) and transmembrane TNFa (mTNFa). Soluble homotrimers are released by cells after proteolytic cleavage of transmembrane TNFa (homotrimers of 26 kDa monomers) by the
metalioprotease TNF-alpha-converting enzyme (TACE) (Wajant et al., 2003). Both forms, the sTNFa or mTNFa interact with two distinct receptors, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Both receptors differ in their cellular expression profiles and signaling mechanisms. Complexity of the interaction network increases as mTNFa itself can act either as ligand or receptor to both TNF receptors (Wajant et al., 2003). During disease, high expression of TNFa triggers and mediates downstream mechanisms that can lead to chronic inflammation and pathogenesis within affected compartments (Tracey et al., 2008). Common consequences of TNFa activities in autoimmune diseases are modulation of immune cell recruitment, cell proliferation, cell death and immune regulation. Other effects like matrix degradation and osteoclastogenesis are more disease specific and may be related to different cell types in the affected tissues (Reviewed in Tracey et al., 2008, Choy & Panayi, 2001 ; Feldmann, 2002; Schottelius et al., 2004).
TNFa has a particularly important role in the regulation of pathogenic events in e.g.
rheumatoid arthritis, Crohn's disease and plaque psoriasis and rapidly induces other cytokines (e.g. IL-1 β and IL-6) (Tracey et al., 2008). In several inflammatory autoimmune diseases the positive clinical outcome upon TNFa-blockade by therapeutic anti-TNFa antibodies has corroborated the link between excessive TNFa exposition and disease pathologies (Aggawal, 2003; Tracey et al., 2008).
Adalimumab:
Adalimumab (also known by its trademark name HUMIRA® ) is a fully human 148 kDa IgGlK monoclonal antibody against TNFa that originally was developed by using phage display (Abbott Laboratories, 2014). Since market launch in 2002, adalimumab generated huge sales that achieved $4.6 billion just on the US market in 2012 (Aggarwal, 2014). Adalimumab binds to TNFa with high sub-nanomolar affinity and thereby blocks the interaction between TNFa and p55 and p75 cell surface receptors TNFR1 or TNFR2 (Abbott Laboratories, 2014).
As adalimumab binds also to mTNFa with high affinity further possible modes of action include apoptosis or cytokine suppression upon reverse signaling mechanisms and CDC or ADCC mediated cell killing (Reviewed in Tracey et al., 2008 and Horiuchi et al, 2010).
The amino acid sequences of Adalimumab (and variants thereof) and its pharmacological and therapeutic properties are disclosed, for example in WO 97/029131.
The sequences which are important in view of the present invention are listed below in detail:
Adalimumab full light chain sequence:
DIQ TQSPSS LSASVGDRVT ITCRASQGIR NYIA YQQKP GKAPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQR YNRAPYTFGQ GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDS D STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1)
Adalimumab light chain sequence, variable region (VL): DIQMTQSPSS LSASVGDRVT ITCRASQGIR NYLAWYQQKP GKAPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQR YNRAPYTFGQ GTKVEIK (SEQ ID NO: 2)
Adalimumab CDR1 sequence of VL
RASQGIRNYLA (SEQ ID NO: 3)
Adalimumab CDR2 sequence of VL
AASTLQS (SEQ ID NO: 4)
Adalimumab CDR3 sequence of VL
QRYNRAPYT (SEQ ID NO: 5)
Adalimumab full heavy chain sequence:
EVQLVESGGG LVQPGRSLRL SCAASGFTFD DYAMHWVRQA PGKGLEWVSA ITWNSGHIDY ADSVEGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCAKVS YLSTASSLDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSW TVPSSSLGTQ TYICNVNHKP SNTKVDKKVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK PKDTLMISRT PEVTCVWDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY NSTYRWSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP QVYTLPPSRD ELTKNQVSLT CLVKGFYPSD lAVEWESNGQ PENNYKTTPP VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K (SEQ ID NO: 6)
Adalimumab heavy chain sequence, variable region (VH):
EVQLVESGGG LVQPGRSLRL SCAASGFTFD DYAMHWVRQA PGKGLEWVSA ITWNSGHIDY ADSVEGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCAKVS YLSTASSLDY WGQGTLVTVS S
(SEQ ID NO: 7)
Adalimumab CDR1 sequence of VH:
DYAMH (SEQ ID NO: 8)
Adalimumab CDR2 sequence of VH:
AITWNSGHIDYADSVEG (SEQ ID NO: 9)
Adalimumab CDR3 sequence of VH:
VSYLSTASSLDY (SEQ ID NO: 10)
Adalimumab human heavy chain lgG1 constant region:
ASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSW TVPSSSLGTQ TYICNVNHKP SNTKVDKKVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK PKDTLMISRT PEVTCVWDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY NSTYRWSVL TVLHQDWL G KEYKC VSNK ALPAPIEKTI SKAKGQPREP QVYTLPPSRD ELTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP VLDSDGSFFL YSKLTVDKSR QQG VFSCS VMHEALHNHY TQKSLSLSPG K (SEQ ID NO: 11)
Adalimumab is approved in many countries for a couple of therapeutic treatments, such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and Crohn's disease.
Therefore, the histidine-mutated adalimumab versions according to the invention are also applicable in the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and Crohn's disease, but also in the treatment of other diseases which are induced or triggered by TNFa. This may include autoimmune disorders as well as cancer diseases.
Selection of antibodies:
Selection of suitable anti-TNFa antibody versions of adalimumab and fragments thereof according to the invention may be achieved by well established and known methods and techniques in the art, such as by histidine substitution via page display libraries or from combinatorial histidine substitution libraries by yeast surface display. Details are provided in the Example section.
Terms, Definitions, Details
The term "antibody" or "immunoglobulin" is used according to the invention in the broadest sense and specifically covers intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g. bispecific antibodies) formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity. Depending on the amino acid sequence of their constant regions, intact or whole antibodies can be assigned to different classes. There are five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into "subclasses" (isotypes), e.g., lgG1, lgG2, lgG3, lgG4, IgA, and lgA2.
Preferred major class for antibodies according to the invention is IgG, in more detail lgG1 and lgG2, most preferably lgG1.
"Antibody fragments" according to the invention comprise a portion of an intact antibody, preferably comprising the antigen-binding or variable region thereof. Examples of antibody fragments include Fab, Fab', F(ab')2, Fv and Fc fragments, diabodies, linear antibodies, single-chain antibody molecules; bispecific and multispecific antibodies formed from antibody fragment(s).
A "whole or complete" antibody according to the invention is an antibody which comprises an antigen-binding variable region as well as a light chain constant domain (CL) and heavy chain constant domains, CH1, CH2 and CH3.
A "Fc" region of an antibody according to the invention comprises, as a rule, a CH2, CH3 and the hinge region of an lgG1 or lgG2 antibody major class. The hinge region is a group of about 15 amino acid residues which combine the CH1 region with the CH2-CH3 region.
A "Fab" fragment also contains the constant domain of the light chain and the first constant domain (CH1) of the heavy chain and has one antigen-binding site only.
A "Fab' " fragments differ from Fab fragments by the addition of a few residues at the carboxy-terminus of the heavy chain CH1 domain including one or more cysteine residues from the antibody hinge region.
A "F(ab')2' antibody according to this invention is produced as pairs of Fab' fragments which have hinge cysteines between them.
"Single-chain Fv" or "scFv" antibody fragments according to the invention comprise the V, and V, domains of antibody, wherein these domains are present in a single polypeptide chain. Preferably, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen binding. The "variable domain" of an antibody according to the invention comprises the framework regions (usually FR1 to FR4) as well as the CDR domains (usually CDR1 , CDR2 and CDR3) which are designated as "hypervariable regions".
The term "hypervariable region" or "CDR' when used herein refers to the amino acid residues of an antibody which are responsible for antigen-binding. The hypervariable region generally comprises amino acid residues from a "complementarity determining region" or "CDR" (e.g. residues 24-34 (L1), 50-56 (L2) and 89-97 (L3) in the light chain variable domain and 31-35 (H1), 50-65 (H2) and 95-102 (H3) in the heavy chain variable domain; and/or those residues from a "hypervariable loop" (e.g. residues 26-32 (L1 ), 50-52 (L2) and 91-96 (L3) in the light chain variable domain and 26-32 (H1), 53-55 (H2) and 96-101 (H3) in the heavy
chain variable domain; Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). If not otherwise pointed out, the amino acid positions within the antibody molecules according to this invention are numbered according to Kabat.
"Framework Region" or "FR" residues are those variable domain residues other than the hypervariable region residues as herein defined. "Antibody variants" according to the invention include antibodies that have a modified amino acid sequence compared to the parental antibody but have same or changed binding affinity to the targeted antigen. Antibody variants differ from the parental antibody by replacement or deletion or addition of one or more amino acid residues at specific positions within the variable domains, including the CDR domains, and or the constant regions of the antibody, in order to modify certain properties of the antibody, such as binding affinity and/or receptor functions, like ADCC, FcRn binding and the more. The histidine-mutated antibodies of this invention without further modifications are not designated as "antibody variants" according to this invention. Antibody variants according to the invention exhibit a sequence homology of 80 - 99% compared to the parental antibody, preferably 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% and 99%, dependent on the specific location of the amino acid residue to be replaced, deleted or added. Antibody variants of adalimumab are, for example, disclosed in
The term "fusion protein" refers to a natural or synthetic molecule consisting of one ore more biological molecules as defined above, wherein two or more peptide- or protein-based (glycoproteins included) molecules having different specificity are fused together optionally by chemical or amino acid based linker molecules. The linkage may be achieved by C-N fusion or N-C fusion (in 5'→ 3' direction), preferably C-N fusion. A fusion protein according to the invention is said fusion of an antibody or antibody variant of this invention fused to another protein or polypeptide, preferably a cytokine.
The term "antibody-drug conjugate (ADC)" refers according to the invention to an
immunoconjugate composed of an antibody, preferably complete antibody, according to the invention, and a preferably chemical cytotoxic agent. The components are chemically attached to each other by specific linkers. The antibody of the invention (preferably within its heavy chain constant region) may be modified at one or more amino acid positions in order to create a suitable linkage to the linker and/or the cytotoxic payload drug. Method and techniques to generate such ADCs are well known in the art.
The term "Fc receptor" means, according to the invention, receptors for the Fc region of immunoglobulins (FcRs) that link humoral responses to cellular activities within the immune system. Based on their function, two general groups of FcR can be distinguished: those expressed predominantly by leucocytes that trigger antibody effector functions and those that primarily mediate transport of immunoglobulins across epithelial or endothelial surfaces.
ADCC is triggered through interaction of target-bound antibodies (belonging to IgG or IgA or IgE classes) with certain Fc receptors (FcRs). ADCC involving human lgG1 is highly dependent on the glycosylation profile of its Fc portion and on the polymorphism of Fey receptors. The term "FcRn" means the specific neonatal Fc receptor, which binds binds IgG at acidic pH of (<6.5) but not at neutral or higher pH. The receptor is responsible for extending half-life of IgG antibodies in serum.
The term "cytokine" is a generic term for proteins released by one cell population which act on another cell as intercellular mediators. Examples of such cytokines are lymphokines, monokines, and traditional polypeptide hormones, such as vascular endothelial growth factor (VEGF); integrin; thrombopoietin (TPO); nerve growth factors such as NGFB; platelet- growth factor; transforming growth factors (TGFs) such as TGFa and TGFB; erythropoietin (EPO); interferons such as IFNa, IFNB, and IFNy; colony stimulating factors such as M-CSF, GM-CSF and G-CSF; interleukins such as IL-1, IL-1a, IL-2, IL-3, IL- , IL-5, IL-6, IL-7, IL-8, IL- 9, IL-10, IL-11 , IL-12; and TNF-a or TNF-β.
The term "biologically/functionally effective" or "therapeutically effective (amount)" refers to a drug / molecule which causes a biological function or a change of a biological function in vivo or in vitro, and which is effective in a specific amount to treat a disease or disorder in a mammal, preferably in a human.
The term "pharmaceutical treatment' means a variety of modalities for practicing the invention in terms of the steps. For example, the agents according to the invention can be administered simultaneously, sequentially, or separately. Furthermore, the agents can be separately administered within one or more time intervals between administrations. Therapeutic compositions of the present invention contain a physiologically tolerable carrier together with the relevant agent as described herein, dissolved or dispersed therein as an active ingredient.
As used herein, the term "pharmaceutically acceptable" refers to compositions, carriers, diluents and reagents which represent materials that are capable of administration to or upon a mammal without the production of undesirable physiological effects such as nausea, dizziness, gastric upset and the like. The preparation of a pharmacological composition that contains active ingredients dissolved or dispersed therein is well understood in the art and need not be limited based on formulation. Typically, such compositions are prepared as injectable preparation either as liquid solutions or suspensions, however, solid forms suitable for solution, or suspensions, in liquid prior to use can also be prepared. The preparation can also be emulsified. The active ingredient can be mixed with excipients which are
pharmaceutically acceptable and compatible with the active ingredient and in amounts suitable for use in the therapeutic methods described herein. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof. In addition, if desired, the composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like which may enhance the effectiveness of the active ingredient. The therapeutic composition of the present invention can include pharmaceutically acceptable salts of the components therein. The histidine-mutated adalimumab versions according to the invention are suitable for the treatment of the same disorders and diseases as the approved and marketed non-histidine mutated adalimumab (HUMIRA®), which are rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis and chronic plaque psoriasis, wherein the drug is preferably administered by subcutaneous injection. Like the marketed drug, the histidine-mutated adalimumab according to the invention can be used alone or in combination with other drugs which support the therapy, such as
methotrexate, DMARDS, glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics.
The standard dose regimen of HUMIRA® is usually 40mg every week as single dose. The histidine-mutated adalimumab versions according exhibit, as pointed out earlier, a
significantly stronger pH-dependency as HUMIRA® , and thus can be administered in doses which correspond only 10 - 90%, in detail 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% and 90%, of the recommended dose of HUMIRA®, dependent on the respective KdiS values of the used histidine-mutated adalimumab versions. Short Description of the Figures:
Figure 1: Proposed differences between a) conventional and b) pH-dependent antibody on soluble antigen binding (Modified from: Igawa et al., 2010).
Figure 2: Adalimumab amino acid sequences of the variable regions. The complementary determining regions are highlighted with red boxes, a) Variable region of the heavy chain (VH). b) Variable region of the light chain (VL). Figure 3: Aligned protein sequences of seven unique VH variants with the parental VH. Unique sequences were isolated from the heavy chain library approach after three rounds of screening. Parental VH sequence is shown on top and residues that vary from the parental VH are highlighted for every variant. Figure 4A: First part of protein sequence alignment (1-3 parts) of the parental VL and 38 unique VL variants that were isolated from the light chain library after three rounds of screening. Parental VL sequence is shown on top and residues that vary from the parental VL are highlighted for every variant.
Figure 4B: Second part of protein sequence alignment (1-3 parts) of the parental VL and 38 unique VL variants that were isolated from the light chain library after three rounds of screening. Parental VL sequence is shown on top and residues that vary from the parental VL are highlighted for every variant.
Figure 4C: Third part of protein sequence alignment (1-3 parts) of the parental VL and 38 unique VL variants that were isolated from the light chain library after three rounds of screening. Parental VL sequence is shown on top and residues that vary from the parental VL are highlighted for every variant.
Figure 5: Octet Red sensorgrams of adalimumab and three variants with pH-dependent binding to rhTNFa. Association was done with rhTNFa concentrations ranging between 0.26 nM - 2 nM at pH 7.4 and dissociation was carried out at pH 7.4. Kinetics binding constants were determined through global fitting using Octet 8.0 Software.
Figure 6: Octet Red sensorgrams of adalimumab and three variants with pH-dependent binding. Association was done with rhTNFa concentrations ranging between 0.26 nM - 2 nM at pH 7.4 and dissociation was carried out at pH 6. Off-rates were determined for PSV#1 , PSV#2 and PSV#3 through local partial fitting using Octet 8.0 Software. Off-rates for adalimumab were generated by using global fitting.
Figure 7: Octet Red sensorgrams of adalimumab and three variants with pH-dependent binding (PSV#1 , PSV#2, PSV#3). Adalimumab shows fast association of rhTNFa and maintains tight binding during the dissociation step at pH 6. In contrast, pH-dependent binding variants show reversible rhTNFa binding at pH 7.4 after fast release of rhTNFa during the dissociation step at pH 6. Association to 13 nM rhTNFa was measured for 200 sec and dissociation carried out for 400 sec. After two binding cycles the last dissociation step was done at pH 7.4, showing slow release of rhTNFa. REFERENCES
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Example 1: Selection of pH-sensitive anti-TNFa antibodies derived from adalimumab
Selection of anti-TNFa antibody fragments from combinatorial histidine substitution libraries by yeast surface display: Based on the heavy and light chains of adalimumab, two antibody libraries were synthesized by Geneart, Regensburg by using pre-assembled trinucelotides building blocks. During the synthesis either parental or histidine residues were sampled whereby sampling of histidines was restricted to the complementary determining regions (CDRs) of the heavy and light chains. Most adalimumab library members carried three histidine residues that were spread over all three CDRs (Fig. 2) but variants were also synthesized that carried more or less histidine substitutions (ranging between 0 to ~20). Theoretical diversities: Heavy chain library ~10'000 variants, light chain library ~3000 variants.
Both libraries were separately subcloned into plasmid vectors by gap-repair cloning in the EBY100 yeast strain that allows covalent yeast surface display of antibody Fab-fragments (Boder and Wittrup, 1997). Corresponding parental chains were paired with the heavy or light chain libraries and the two resulting libraries were separately screened by fluorescence activated cell sorting (FACS). Cells that carried pH-sensitive adalimumab variants were subsequently enriched over three rounds of screening by applying a specific staining & selection strategy (not explained here).
Fab-fragments were selected that do reversible high affinity (KD within sub nanomolar ranges) binding to recombinant human TNFa (rhTNFa) at pH 7.4, once after rhTNFa has been released within 30 minutes at pH 6. After three rounds of screening for variants that bind to rhTNFa in pH-dependent manner, sequence analysis of isolated single clones revealed variants that carried specific histidine substitutions patterns (shown in Figure 3 & 4). One mutational hot-spot was identified within the CDR3 region of the heavy chain sequence data set. Two mutational hot-spots were identified within CDR-L1 and CDR-L3 regions of the light chain sequence data set. Only abundant heavy and light chain variants (occurrence within analyzed sequence set: N>1) were selected for further processing & characterization, resulting in eight light chain and three heavy chain candidates shown in Table 1 and Table 2: Table 1. Three abundant (N>1) heavy chain sequences within 38 isolated single clones after three rounds of screening.
Table 2. Eight abundant (N>1) light chain sequences within 98 isolated single clones after three rounds of screening.
Variable regions of abundant VH/VL variants as well as parental adalimumab sequences were cloned into vectors that allow expression of full length IgGl molecules in mammalian cells (HEK293 & Expi293). All possible combinations of heavy and light chain variants were co-expressed in mammalian cells. Herein 24 heavy chain and light chain variant combinations were expressed as well as 11 IgG species that derived from combinations of the heavy or light chain variants with the corresponding parental chains. Initial Octet Red experiments with immobilized antibodies assessed differential dissociation behavior at pH 6 or pH 7.4 after associating rhTNFa at pH 7.4. Ten variants were selected according to their binding profiles in regard of high affinity binding at pH 7.4 (association / dissociation at pH 7.4) and fast release of the antigen at pH 6 (association at pH 7.4 / dissociation at pH 6). For further characterization antibodies were purified via protein-A purification from crude supernatants and finally buffer was exchanged to PBS. Further octet assays revealed differences in binding at pH 7.4 and differences in rhTNFa release at pH 6. Subsequently three variants (IDs according to figures 3-4: VH#2 + VL#9: PSV#1 , VH#2 + VL#16: PSV#2 and VH#1+ VL#14: PSV#3) were selected for final characterization on Octet Red.
Binding characteristics of several histidine-mutated adalimumab variants were analyzed in Octet Red experiments. Different histidine mutations in heavy and light chains as well as different heavy and light chain variant combinations have been shown to affect binding affinities at pH 7.4 and the dissociation rates at pH 6.
A combination of several mutations including Leu98His in the heavy chain and Tyr32His, Leu33His in the light chain generated PSV#3. Light chain mutations Gln89His, Arg90His and Asn92His generated the light chain of PSV#2. The mutations Arg90His, Asn92His and Thr97His generated the light chain of PSV#1. For both, PSV#1 and PSV#2, mutations of Se OO.bHis and Se OO.cHis generated the heavy chain.
(The sequences were numbered as shown in figures 3 and 4a-c according to kabat numbering. For this purpose, sequences of the variants were aligned together with the parental sequence by using Clustal Wand numbering was applied considering the rules for kabat numbering.)
Representative sensorgrams of the Octet Red measurements are shown in figure 5 & 6 and corresponding mean values (N=3) of calculated kinetic parameters for adalimumab, PSV#1 , PSV#2 and PSV#3 are shown in table 4.
Table 3. Binding kinetics of adalimumab and pH-dependent binding variants to rhTNFa at pH 7.4 and pH 6. Association rate (kon), dissociation rate (kdis) and binding affinity (KD) of adalimumab, PSV#1, PSV#2 and PSV#3 at pH 7.4. Dissociation rates were determined also at pH 6. Experiments were done at 25°C and for every experiment mean values of triplicates are shown (exception: Adalimumab was measured at pH 6 in duplicates). Representative sensorgrams that correspond to the data are shown in figures 7 and 8. pH 7.4 pH 6
Antibody KD (M) kon kdis (S"1) kdis (S ) kdis kdis ratio
(M-V1) ratio (pH 6)
pH 6 / vs.
pH 7.4 adalimumab
Adalimumab 0.46E-11 1.32E+06 0.55E-05 4.81 E-05 9 1
PSV#1 4.63E-11 0.67E+06 3.26E-05 754E-05 231 157
PSV#2 7.73E-11 1.14E+06 9.35E-05 7340E-05 785 1527
PSV#3 11.2E-11 1.93E+06 21.8E-05 11000 E-05 505 2293
Parental adalimumab binds with high affinity to rhTNFa at pH 7.4 that was also shown in Kaymakcalan et al., 2009. For the three variants the increasing kdis-values result in a decrease in binding affinity (10-24fold decrease in KD), however interaction with TNFa with picomolar binding affinities in the three-diget range still represents very tight binding (figure 5 and table 3).
Octet Red measurements were also performed to assess the antibodies' pH-sensitivities. Improved antibody efficacy in context of the FcRn-mediated recycling requires tight binding to TNFa in the circulation at pH 7.4 and its fast release in the acidic endosome. In order to evaluate the release of TNFa within the acidic endosome, dissociation was measured at pH 6 after association of rhTNFa at pH 7.4 (figure 6 and table 3). Ratios of dissociation rates at pH 6 and pH 7.4 were determined and all variants showed considerably increased dissociation at pH 6 (59-160fold increased kdis at pH 6, in contrast to adalimumab with a kdis ratio (pH6/pH7.4) of 6 (table 3).
One additional experiment addressed the ability of PSV#1 , PSV#2 and PSV#3 to reversibly bind rhTNFa at pH 7.4, after dissociation at pH 6. To ensure that incubation at pH 6 does not irreversibly change TNFa binding capabilities, two cycles of binding (pH 7.4) and release (pH 6) were performed (figure 7). As shown in figure 8, PSV#1 , PSV#2 and PSV#3 can reversibly bind after TNFa has been released at pH 6. In contrast to that, adalimumab maintains tight binding during incubation at pH 6. Example 2: In vivo characterization of mutants
The effect of parental IgG construct and mutants thereof on the PK of human TNFa was investigated in heterozygous transgenic human FcRn mice, line 176, as well as in homozygous line 32 mice. The former line was more suitable to investigate PK differences between administered IgG constructs, while the latter mouse line provided a better FcRn protection, resulting in longer half-lives, closer to what was expected in human. This longer residence of the scavenger allowed better to evaluate the impact of the antibody on the clearance of the TNFa.
Human TNFa and scavenger were administered by SC route in predefined ratios. Plasma concentration profiles of both total scavenger and total hTNFa was investigated. pH- dependent hTNFa binding was expected to result in increased clearance of the cytokine and decreased clearance of the scavenger.
Selected tissues were collected from the mice, in order to investigate distribution of the scavenger and the target cytokine. Parental IgG were used as reference compound in this study.
The in vitro and in vivo data sets were used to establish correlations between:
• physico-chemical properties and in vivo pharmacokinetics
• FcRn affinity and in in vivo pharmacokinetics and tissue distribution
The correlations were used to build a physiologically-based pharmacokinetic (PBPK) model capable of characterizing and simulating plasma and tissue pharmacokinetics.
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WO2018139623A1 (en) * | 2017-01-30 | 2018-08-02 | Chugai Seiyaku Kabushiki Kaisha | Anti-sclerostin antibodies and methods of use |
WO2018167322A1 (en) * | 2017-03-16 | 2018-09-20 | Medimmune Limited | Anti-par2 antibodies and uses thereof |
US10253100B2 (en) | 2011-09-30 | 2019-04-09 | Chugai Seiyaku Kabushiki Kaisha | Therapeutic antigen-binding molecule with a FcRn-binding domain that promotes antigen clearance |
US10472623B2 (en) | 2008-04-11 | 2019-11-12 | Chugai Seiyaku Kabushiki Kaisha | Antigen-binding molecule capable of binding two or more antigen molecules repeatedly |
US10556949B2 (en) | 2011-09-30 | 2020-02-11 | Chugai Seiyaku Kabushiki Kaisha | Antigen-binding molecule inducing immune response to target antigen |
US10618965B2 (en) | 2011-02-25 | 2020-04-14 | Chugai Seiyaku Kabushiki Kaisha | Method for altering plasma retention and immunogenicity of antigen-binding molecule |
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