Non-human animals expressing humanized c1q complex

Abstract

Disclosed herein are nucleic acids encoding for and proteins expressing chimeric C1q polypeptides, non-human animals comprising said nucleic acids, and methods of making or using said non-human animals.

What is claimed is: 
     
         1 . A genetically modified non-human animal comprising in its genome a nucleic acid encoding a chimeric C1q polypeptide, wherein the nucleic acid comprises a non-human nucleic acid sequence and a human nucleic acid sequence, wherein the chimeric C1q polypeptide is selected from the group consisting of a chimeric C1qa polypeptide, a chimeric C1qb polypeptide, and a chimeric C1qc polypeptide, and wherein the chimeric C1q polypeptide comprises a globular head domain that is substantially human and an N-terminal stalk-stem region that is substantially non-human. 
     
     
         2 . The genetically modified non-human animal of  claim 1 , wherein the non-human animal expresses a chimeric C1qa polypeptide, a chimeric C1qb polypeptide, a chimeric C1qc polypeptide, or a combination thereof. 
     
     
         3 . The genetically modified non-human animal of  claim 1  or  2 , wherein the non-human animal is a mammal. 
     
     
         4 . The genetically modified non-human animal of  claim 1  or  2 , wherein the non-human animal is a rodent. 
     
     
         5 . The genetically modified non-human animal of  claim 1  or  2 , wherein the non-human animal is a rat or a mouse. 
     
     
         6 . The genetically modified non-human animal of any one of  claims 1 - 5 , wherein the chimeric C1q polypeptide is a chimeric C1qa polypeptide. 
     
     
         7 . The genetically modified non-human animal of  claim 6 , wherein the chimeric C1qa polypeptide comprises a globular head domain that is substantially identical to the globular head domain of a human C1qa polypeptide, and an N-terminal stalk-stem region that is substantially identical to the N-terminal stalk-stem region of a non-human C1qa polypeptide. 
     
     
         8 . The genetically modified non-human animal of  claim 7 , wherein the globular head domain of a human C1qa polypeptide comprises 108-245 of SEQ ID NO: 4. 
     
     
         9 . The genetically modified non-human animal of any one of  claims 6 - 8 , wherein the non-human animal is a mouse. 
     
     
         10 . The genetically modified non-human animal of  claim 9 , wherein the chimeric C1qa polypeptide comprises an N-terminal stalk-stem region substantially identical to the N-terminal stalk-stem region of the endogenous mouse C1qa polypeptide, and wherein the N-terminal stalk-stem region of the endogenous mouse C1qa polypeptide comprises amino acids 23-107 of SEQ ID NO: 1. 
     
     
         11 . The genetically modified non-human animal of  claim 9  or  10 , wherein the chimeric C1qa polypeptide comprises amino acids 23-245 of SEQ ID NO: 10. 
     
     
         12 . The genetically modified non-human animal of any one of  claims 6 - 8 , wherein the non-human animal is a rat. 
     
     
         13 . The genetically modified non-human animal of  claim 12 , wherein the chimeric C1qa polypeptide comprises an N-terminal stalk-stem region substantially identical to the N-terminal stalk-stem region of the endogenous rat C1qa polypeptide, and wherein the N-terminal stalk-stem region of the endogenous rat C1qa polypeptide comprises amino acids 23-107 of SEQ ID NO: 7. 
     
     
         14 . The genetically modified non-human animal of  claim 12  or  13 , wherein the chimeric C1qa polypeptide comprises amino acids 23-245 of SEQ ID NO: 55. 
     
     
         15 . The genetically modified non-human animal of any one of  claims 1 - 5 , wherein the chimeric C1q polypeptide is a chimeric C1qb polypeptide. 
     
     
         16 . The genetically modified non-human animal of  claim 15 , wherein the chimeric C1qb polypeptide comprises a globular head domain that is substantially identical to the globular head domain of a human C1qb polypeptide, and an N-terminal stalk-stem region that is substantially identitical to the N-terminal stalk-stem region of a non-human C1qb polypeptide. 
     
     
         17 . The genetically modified non-human animal of  claim 16 , wherein the globular head domain of a human C1qb polypeptide comprises amino acids 115-251 of SEQ ID NO: 5. 
     
     
         18 . The genetically modified non-human animal of any one of  claims 15 - 17 , wherein the non-human animal is a mouse. 
     
     
         19 . The genetically modified non-human animal of  claim 18 , wherein the chimeric C1qb polypeptide comprises an N-terminal stalk-stem region substantially identical to the N-terminal stalk-stem region of the endogenous mouse C1qb polypeptide, and wherein the N-terminal stalk-stem region of the endogenous mouse C1qb polypeptide comprises amino acids 26-114 of SEQ ID NO: 2. 
     
     
         20 . The genetically modified non-human animal of  claim 18  or  19 , wherein the chimeric C1qb polypeptide comprises amino acids 26-251 of SEQ ID NO: 11. 
     
     
         21 . The genetically modified non-human animal of any one of  claims 15 - 17 , wherein the non-human animal is a rat. 
     
     
         22 . The genetically modified non-human animal of  claim 21 , wherein the chimeric C1qb polypeptide comprises an N-terminal stalk-stem region substantially identical to the N-terminal stalk-stem region of the endogenous rat C1qb polypeptide, and wherein the N-terminal stalk-stem region of the endogenous rat C1qb polypeptide comprises amino acids 26-114 of SEQ ID NO: 8. 
     
     
         23 . The genetically modified non-human animal of  claim 21  or  22 , wherein the chimeric C1qb polypeptide comprises amino acids 26-251 of SEQ ID NO: 56. 
     
     
         24 . The genetically modified non-human animal of any one of  claims 1 - 5 , wherein the chimeric C1q polypeptide is a chimeric C1qc polypeptide. 
     
     
         25 . The genetically modified non-human animal of  claim 24 , wherein the chimeric C1qc polypeptide comprises a globular head domain that is substantially identical to the globular head domain of a human C1qc polypeptide, and an N-terminal stalk-stem region that is substantially identical to the N-terminal stalk-stem region of a non-human C1qc polypeptide. 
     
     
         26 . The genetically modified non-human animal of  claim 25 , wherein the globular head domain of a human C1qc polypeptide comprises amino acids 113-245 of SEQ ID NO: 6. 
     
     
         27 . The genetically modified non-human animal of any one of  claims 24 - 26 , wherein the non-human animal is a mouse. 
     
     
         28 . The genetically modified non-human animal of  claim 27 , wherein the chimeric C1qc polypeptide comprises an N-terminal stalk-stem region substantially identical to the N-terminal stalk-stem region of the endogenous mouse C1qc polypeptide, and wherein the N-terminal stalk-stem region of the endogenous mouse C1qc polypeptide comprises amino acids 30-113 of SEQ ID NO: 3. 
     
     
         29 . The genetically modified non-human animal of  claim 27  or  28 , wherein the chimeric C1qc polypeptide comprises amino acids 30-246 of SEQ ID NO: 11. 
     
     
         30 . The genetically modified non-human animal of any one of  claims 24 - 26 , wherein the non-human animal is a rat. 
     
     
         31 . The genetically modified non-human animal of  claim 30 , wherein the chimeric C1qc polypeptide comprises an N-terminal stalk-stem region substantially identical to the N-terminal stalk-stem region of the endogenous rat C1qc polypeptide, and wherein the N-terminal stalk-stem region of the endogenous rat C1qc polypeptide comprises amino acids 32-115 of SEQ ID NO: 9. 
     
     
         32 . The genetically modified non-human animal of  claim 30  or  31 , wherein the chimeric C1qc polypeptide comprises amino acids 32-248 SEQ ID NO: 57. 
     
     
         33 . The genetically modified non-human animal of any of the preceding claims, wherein the chimeric C1q polypeptide comprises a non-human C1q signal peptide, optionally an endogenous non-human C1q signal peptide. 
     
     
         34 . The genetically modified non-human animal of  claim 1 , wherein the nucleic acid encoding the chimeric C1q polypeptide is at an endogenous non-human C1q locus. 
     
     
         35 . The genetically modified non-human animal of  claim 34 , wherein an endogenous genomic sequence at the endogenous non-human C1q locus has been replaced by the human nucleic acid sequence. 
     
     
         36 . The genetically modified non-human animal of any one of  claim 1 ,  2 ,  34  or  35 , wherein the human nucleic acid sequence encodes substantially the globular head domain of a human C1q polypeptide. 
     
     
         37 . The genetically modified non-human animal of  claim 36 , wherein the human nucleic acid sequence is a genomic fragment of a human C1q gene. 
     
     
         38 . The genetically modified non-human animal of  claim 37 , wherein the genomic fragment comprises the 3′ UTR of the human C1q gene. 
     
     
         39 . The genetically modified non-human animal of any of  claims 36 - 38 , wherein the chimeric C1q polypeptide is a chimeric C1qa polypeptide, and the human nucleic acid sequence encodes substantially the globular head domain of a human C1qa polypeptide. 
     
     
         40 . The genetically modified non-human animal of  claim 39 , wherein the globular head domain of the human C1qa polypeptide comprises amino acids 108-245 of SEQ ID NO: 4. 
     
     
         41 . The genetically modified non-human animal of  claim 39  or  40 , wherein the human nucleic acid sequence encodes amino acids 112-245 of SEQ ID NO: 4. 
     
     
         42 . The genetically modified non-human animal of any of  claims 36 - 38 , wherein the chimeric C1q polypeptide is a chimeric C1qb polypeptide, and the human nucleic acid sequence encodes substantially the globular head domain of a human C1qb polypeptide. 
     
     
         43 . The genetically modified non-human animal of  claim 42 , wherein the globular head domain of the human C1qb polypeptide comprises amino acids 115-251 of SEQ ID NO: 5. 
     
     
         44 . The genetically modified non-human animal of  claim 42  or  43 , wherein the human nucleic acid sequence encodes amino acids 118-251 of SEQ ID NO: 5. 
     
     
         45 . The genetically modified non-human animal of any of  claims 36 - 38 , wherein the chimeric C1q polypeptide is a chimeric C1qc polypeptide, and the human nucleic acid sequence encodes substantially the globular head domain of a human C1qc polypeptide. 
     
     
         46 . The genetically modified non-human animal of  claim 45 , wherein the globular head domain of the human C1qc polypeptide comprises amino acids 113-245 of SEQ ID NO: 6. 
     
     
         47 . The genetically modified non-human animal of  claim 45  or  46 , wherein the human nucleic acid sequence encodes amino acids 114-245 of SEQ ID NO: 6. 
     
     
         48 . The genetically modified non-human animal of any one of  claim 1 ,  2 , or  34 - 36 , wherein the non-human nucleic acid sequence encodes substantially the N-terminal stalk-stem region of a non-human C1q polypeptide. 
     
     
         49 . The genetically modified non-human animal of  claim 48 , wherein the the non-human animal is a mouse, and the N-terminal stalk-stem region of mouse C1q polypeptide comprises amino acids 23-107 of SEQ ID NO: 1 (for C1qa), amino acids 26-114 of SEQ ID NO: 2 (for C1qb), or amino acids 30-113 of SEQ ID NO: 3 (for C1qc), respectively. 
     
     
         50 . The genetically modified non-human animal of  claim 49 , wherein the mouse comprises a nucleic acid encoding a chimeric C1qa polypeptide, wherein the nucleic acid comprises a mouse nucleic acid sequence and a human nucleic acid sequence, wherein the mouse nucleic acid sequence encodes amino acids 23-111 of SEQ ID NO: 1. 
     
     
         51 . The genetically modified non-human animal of  claim 49 , wherein the mouse comprises a nucleic acid encoding a chimeric C1qb polypeptide, wherein the nucleic acid comprises a mouse nucleic acid sequence and a human nucleic acid sequence, wherein the mouse nucleic acid sequence encodes amino acids 26-117 of SEQ ID NO: 2. 
     
     
         52 . The genetically modified non-human animal of  claim 49 , wherein the mouse comprises a nucleic acid encoding a chimeric C1qc polypeptide, wherein the nucleic acid comprises a mouse nucleic acid sequence and a human nucleic acid sequence, wherein the mouse nucleic acid sequence encodes amino acids 30-114 of SEQ ID NO: 3. 
     
     
         53 . The genetically modified non-human animal of  claim 48 , wherein the the non-human animal is a rat, and the N-terminal stalk-stem region of the endogenous C1q polypeptides comprises amino acids 23-107 of SEQ ID NO: 7 (for C1qa), amino acids 26-114 of SEQ ID NO: 8 (for C1qb), and amino acids 32-115 of SEQ ID NO: 9 (for C1qc), respectively. 
     
     
         54 . The genetically modified non-human animal of  claim 53 , wherein the rat comprises a nucleic acid encoding a chimeric C1qa polypeptide, wherein the nucleic acid comprises a rat nucleic acid sequence and a human nucleic acid sequence, wherein the rat nucleic acid sequence encodes amino acids 23-111 of SEQ ID NO: 7. 
     
     
         55 . The genetically modified non-human animal of  claim 53 , wherein the rat comprises a nucleic acid encoding a chimeric C1qb polypeptide, wherein the nucleic acid comprises a rat nucleic acid sequence and a human nucleic acid sequence, wherein the rat nucleic acid sequence encodes amino acids 26-117 of SEQ ID NO: 8. 
     
     
         56 . The genetically modified non-human animal of  claim 53 , wherein the rat comprises a nucleic acid encoding a chimeric C1qc polypeptide, wherein the nucleic acid comprises a rat nucleic acid sequence and a human nucleic acid sequence, wherein the rat nucleic acid sequence encodes amino acids 32-116 of SEQ ID NO: 9. 
     
     
         57 . The genetically modified non-human animal of  claim 1 , wherein the animal is a rat and comprises in its genome:
 a. at the endogenous C1qa locus a nucleic acid sequence encoding a chimeric rat/human C1qa polypeptide wherein the nucleic acid sequence comprises, 5′-3′ and in operable linkage a first nucleotide sequence encoding amino acids 1-111 of a rat C1qa polypeptide of SEQ ID NO: 7 and a second nucleotide sequence encoding amino acids 112-245 of a human C1qa polypeptide of SEQ ID NO: 4;   b. at the endogenous C1qb locus a nucleic acid sequence encoding a chimeric rat/human C1qb polypeptide wherein the nucleic acid sequence comprises, 5′-3′ and in operable linkage a third nucleotide sequence encoding amino acids 1-117 of a rat C1qb polypeptide of SEQ ID NO: 8 and a fourth nucleotide sequence encoding amino acids 118-251 of a human C1qb polypeptide of SEQ ID NO: 5; and   c. at the endogenous C1qc locus a nucleic acid sequence encoding a chimeric rat/human C1qc polypeptide wherein the nucleic acid sequence comprises, 5′-3′ and in operable linkage a fifth nucleotide sequence encoding amino acids 1-116 of a rat C1qc polypeptide of SEQ ID NO: 9 and a sixth nucleotide sequence encoding amino acids 114-245 of a human C1qc polypeptide of SEQ ID NO: 6.   
     
     
         58 . The genetically modified non-human animal of  claim 1 , wherein the animal is a mouse and comprises in its genome:
 a. at the endogenous C1qa locus a nucleic acid sequence encoding a chimeric mouse/human C1qa polypeptide wherein the nucleic acid sequence comprises, 5′-3′ and in operable linkage a first nucleotide sequence encoding amino acids 1-111 of a mouse C1qa polypeptide of SEQ ID NO: 1 and a second nucleotide sequence encoding amino acids 112-245 of a human C1qa polypeptide of SEQ ID NO: 4;   b. at the endogenous C1qb locus a nucleic acid sequence encoding a chimeric mouse/human C1qb polypeptide wherein the nucleic acid sequence comprises, 5′-3′ and in operable linkage a third nucleotide sequence encoding amino acids 1-117 of a mouse C1qb polypeptide of SEQ ID NO: 2 and a fourth nucleotide sequence encoding amino acids 118-251 of a human C1qb polypeptide of SEQ ID NO: 5; and   c. at the endogenous C1qc locus a nucleic acid sequence encoding a chimeric mouse/human C1qc polypeptide wherein the nucleic acid sequence comprises, 5′-3′ and in operable linkage a fifth nucleotide sequence encoding amino acids 1-114 of a mouse C1qc polypeptide of SEQ ID NO: 3 and a sixth nucleotide sequence encoding amino acids 114-245 of a human C1qc polypeptide of SEQ ID NO: 6.   
     
     
         59 . The genetically modified non-human animal of any one of  claims 1 - 58 , wherein the non-human animal does not express a functional endogenous C1qa, C1qb, and/or C1qc polypeptide(s). 
     
     
         60 . A method of making a genetically modified non-human animal, comprising modifying the genome of a non-human animal to comprise a nucleic acid encoding a chimeric C1q polypeptide, wherein the nucleic acid comprises a non-human nucleic acid sequence and a human nucleic acid sequence, wherein the chimeric C1q polypeptide is selected from the group consisting of a chimeric C1qa polypeptide, a chimeric C1qb polypeptide, a chimeric C1qc polypeptide, and a combination thereof, and wherein the chimeric C1q polypeptide comprises a globular head domain that is substantially human and an N-terminal stalk-stem region that is substantially non-human. 
     
     
         61 . The method of  claim 60 , wherein the genome of the non-human animal is modified to comprise a nucleic acid encoding a chimeric C1qa polypeptide, a nucleic acid encoding a chimeric C1qb polypeptide, and a nucleic acid encoding a chimeric C1qc polypeptide. 
     
     
         62 . The method of  claim 60  or  61 , wherein the nucleic acid encoding a chimeric C1q polypeptide is introduced at the endogenous non-human C1q locus. 
     
     
         63 . The method of  claim 62 , wherein the nucleic acid encoding a chimeric C1q polypeptide replaces a nucleotide sequence of the endogenous non-human C1q gene at the endogenous non-human C1q locus. 
     
     
         64 . The method of any one of  claims 60 - 63 , wherein the animal is a rodent, such as a mouse or a rat. 
     
     
         65 . The method of  claim 64 , wherein said modifying comprises
 a. introducing a nucleic acid molecule comprising the human nucleic acid sequence into the genome of a rodent embryonic stem (ES) cell,   b. obtaining a rodent ES cell in which the human nucleic acid sequence is integrated into an endogenous C1q locus in an operable linkage to the endogenous non-human nucleic acid sequence so as to encode said chimeric C1q polypeptide, and   c. generating a rodent animal from the rodent ES cell obtained in b.   
     
     
         66 . The method of  claim 65 , wherein the nucleic acid molecule comprises a nucleic acid encoding a chimeric C1qa polypeptide, a nucleic acid encoding a chimeric C1qb polypeptide, and a nucleic acid encoding a chimeric C1qc polypeptide. 
     
     
         67 . A chimeric C1q polypeptide comprising a globular head domain that is substantially human and an N-terminal stalk-stem region that is substantially non-human, wherein the chimeric C1q polypeptide is selected from the group consisting of a chimeric C1qa polypeptide, a chimeric C1qb polypeptide, and a chimeric C1qc polypeptide. 
     
     
         68 . A chimeric C1q polypeptide made from the non-human animal of any of  claims 1 - 59 . 
     
     
         69 . A chimeric C1q protein comprising one or more of the chimeric C1q polypeptides of  claim 67  or  68 . 
     
     
         70 . The chimeric C1q protein of  claim 69 , wherein the protein comprises at least one chimeric C1qa, at least one chimeric C1qb, and at least one chimeric C1qc polypeptide. 
     
     
         71 . The chimeric C1q protein of  claim 70 , wherein the protein comprises 6 each of the chimeric C1qa polypeptide, chimeric C1qb polypeptide, and chimeric C1qc polypeptide. 
     
     
         72 . An isolated nucleic acid encoding a functional chimeric C1q polypeptide comprising a non-human mammal nucleic acid sequence and a human nucleic acid sequence, wherein the human nucleic acid sequence encodes substantially the globular head domain of a human C1q polypeptide and the non-human nucleic acid sequence encodes substantially the N-terminal stalk-stem region of a cognate non-human C1q polypeptide, and wherein the C1q polypeptide is selected from a C1qa polypeptide, a C1qb polypeptide or a C1qc polypeptide. 
     
     
         73 . An isolated nucleic acid encoding a chimeric non-human mammal C1q protein, comprising one or more of a first, second or third nucleotide sequences, wherein:
 a. the first nucleotide sequence encodes a chimeric C1qa polypeptide,   b. the second nucleotide sequence encodes a chimeric C1qb polypeptide, and   c. the third nucleotide sequence encodes a chimeric C1qc polypeptide,   wherein each of the first, second, and third nucleotide sequences comprises a non-human mammal nucleic acid sequence and a human nucleic acid sequence, wherein the human nucleic acid sequence encodes substantially the globular head domain of a human C1qa, C1qb, and C1qc polypeptide, respectively, and the non-human nucleic acid sequence encodes substantially the N-terminal stalk-stem region of a cognate non-human C1q polypeptide C1qa, C1qb, and C1qc polypeptide, respectively.   
     
     
         74 . A cell comprising an isolated nucleic acid of  claim 73  or  74 . 
     
     
         75 . The cell of  claim 74 , wherein the cell is an embryonic stem cell. 
     
     
         76 . A genetically modified non-human animal comprising the cell of  claim 75 . 
     
     
         77 . A transgenic rodent model for testing a C1q-based bi-specific antigen-binding protein, wherein the antigen-binding protein binds both human C1q and a non-rodent antigen of interest, comprising a genetically modified rodent of any of  claims 1 - 59 , and further comprising the non-rodent antigen of interest or a cell expressing the non-rodent antigen of interest. 
     
     
         78 . A method of screening drug candidate that targets an antigen of interest comprising
 a. introducing the antigen of interest into a genetically modified rodent as defined by any of  claims 1 - 59 ,   b. contacting said rodent with a drug candidate of interest, wherein the drug candidate is directed against the human C1q and the antigen of interest, and   c. assaying if the drug candidate is efficacious in preventing, reducing, or eliminating cells characterized by the presence or expression of the antigen of interest.   
     
     
         79 . The method of  claim 78 , wherein the step of introducing comprises expressing in the rodent the antigen of interest. 
     
     
         80 . The method of  claim 78 , wherein the step of introducing comprises introducing into said rodent a cell expressing the antigen of interest. 
     
     
         81 . The method of any of  claims 78 - 80 , wherein the antigen of interest is a tumor associated antigen. 
     
     
         82 . The method of any of  claims 78 - 80 , wherein the cell is a bacterial cell such as a  Staphylococcus  cell, and the antigen is a bacterial antigen such as a  Staphylococcus  antigen. 
     
     
         83 . The method of any of  claims 78 - 80 , wherein the antigen is a viral antigen. 
     
     
         84 . The method of  claim 82  or  83 , wherein the step of introducing comprises infecting the rodent with the antigen of interest. 
     
     
         85 . The method of  claim 78 , wherein the rodent is an immunocompetent mouse or an immunocompetent rat. 
     
     
         86 . The method of  claim 78 , wherein the drug candidate is an antibody or an antigen-binding protein. 
     
     
         87 . The method of  claim 86 , wherein the antibody or the antigen-binding protein is a bispecific antibody or a bispecific antigen-binding protein, respectively, which is capable of binding both human C1q protein and the antigen of interest. 
     
     
         88 . A method for assessing whether a candidate antibody activates complement pathway, comprising
 a. providing a cell expressing an antigen of interest on the cell surface, a candidate antibody comprising a human Fc region and directed to the antigen of interest, and a serum sample from a genetically modified non-human animal of any of  claims 1 - 59 ;   b. mixing the cell with the candidate antibody to allow the antibody to bind to the antigen of interest expressed on the cell surface;   c. adding the serum sample to the cell-antibody mixture to permit binding of the humanized C1q proteins in the serum sample to antibodies bound to the antigen of interest on the cell; and   d. measuring cytotoxicity of the cell.   
     
     
         89 . A method for assessing a candidate bispecific antibody targeting an antigen of interest and human C1q, comprising
 a. mixing a cell or virus expressing the antigen of interest, the candidate bispecific antibody, and a blood sample from a genetically modified non-human animal of any of  claims 1 - 59 , and incubating to allow the antibody to bind to the antigen of interest expressed by the cell or virus and to the humanized C1q molecules in the blood sample; and   b. measuring survival of the cell or virus.   
     
     
         90 . The method of  claim 89 , wherein the cell is a bacterial cell such as a  Staphylococcus  cell, and the antigen is a bacterial antigen such as a  Staphylococcus  antigen. 
     
     
         91 . The genetically modified non-human animal of  claim 57 , wherein the rat comprises in its genome:
 a. at the endogenous C1qa locus a nucleic acid sequence encoding a chimeric rat/human C1qa polypeptide which comprises the amino acid sequence of SEQ ID NO: 55;   b. at the endogenous C1qb locus a nucleic acid sequence encoding a chimeric rat/human C1qb polypeptide which comprises the amino acid sequence of SEQ ID NO: 56; and   c. at the endogenous C1qa locus a nucleic acid sequence encoding a chimeric rat/human C1qc polypeptide which comprises the amino acid sequence of SEQ ID NO: 57.   
     
     
         92 . The genetically modified non-human animal of  claim 58 , wherein the mouse comprises in its genome:
 a. at the endogenous C1qa locus a nucleic acid sequence encoding a chimeric mouse/human C1qa polypeptide which comprises the amino acid sequence of SEQ ID NO: 10;   b. at the endogenous C1qb locus a nucleic acid sequence encoding a chimeric mouse/human C1qb polypeptide which comprises the amino acid sequence of SEQ ID NO: 11; and   c. at the endogenous C1qa locus a nucleic acid sequence encoding a chimeric mouse/human C1qc polypeptide which comprises the amino acid sequence of SEQ ID NO: 12.