Directed sequence polymer compositions and antibodies thereof for the treatment of protein conformational disorders

A process for generating antibodies comprising the steps of:

• (i) preparing a composition comprising directed-sequence polymers (DSPs), wherein the DSP composition has a complexity of greater than 5×102 different DSPs, comprising the steps of:
• (1) selecting a base peptide sequence, wherein the base peptide sequence is derived from an epitope of an antigen associated with a protein conformational disorder,
• (2) synthesizing by solid phase peptide synthesis a first cassette of the DSPs, the cassette having a sequence of amino acid positions corresponding to each amino acid of the base peptide sequence,
• wherein, for at least one amino acid position of the first cassette of the DSPs, an amino acid is added, said amino acid randomly selected from a mixture of amino acids consisting of the original amino acid found at the corresponding amino acid position of the base peptide sequence, optionally alanine (A), and, optionally, at least one conserved substitution,
• wherein the amino acids in the mixture are present in a fixed molar input ratio relative to each other, determined prior to starting synthesis,
• wherein the relative molar amount of A is more than 10% and less than 90% of the total amino acid concentration of the DSPs;
• (3) optionally extending the length of the DSPs by
• (a) repeating step (2) for 1 to 15 cycles and elongating the DSPs under the same condition including the input ratio of amino acids in the mixture;
• (b) repeating step (2) for 1 to 15 cycles and elongating the DSPs, for each cycle, using a different input ratio of amino acids in the mixture;
• (c) repeating steps (1) and (2) for 1 to 15 cycles and elongating the DSPs using cassettes based on more than one base peptide;
• (d) assembling 1 to 15 cassettes synthesized in a single cycle of step (2);
• or
• (e) assembling 1 to 15 cassettes, the first cassette synthesized under one condition of step (2), and second and more cassettes synthesized under one or more different conditions of step (2);
• wherein the number of cycles selected in step (3) is selected so that the final length of the DSPs is 10 to 300 amino acid residues;
• (ii) administering said DSP composition to an animal;
• and
• (iii)(a) isolating antibodies immunoreactive with said DSP composition from said animal, or
• (iii)(b) isolating cells that produce antibodies immunoreactive with said DSP composition from said animal, and then isolating antibodies immunoreactive with said DSP composition from said isolated cells.

A process for manufacturing a composition comprising directed-sequence polymers (DSPs), wherein the DSP composition has a complexity of greater than 5×102 different DSPs, comprising the steps of:

• (1) selecting a base peptide sequence, wherein the base peptide sequence is derived from an epitope of an antigen associated with a protein conformational disorder,
• (2) synthesizing by solid phase peptide synthesis a first cassette of the DSPs, the cassette having a sequence of amino acid positions corresponding to each amino acid of the base peptide sequence,
• wherein, for at least one amino acid position of the first cassette of the DSPs, an amino acid is added, said amino acid randomly selected from a mixture of amino acids consisting of the original amino acid found at the corresponding amino acid position of the base peptide sequence, optionally alanine (A), and, optionally, at least one conserved substitution,
• wherein the amino acids in the mixture are present in a fixed molar input ratio relative to each other, determined prior to starting synthesis,
• wherein the relative molar amount of A is more than 10% and less than 90% of the total amino acid concentration of the DSPs;
• (3) optionally extending the length of the DSPs by
• (a) repeating step (2) for 1 to 15 cycles and elongating the DSPs under the same condition including the input ratio of amino acids in the mixture;
• (b) repeating step (2) for 1 to 15 cycles and elongating the DSPs, for each cycle, using a different input ratio of amino acids in the mixture;
• (c) repeating steps (1) and (2) for 1 to 15 cycles and elongating the DSPs using cassettes based on more than one base peptide;
• (d) assembling 1 to 15 cassettes synthesized in a single cycle of step (2);
• or
• (e) assembling 1 to 15 cassettes, the first cassette synthesized under one condition of step (2), and second and more cassettes synthesized under one or more different conditions of step (2);
• wherein the number of cycles selected in step (3) is selected so that the final length of the DSPs is 10 to 300 amino acid residues.