Anti-beta amyloid / Anti-transferrin receptor bispecific antibodies and uses thereof

Abstract

The present disclosure provides bispecific antibodies capable of binding human beta amyloid (AP) and / or human transferrin receptor (TfR), compositions comprising the same, and methods of use thereof. Among other things, this disclosure provides methods of preventing or treating neurological diseases comprising anti-Ap / anti-TfR bi specific antibodies. This disclosure also provides polynucleotides and vectors encoding the anti-transferrin receptor antibodies and cells comprising the same, methods of making the antibodies, and molecules comprising the antibodies.

Description

Attorney Docket No. 2011256-2654 / P1939PCT01ANTI-BETA AMYLOID / ANTI-TRANSFERRIN RECEPTOR BISPECIFIC ANTIBODIES AND USES THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of U. S. Provisional Application No. 63 / 754,939, filed February 6, 2025, the entire contents of which are hereby incorporated by reference herein.TECHNICAL FIELD

[0002] This disclosure relates to bispecific antibodies capable of binding human beta amyloid (A ) and / or human transferrin receptor (TfR), compositions comprising the same, and methods of use thereof. This disclosure also provides related polynucleotides and vectors encoding the bispecific antibodies disclosed and cells comprising the same.BACKGROUND

[0003] Alzheimer’s disease (AD) is a progressive neurodegenerative disorder clinically characterized by cognitive impairment, behavioral disturbances, psychiatric symptoms, and disability in activities of daily living. These clinical manifestations constitute AD dementia. AD International estimates that the number of people living with dementia worldwide will increase from the current value of 47 million to 131 million by 2050. Being the most common cause of dementia, AD accounts for 60 to 80% of dementia cases. In the United States, it is estimated that 5.2 million Americans suffer from dementia caused by AD, and that by 2050 the prevalence will double or triple unless an effective treatment is found.

[0004] Ap is a peptide generated from the metabolism of amyloid precursor protein. Several Ap peptide alloforms exist (e.g., Ap40, Aβ42). These monomeric peptides have a variable tendency to aggregate into higher order dimers and oligomers. Through a process of fibrillogenesis, soluble oligomers may transition into insoluble deposits having a β pleated sheet structure. These deposits are also referred to as amyloid plaques and are composed of predominantly fibrillar amyloid. Both soluble and fibrillar forms of A appear to contribute to the disease process._ 1 _13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0005] AD patients having high serum titers of anti-Ap antibodies that recognize amyloid plaques have slower rates of cognitive decline and disability as compared to patients that do not have anti-Ap antibodies. Moreover, patients who develop high titers of anti-Ap antibodies show reduced numbers of brain A plaques and improved cognitive performance assessed after long-term follow up. These clinical data suggest that AD patients treated with anti-Ap antibodies in a passive immunotherapy paradigm are likely to show reduced cognitive impairment, a lower density of brain Ap deposits, and reduced rates of cognitive deterioration. Antibody -mediated removal of A from the brain is hypothesized to decrease Ap burden, thereby preventing neuronal dysfunction, slowing the progression of pathology and reducing the rate of cognitive decline in AD.

[0006] The delivery of drugs to the central nervous system has been a challenge in the treatment of neurological diseases such as Alzheimer’s disease and Parkinson’s disease. For drugs to reach the brain, they first have to penetrate the blood brain barrier, which is a major challenge due to the selectivity of the blood brain barrier. The blood brain barrier acts as a semipermeable membrane, preventing most molecules from entering the nervous system from the blood and allows only low molecular weight (<400 Da) and lipophilic compounds to pass. Most small molecules and large molecules, such as monoclonal antibodies, cannot pass through this barrier. Due to this challenging process of drug penetration across the blood brain barrier, a small fraction of therapeutic agents for neurological diseases make it to clinical trials.

[0007] There is a need in the art for improved compositions and methods for delivering a therapeutic agent to the central nervous system.SUMMARY

[0008] This disclosure relates, in part, to bispecific antibodies capable of binding human beta amyloid (AP) and human transferrin receptor (TfR), compositions comprising the same, and methods of use thereof. This disclosure also relates to the use of bispecific antibodies described herein in the treatment of neurological disorders.

[0009] Provided herein are anti-Ap / anti-TfR bispecific antibodies. In some embodiments, a bispecific antibody comprises an anti-Ap antibody or antigen binding fragment thereof, and an anti-TfR antibody or antigen binding fragment thereof.- 2 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0010] In some embodiments, a bi specific antibody described herein comprises a first heavy chain variable region (VH) comprising a first VH complementarity determining region (CDR)l, a first VH CDR2, and a first VH CDR3, and a first light chain variable region (VL) comprising a first VL CDR1, a first VL CDR2, and a first VL CDR3. In some embodiments, a bispecific antibody described herein comprises a second VH comprising a second VH CDR1, a second VH CDR2, and a second VH CDR3, and a second VL comprising a second VL CDR1, a second VL CDR2, and a second VL CDR3. In some embodiments, a bispecific antibody described herein comprises (i) a first VH comprising a first VH CDR1, a first VH CDR2, and a first VH CDR3, and a first VL comprising a first VL CDR1, a first VL CDR2, and a first VL CDR3; and (ii) a second VH comprising a second VH CDR1, a second VH CDR2, and a second VH CDR3, and a second VL comprising a second VL CDR1, a second VL CDR2, and a second VL CDR3.

[0011] In some embodiments, a bispecific antibody comprises an anti-Ap antibody or antigen binding fragment thereof, and an anti-TfR antibody or antigen binding fragment thereof, comprising a second VH CDR1 comprises the amino acid sequence GFTFSSYX1MN (SEQ ID NO: 18), wherein XI is S or A; the second VH CDR2 comprises the amino acid sequence SISX₂SSSX₃IYYADSVKG (SEQ ID NO:19), wherein X₂ is S or A, and wherein X₃ is Y or S; and the second VH CDR3 comprises the amino acid sequence KX4X5X6GDFDY (SEQ ID NO: 20), wherein X4 is Y or S, wherein X5 is R or S, and wherein X6 is A or Y; the second VL CDR1 comprises the amino acid sequence RASQSVSSX7X8LA (SEQ ID NO: 21), wherein X7 is S or N, and wherein X8 is Y or N; the second VL CDR2 comprises the amino acid sequence GASX9RAT (SEQ ID NO: 22), wherein X9 is N or S; and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO: 8).

[0012] In some embodiments, a bispecific antibody comprises an anti-Ap antibody or antigen binding fragment thereof, comprising a first heavy chain variable region (VH) comprising a first VH complementarity determining region (CDR)l, a first VH CDR2, and a first VH CDR3, and a first light chain variable region (VL) comprising a first VL CDR1, a first VL CDR2, and a first VL CDR3, wherein: the first VH CDR1 comprises the amino acid sequence of SEQ ID NO: 501 or 512; the first VH CDR2 comprises the amino acid sequence of SEQ ID NO: 502 or 513; and the first VH CDR3 comprises the amino acid sequence of SEQ ID NO: 503; the first VL CDR1 comprises the amino acid sequence of SEQ ID NO: 507 or 519; the first VL- 3 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01CDR2 comprises the amino acid sequence of SEQ ID NO: 508; and the first VL CDR3 comprises the amino acid sequence of SEQ ID NO: 509; and an anti-TfR antibody or antigen binding fragment thereof.

[0013] In some embodiments, a bispecific antibody comprises a) a first heavy chain variable region (VH) comprising a first VH complementarity determining region (CDR)1, a first VH CDR2, and a first VH CDR3, and a first light chain variable region (VL) comprising a first VL CDR1, a first VL CDR2, and a first VL CDR3, wherein: the first VH CDR1 comprises the amino acid sequence of SEQ ID NO: 501 or 512; the first VH CDR2 comprises the amino acid sequence of SEQ ID NO: 502 or 513; and the first VH CDR3 comprises the amino acid sequence of SEQ ID NO: 503; the first VL CDR1 comprises the amino acid sequence of SEQ ID NO: 507 or 519; the first VL CDR2 comprises the amino acid sequence of SEQ ID NO: 508; and the first VL CDR3 comprises the amino acid sequence of SEQ ID NO: 509; and b) a second VH comprising a second VH CDR1, a second VH CDR2, and a second VH CDR3, and a second VL comprising a second VL CDR1, a second VL CDR2, and a second VL CDR3, wherein: the second VH CDR1 comprises the amino acid sequence GFTFSSYX1MN (SEQ ID NO: 18), wherein XI is S or A; the second VH CDR2 comprises the amino acid sequence SISX₂SSSX₃IYYADSVKG (SEQ ID NO:19), wherein X₂ is S or A, and wherein X₃ is Y or S; and the second VH CDR3 comprises the amino acid sequence KX4X5X6GDFDY (SEQ ID NO:20), wherein X4 is Y or S, wherein X5 is R or S, and wherein X6 is A or Y; the second VL CDR1 comprises the amino acid sequence RASQSVSSX7X8LA (SEQ ID NO:21), wherein X7 is S or N, and wherein X8 is Y or N; the second VL CDR2 comprises the amino acid sequence GASX₉RAT (SEQ ID NO:22), wherein X₉ is N or S; and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8).

[0014] In some embodiments, a bispecific antibody comprises (i) the first VH is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 504; and (ii) the first VL is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 510.

[0015] In some embodiments, a bispecific antibody comprises (i) the first heavy chain is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 603-611; and (ii) the first light chain is at least 80%, at- 4 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 700-702.

[0016] In some embodiments, a bispecific antibody comprises (i) the first VH is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 514; and (ii) the first VL is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 520.

[0017] In some embodiments, at least one of second VH CDRl, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 are selected from the mutant CDRs depicted in Table 1, and any of second VH CDR1, VH CDR2, VH CDR3, VL CDRl, VL CDR2, or VL CDR3 that are not selected from the mutant CDRs depicted in Table 1 are selected from the parental CDRs depicted in Table 1. In some embodiments, one of second VH CDRl, VH CDR2, VH CDR3, VL CDRl, VL CDR2, or VL CDR3 is selected from the mutant CDRs depicted in Table 1 and five of second VH CDRl, VH CDR2, VH CDR3, VL CDRl, VL CDR2, and / or VL CDR3 are selected from the parental CDRs depicted in Table 1 In some embodiments, two of second VH CDRl, VH CDR2, VH CDR3, VL CDRl, VL CDR2, and / or second VL CDR3 are selected from the mutant CDRs depicted in Table 1 and four of second VH CDRl, VH CDR2, VH CDR3, VL CDRl, VL CDR2, and / or VL CDR3 are selected from the parental CDRs depicted in Table 1. In some embodiments, three of second VH CDRl, VH CDR2, VH CDR3, VL CDRl, VL CDR2, and / or VL CDR3 are selected from the mutant CDRs depicted in Table 1 and three of second VH CDRl, VH CDR2, VH CDR3, VL CDRl, VL CDR2, and / or VL CDR3 are selected from the parental CDRs depicted in Table 1. In some embodiments, four of second VH CDRl, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 are selected from the mutant CDRs depicted in Table 1 and two of second VH CDRl, VH CDR2, VH CDR3, VL CDRl, VL CDR2, and / or VL CDR3 are selected from the parental CDRs depicted in Table 1. In some embodiments, five of second VH CDRl, VH CDR2, VH CDR3, VL CDRl, VL CDR2, and / or VL CDR3 are selected from the mutant CDRs depicted in Table 1 and one of VH CDRl, VH CDR2, VH CDR3, VL CDRl, VL CDR2, or VL CDR3 is selected from the parental CDRs depicted in Table 1.

[0018] In some embodiments, second VH CDRl comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid- 5 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01sequence KYRAGDFDY (SEQ ID NO:5); second VL CDRl comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8); orsecond VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNR AT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8).

[0019] In some embodiments, second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4), second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDRl comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8), wherein second VL comprises a Y57S conservative substitution;second VH CDRl comprises the amino acid sequence GFTFSSYAMN (SEQ ID NO:9); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDRl comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7), and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDRl comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:7); second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:7); second VL CDRl comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO: 7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDRl comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:7); second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID- 6 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01NO: 10); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:7), wherein second VL comprises a Y57S conservative substitution;second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:7); second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:7); second VL CDR1 comprises the amino acid sequence RASQSVSSNYLA (SEQ ID NO: 15); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:7);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISSSSSSIYYADSVKG (SEQ ID NO: 11); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KSRAGDFDY (SEQ ID NO:12); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7), and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:7);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYSAGDFDY (SEQ ID NO: 13); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID- 7 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01NO:4); second VH CDR3 comprises the amino acid sequence KYRYGDFDY (SEQ ID NO: 14); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NOV); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NOV); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NOV);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISASSSSIYYADSVKG (SEQ ID NO:25); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); second VH CDR3 comprises the amino acid sequence KYSAGDFDY (SEQ ID NO: 13); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO: 7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSNYLA (SEQ ID NO: 15); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSNLA (SEQ ID NO: 16); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7), and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NOV); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NOV); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NOV);- 8 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASSRAT (SEQ ID NO: 17); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:7); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:7); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8), wherein second VL comprises a Y57S conservative substitution;second VH CDR1 comprises the amino acid sequence SYAMN (SEQ ID NO:24); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO: 5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:7); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10), second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8),second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8), wherein second VL comprises a Y57S conservative substitution;second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10);- 9 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO: 5); second VL CDR1 comprises the amino acid sequence RASQSVSSNYLA (SEQ ID NO: 15); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSSIYYADSVKG (SEQ ID NO:11); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO: 5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNR AT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KSRAGDFDY (SEQ ID NO: 12); second VL CDRI comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYSAGDFDY (SEQ ID NO: 13); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8),second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRYGDFDY (SEQ ID NO: 14); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISASSSSIYYADSVKG (SEQ ID NO:25); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO: 5); second- 10 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:7); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:7);second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); second VH CDR3 comprises the amino acid sequence KYSAGDFDY (SEQ ID NO: 13); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSNYLA (SEQ ID NO: 15); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:7);second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23), second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:7); second VL CDR1 comprises the amino acid sequence RASQSVSSSNLA (SEQ ID NO: 16); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8); orsecond VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:7); second VL CDRl comprises the amino acid sequence R / XSQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASSRAT (SEQ ID NO: 17); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8).

[0020] In some embodiments, (i) second VH is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 100-108; and (ii) second VL is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs:200-204. In- 11 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01some embodiments, second VH comprises the amino acid sequence of any one of SEQ ID NOs: 100-108 and second VL comprises the amino acid sequence of any one of SEQ ID NOs:200-204.

[0021] In some embodiments, a bispecific antibody comprises or is (a) monovalent and has a monovalent affinity (KD) for hTfR1 of > 10 nM or is bivalent and has a monovalent affinity (KD) for hTfRl of >100 nM and / or (b) has an off rate (kd) of >= 0.01 / s.

[0022] In some embodiments, second VH comprises the amino acid sequence of SEQ ID NO: 100 and second VL comprises the amino acid sequence of SEQ ID NO:200.

[0023] In some embodiments, second VH comprises the amino acid sequence of SEQ ID NO: 101 and second VL comprises the amino acid sequence of SEQ ID NO:200; second VH comprises the amino acid sequence of SEQ ID NO: 102 and second VL comprises the amino acid sequence of SEQ ID NO: 200; second VH comprises the amino acid sequence of SEQ ID NO: 102 and second VL comprises the amino acid sequence of SEQ ID NO:201; second VH comprises the amino acid sequence of SEQ ID NO: 102 and second VL comprises the amino acid sequence of SEQ ID NO:203; second VH comprises the amino acid sequence of SEQ ID NO: 103 and second VL comprises the amino acid sequence of SEQ ID NO:200, second VH comprises the amino acid sequence of SEQ ID NO: 104 and second VL comprises the amino acid sequence of SEQ ID NO:200; second VH comprises the amino acid sequence of SEQ ID NO: 105 and second VL comprises the amino acid sequence of SEQ ID NO:200; second VH comprises the amino acid sequence of SEQ ID NO: 106 and second VL comprises the amino acid sequence of SEQ ID NO:200; second VH comprises the amino acid sequence of SEQ ID NO: 107 and second VL comprises the amino acid sequence of SEQ ID NO:200; second VH comprises the amino acid sequence of SEQ ID NO: 108 and second VL comprises the amino acid sequence of SEQ ID NO:200; second VH comprises the amino acid sequence of SEQ ID NO: 100 and second VL comprises the amino acid sequence of SEQ ID NO:201; second VH comprises the amino acid sequence of SEQ ID NO: 100 and second VL comprises the amino acid sequence of SEQ ID NO:202; second VH comprises the amino acid sequence of SEQ ID NO: 100 and second VL comprises the amino acid sequence of SEQ ID NO:203; or second VH comprises the amino acid sequence of SEQ ID NO: 100 and second VL comprises the amino acid sequence of SEQ ID NO:204.- 12 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0024] In some embodiments, a bispecific antibody described herein is a single chain antibody, an Fab fragment, an F(ab’)2 fragment, an Fab’ fragment, an Fsc fragment, an Fv fragment, an scFv, an sc(Fv)₂, or a diabody. In some embodiments, a bispecific antibody described herein comprises or is a bivalent antibody, a monovalent antibody, or any combination thereof.

[0025] In some embodiments, a bispecific antibody described herein comprises a constant heavy chain (CH) domain and a constant light chain (CL) domain. In some embodiments, a bispecific antibody comprises substitutions, insertions, or deletions occur outside hypervariable regions. In some embodiments, a bispecific antibody comprises one or more mutations in the amino acid sequence of a constant region CHI, CH2, CH3, CL, or any combination thereof In some embodiments, a bi specific antibody compri ses an amino acid sequence of the constant region is modified by mutation of one or more amino acid residues to impart a desired functional property (e g., altered effector function or half-life, reduced glycosylation). In some embodiments, a bispecific antibody comprises (i) the first heavy chain comprises one or more mutations in at least one constant region; (ii) the first light chain comprises one or more mutations in at least one constant region, (iii) the second heavy chain comprises one or more mutations in at least one constant region; and / or (iv) the second light chain comprises one or more mutations in at least one constant region.

[0026] In some embodiments, a bispecific antibody described herein comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identity to the amino acid sequence of any one of SEQ ID Nos: 400-407, 412-414, 603-611, 700-702, and 800-802.

[0027] In some embodiments, a bispecific antibody comprises: (a) an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identity to the amino acid sequence of any one of SEQ ID Nos: 400 to 401, and / or (b) an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identity to the amino acid sequence of any one of SEQ ID NOs: 401 to 402.

[0028] In some embodiments, a bispecific antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises or consists of the amino acid sequences set forth in SEQ ID NO:400 and the light chain comprises or consists of the amino acid sequence set forth in SEQ ID NO:401.- 13 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0029] In some embodiments, a bispecific antibody comprises a Fab fragment. In some embodiments, a bi specific antibody comprises a Fab fragment, wherein the Fab fragment comprises the amino acid sequences set forth in SEQ ID NOs: 401 and 402.

[0030] In some embodiments, a bispecific antibody comprises a Fab-Fc. In some embodiments, a bispecific antibody comprises a Fab-Fc, wherein the Fab-Fc comprises the amino acid sequences set forth in SEQ ID NOs: 401, 404, and 406. In some embodiments, a bispecific antibody comprises a Fab-Fc, wherein the Fab-Fc comprises the amino acid sequences set forth in SEQ ID NOs: 400 and 401.

[0031] In some embodiments, a bispecific antibody comprises an Fc-Fab. In some embodiments, a bispecific antibody comprises an Fc-Fab, wherein the Fc-Fab comprises the amino acid sequences set forth in SEQ ID NOs: 401, 405, and 406. In some embodiments, a bispecific antibody comprises an Fc-Fab, wherein the Fc-Fab comprises the amino acid sequences set forth in SEQ ID NOs: 401 and 403.

[0032] In some embodiments, a bispecific antibody comprises: (a) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 400, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 401; (b) amino acid sequences set forth in SEQ ID NOs: 401 and 402; (c) amino acid sequences set forth in SEQ ID NOs: 401, 404, and 406; (d) amino acid sequences set forth in SEQ ID NOs: 400 and 401; (e) amino acid sequences set forth in SEQ ID NOs: 401, 405, and 406; or (f) amino acid sequences set forth in SEQ ID NOs: 401 and 403.

[0033] Also provided herein is a nucleotide sequence or nucleotide sequences encoding any one of the foregoing antibodies.

[0034] Also provided herein is an expression vector or expression vectors comprising the foregoing nucleotide sequence or nucleotide sequences operably linked to a promoter.

[0035] Also provided herein is an isolated cell comprising the foregoing nucleotide sequence or nucleotide sequences or the foregoing expression vector or expression vectors.

[0036] Also provided herein is an isolated cell comprising (i) a first expression vector comprising a first nucleotide sequence encoding a first polypeptide comprising a first VH of any one of the foregoing antibodies operably linked to a promoter; (ii) a second expression vector comprising a second nucleotide sequence encoding a second polypeptide comprising a first VL of any one of the foregoing antibodies operably linked to a promoter; (iii) a third expression> 14 >13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01vector comprising a third nucleotide sequence encoding a third polypeptide comprising a second VH of any one of the foregoing antibodies operably linked to a promoter; and / or (iv) a fourth expression vector comprising a fourth nucleotide sequence encoding a fourth polypeptide comprising a second VL of any one of the foregoing antibodies operably linked to a promoter.

[0037] In some embodiments, a host cell comprises a first expression vector comprising a first nucleotide sequence encoding a first polypeptide comprising a first VH of any one of the foregoing antibodies operably linked to a promoter. In some embodiments, a host cell comprises a second expression vector comprising a second nucleotide sequence encoding a second polypeptide comprising a first VL of any one of the foregoing antibodies operably linked to a promoter. In some embodiments, a host cell comprises a third expression vector comprising a third nucleotide sequence encoding a third polypeptide comprising a second VH of any one of the foregoing antibodies operably linked to a promoter. In some embodiments, a host cell comprises a fourth expression vector comprising a fourth nucleotide sequence encoding a fourth polypeptide comprising a second VL of any one of the foregoing antibodies operably linked to a promoter. In some embodiments, a host cell comprises (i) a first expression vector comprising a first nucleotide sequence encoding a first polypeptide comprising a first VH of any one of the foregoing antibodies operably linked to a promoter; and (ii) a second expression vector comprising a second nucleotide sequence encoding a second polypeptide comprising a first VL of any one of the foregoing antibodies operably linked to a promoter. In some embodiments, a host cell comprises (i) a third expression vector comprising a third nucleotide sequence encoding a third polypeptide comprising a second VH of any one of the foregoing antibodies operably linked to a promoter; and (ii) a fourth expression vector comprising a fourth nucleotide sequence encoding a fourth polypeptide comprising a second VL of any one of the foregoing anti bodies operably linked to a promoter.

[0038] In some embodiments, a host cell comprises (i) a first expression vector comprising a first nucleotide sequence encoding a first polypeptide comprising a first VH of any one of the foregoing antibodies operably linked to a promoter, (ii) a second expression vector comprising a second nucleotide sequence encoding a second polypeptide comprising a first VL of any one of the foregoing antibodies operably linked to a promoter; (iii) a third expression vector comprising a third nucleotide sequence encoding a third polypeptide comprising a second VH of any one of the foregoing antibodies operably linked to a promoter; and (iv) a fourth- 15 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01expression vector comprising a fourth nucleotide sequence encoding a fourth polypeptide comprising a second VL of any one of the foregoing antibodies operably linked to a promoter.

[0039] Also provided herein is a method of making any one of the foregoing antibodies, comprising culturing the foregoing cell and isolating the antibody.

[0040] Also provided herein is a pharmaceutical composition comprising of any one of the foregoing bispecific antibodies and a pharmaceutically acceptable carrier.

[0041] Also provided herein is a method of transporting an anti-Ap antibody or antigen binding fragment thereof, across the blood brain barrier via transcytosis, the method comprising administering to a human subject any one of the foregoing bispecific antibodies.

[0042] Also provided herein is a method of delivering an anti-Ap antibody or antigen binding fragment thereof, in vivo, the method comprising administering to a human subject any one of the foregoing bispecific antibodies. In some embodiments, a human subject has a neurological disease and the method delivers the agent to brain tissue. In some embodiments, a neurological disorder is Alzheimer’s disease, Parkinson’s disease Down's syndrome, amyloidosis disorders, hereditary cerebral hemorrhage with amyloidosis Dutch type, Lewy body dementia, frontotemporal dementia, Guam Parkinson -Dementia complex, A. LS (amyotrophic lateral sclerosis), Creutzfeldt Jacob disease, HIV-related dementia, motor neuropathy, Huntington’s disease, progressive supranuclear palsy, multiple sclerosis, spinal muscular atrophy, muscular dystrophy, spinal cord injury, stroke, ophthalmological conditions, acute or chronic optic neuritis, psychiatric disorders, Tourette’s disease brain injury, brain tumors, epilepsy, cerebral amyloid angiopathy, inflammatory cerebral amyloid angiopathy, cerebral amyloidoma, or any other amyloid-related disease.

[0043] Also provided herein is a method of treating Alzheimer’s disease in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of any one of the foregoing bispecific antibodies.

[0044] Also provided herein is a method of transporting an anti-beta-amyloid antibody or antigen binding fragment thereof, across the blood brain barrier via transcytosis, the method comprising administering to a human subject any one of the foregoing bispecific antibodies or a pharmaceutical composition comprising the same

[0045] Also provided herein is a method of delivering an anti-beta-amyloid antibody or antigen binding fragment thereof, in vivo, the method comprising administering to a human- 16 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01subject any one of the foregoing bispecific antibodies or a pharmaceutical composition comprising the same.

[0046] Also provided herein is a method of reducing the amount of tau and / or beta¬ amyloid in a human subject. In some embodiments, a human subject has a neurological and / or neurodegenerative disease, and the method delivers any one of the foregoing bispecific antibodies to brain tissue.

[0047] Also provided herein is a method of treating a neurological and / or neurodegenerative disease in a human subject, the method comprising administering to the human subject any one of the foregoing bispecific antibodies or a pharmaceutical composition comprising the same. Also provided herein is a method of preventing a neurological and / or neurodegenerative disease in a human subject, the method comprising administering to the human subject any one of the foregoing bispecific antibodies or a pharmaceutical composition comprising the same. In some embodiments, a neurological disease is Alzheimer’s disease, Parkinson’s disease Down's syndrome, amyloidosis disorders, hereditary cerebral hemorrhage with amyloidosis Dutch type, Lewy body dementia, frontotemporal dementia, Guam Parkinson-Dementia complex, ALS (amyotrophic lateral sclerosis), Creutzfeldt Jacob disease, HIV-related dementia, motor neuropathy, Huntington’s disease, progressive supranuclear palsy, multiple sclerosis, spinal muscular atrophy, muscular dystrophy, spinal cord injury, stroke, ophthalmological conditions, acute or chronic optic neuritis, psychiatric disorders, Tourette’s disease brain injury, brain tumors, epilepsy, cerebral amyloid angiopathy, inflammatory cerebral amyloid angiopathy, cerebral amyloidoma, or any other amyloid-related disease.

[0048] Also provided herein is a method of treating Alzheimer’s disease in a human subject, comprising administering to the human subject a therapeutically effective amount of any one of the foregoing bispecific antibodies or a pharmaceutical composition comprising the same. In some embodiments, Alzheimer’s disease is latent, preclinical, or asymptomatic Alzheimer’s disease, early Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease, mild Alzheimer’s disease dementia, mild cognitive impairment due to Alzheimer’s disease, midstage Alzheimer’s disease, or late-stage Alzheimer’s disease.

[0049] Also provided herein is a method of treating abnormal accumulation or deposition of Ap in the central nervous system in a human subject, the method comprising administering to- 17 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01the human subject any one of the foregoing bispecific antibodies or a pharmaceutical composition comprising the same.

[0050] Also provided herein is a method of treating mild cognitive impairment in a human subject, the method comprising administering to the human subject any one of the foregoing bispecific antibodies or a pharmaceutical composition comprising the same.

[0051] Also provided herein is a method of treating and / or preventing a neurological and / or neurodegenerative disease comprising administering to the human subject multiple doses of any one of the foregoing bispecific antibodies or a pharmaceutical composition comprising the same.

[0052] Also provided herein is a method of treating Alzheimer's disease in a human subject, the method comprising administering to the human subject a therapeutically effective amount of any one of the foregoing bispecific antibodies or a pharmaceutical composition comprising the same, wherein the human subject has p-tau tangles, p-tau threads, and / or p-tau neuritic plaques, optionally wherein the human subject has neocortical p-tau tangles, neocortical p-tau threads, and / or neocortical p-tau neuritic plaques. In some embodiments, administration of any one of the foregoing bispecific antibodies or a pharmaceutical composition comprising the same, reduces p-tau tangles, p-tau threads, and / or p-tau neuritic plaques in the brain of the human subject or the amount of phosphorylated tau (p-tau) and / or total tau (t-tau) in the cerebrospinal fluid (CSF) of the human subject.

[0053] Also provided herein is a method of reducing the amount tau in a human subject having Alzheimer’s disease, the method comprising administering to the human subject an effective amount of any one of the foregoing bispecific antibodies or a pharmaceutical composition comprising the same.

[0054] Also provided herein is a method of treating Alzheimer's disease by reducing the amount of tau in a human subject, the method comprising administering to the human subject an effective amount of any one of the foregoing bispecific antibodies or a pharmaceutical composition comprising the same.

[0055] Other features and advantages of the invention will be apparent from the following detailed description and from the claims.- 18 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01BRIEF DESCRIPTION OF THE DRAWINGS

[0056] FIG. 1A is a schematic depicting a bispecific antibody as described herein. As shown, the darker red portions each represent an anti-Abeta heavy chain variable region (VH), the lighter red portions each represent an anti-Abeta light chain variable region (VL), the darker green portions each represent an anti-TfR VH, the lighter green portions each represent an anti-TfR VL, the darker blue portions each represent a heavy chain constant region (CH), and the lighter blue portions each represent a light chain constant region (CL). The triangle and associated triangle-shaped indent represent a knob-in-hole configuration to bias heavy chain pairing. The semi-circle and associated indent, as well as the trapezoid and associated indent, represent heteropairing configurations to bias light chain pairing.

[0057] FIG. IB is a series of cartoons depicting control hlgG (left), ANTIBODY Z (second from left), ANTIBODY Z / ANTIBODY X bivalent (third from left), and ANTIBODY Z / ANTIBODY X monovalent (right).

[0058] FIG. 2 are graphs depicting binding affinity of exemplary anti-Ap / anti-TfR bispecific antibodies for recombinant human and cynomolgus monkey TfRl ectodomain (ECD) was measured and compared to that of the corresponding anti-TfR Fab fragments by surface plasmon resonance (SPR). Kinetics and affinity measurements were made in running buffer consisting of 10mM HEPES, pH7.4 with 150mM NaCI, 3mM EDTA, 0.05% bovine serum albumin, and 0.005% surfactant P20, with the integrated flow cell held at 25°C.

[0059] FIG. 3A is a graph depicting transcytosis of exemplary anti-Ap / anti-TfR bi specific antibodies or control hlgG.

[0060] FIG. 3B is a graph depicting bivalent transcytosis of exemplary anti-Ap / anti-TfR bispecific antibodies plotted against the measured affinity for hTfR1.

[0061] FIG. 4A is a graph depicting Western blot for hTfRl in human cerebral microvascular endothelial cells (hCMEC / D3) following treatment with 1000 nM of the indicated exemplary anti-Ap / anti-TfR bispecific antibodies.

[0062] FIG. 4B is a graph depicting TfRl levels (% of control) in human cerebral microvascular endothelial cells (hCMEC / D3) following treatment with 1000 nM of the indicated exemplary' anti-Ap / anti-TfR bispecific antibodies.

[0063] FIG. 5 is a line graph depicting the binding response (Absorbance, OD450) for exemplary anti-Ap / anti-TfR bispecific antibodies and two control antibodies. Binding of- 19 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01exemplary anti-Ap / anti-TfR bispecific antibodies to human Aβ40 was determined using an Ab- binding ELISA.

[0064] FIG. 6 is a line graph depicting the binding response (Plaque Intensity, % of vehicle) for exemplary anti-Ap / anti-TfR bispecific antibodies and one control antibody.Exemplary anti-Ap / anti-TfR bispecific antibodies function was tested using an ex-vivo plaque clearance assay.

[0065] FIG. 7 is a line graph depicting the binding response (Plaque Intensity, % of vehicle) for exemplar}' anti-Ap / anti-TfR bispecific antibodies and two monospecific control antibodies. Exemplary anti-Ap / anti-TfR bispecific antibodies with different Fc effector functions were tested for plaque phagocytosis activity.

[0066] FIG. SA is a series of cartoons depicting control hlgG (left) and bi specific antibody (right) comprising ANTIBODY Z (bivalent) / ANTIBODY X (monovalent).

[0067] FIG. 8B is a graph depicting serum hlgG concentration (nM) at the indicated timepoints in hTfR KI mice administered 3 mg / kg IV molar IgG equivalent of hlgG control (squares) or four bispecific antibodies incorporating ANTIBODY X variant Fab fragments (ANTIBODY Z bivalent / ANTIBODY X monovalent (VH-S60A) (triangles, pointing up), ANTIBODY Z bivalent / ANTIBODY X monovalent (VL-S39N) (triangles, pointing down), ANTIBODY Z bivalent / ANTIBODY X monovalent (VH-S60A / VL-S39N) (diamonds) or ANTIBODY Z bivalent / ANTIBODY X monovalent (VL-Y57S) (circles)).

[0068] FIG. 8C is a graph depicting brain hlgG concentration (nM) at the indicated timepoints in hTfR KI mice administered 3 mg / kg IV molar IgG equivalent of hlgG control (squares) or four bispecific antibodies incorporating ANTIBODY X variant Fab fragments (ANTIBODY Z bivalent / ANTIBODY X monovalent (VH-S60A) (triangles, pointing up), ANTIBODY Z bivalent / ANTIBODY X monovalent (VL-S39N) (triangles, pointing down), ANTIBODY Z bivalent / ANTIBODY X monovalent (VH-S60A / VL-S39N) (diamonds) or ANTIBODY Z bivalent / ANTIBODY X monovalent (VL-Y57S) (circles)).

[0069] FIG. 8D is a graph depicting reticulocyte levels (% of control) at the indicated timepoints in hTfR KI mice administered 3 mg / kg IV molar IgG equivalent of hlgG control (squares) or four bi specific antibodies incorporating ANTIBODY X variant Fab fragments ( ANTIBODY Z bivalent / ANTIBODY X monovalent (VH-S60A) (triangles, pointing up), ANTIBODY Z bivalent / ANTIBODY X monovalent (VL-S39N) (triangles, pointing down),- 20 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01ANTIBODY Z bivalent / ANTIBODY X monovalent (VH-S60A / VL-S39N) (diamonds) or ANTIBODY Z bivalent / ANTIBODY X monovalent (VL-Y57S) (circles)).

[0070] FIG. 9A is depicts exemplary immunohistochemical image analysis of colocalization of exemplary anti-Ap / anti-TfR bispecific antibodies with amyloid plaques of 1. mouse cerebral cortex containing plaques, 2. plaque area identified from Ab staining, 3. hlgG staining overlay ed with plaque areas, and 4. threshold-based target engagement analysis of hlgG and Ab colocalization. Primary measurements used were: cortex area, plaque area, plaque burden (% plaque area / cortex area), area of hlgG near plaques (10micron or less), and target engagement (% area hlgG near plaques / plaque area).

[0071] FIG. 9B is a graph depicting serum hlgG concentration at two doses (Low Dose and High Dose) of exemplary anti-Ap / anti-TfR bispecific antibodies or control antibodies showing TfR-mediated clearance.

[0072] FIG. 9C is a graph depicting plaque engagement at two doses (Low Dose and High Dose) of exemplary anti-Ap / anti-TfR bispecific antibodies or control antibodies as measured by Ab / hlgG colocalization.

[0073] FIG. 9D is a graph depicting reticulocyte levels (% of control) at at two doses (Low Dose and High Dose) of exemplary anti-Ap / anti-TfR bispecific antibodies or control antibodies.

[0074] FIG. 10 is a graph depicting brain hlgG concentration in TfR KI mice at the indicated timepoints following administration of a single dose of exemplary anti-Ap / anti-TfR bispecific antibodies or control antibodies.

[0075] FIG. 11A is a graph depicting serum hlgG concentration in TfR KI mice at the indicated timepoints following administration of indicated doses of exemplary anti-Ap / anti-TfR bispecific antibodies or control antibodies.

[0076] FIG. 11B is a graph depicting brain hlgG concentration in TfR KI mice at the indicated timepoints following administration of indicated doses of exemplary' anti-Ap / anti-TfR bispecific antibodies or control antibodies.

[0077] FIG. 11C is a graph depicting reticulocyte levels (% of control) in TfR KI mice at the indicated timepoints following administration of indicated doses of exemplary anti-Ap / anti- TfR bispecific antibodies or control antibodies.- 21 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0078] FIG. 12A is a line graph depicting plasma hlgG concentration in TfR KI mice at the indicated timepoints following administration of exemplary anti-Ap / anti-TfR bispecific antibodies or control antibodies to determine plasma clearance rates.

[0079] FIG. 12B is a graph depicting brain hlgG concentration in the hippocampus brain region of TfR KI mice at the indicated timepoints following administration of exemplary anti-Ap / anti -TfR bi specific antibodies or control antibodies to assess regional brain exposure.

[0080] FIG. 12C is a graph depicting brain hlgG concentration in the cerebellum brain region of TfR KI mice at the indicated timepoints following administration of exemplary anti-Ap / anti-TfR bispecific antibodies or control antibodies to assess regional brain exposure.

[0081] FIG. 12D is a graph depicting brain hlgG concentration in the frontal cortex brain region of TfR KI mice at the indicated timepoints following administration of exemplary anti-Ap / anti-TfR bispecific antibodies or control antibodies to assess regional brain exposure.

[0082] FIG. 12E is a graph depicting brain hlgG concentration in the striatum brain region of TfR KI mice at the indicated timepoints following administration of exemplary anti-Ap / anti -TfR bi specific antibodies or control antibodies to assess regional brain exposure.

[0083] FIG. 13A is a graph depicting reticulocyte levels (% CBC) in TfR KI mice at the indicated timepoints following administration of indicated doses of exemplary anti-Ap / anti-TfR bispecific antibodies or control antibodies to assess reticulocyte dynamics.

[0084] FIG. 13B is a graph depicting RBC count in TfR KI mice at the indicated timepoints following administration of indicated doses of exemplary anti-Ap / anti-TfR bispecific antibodies or control antibodies to assess effect in hematology parameters.

[0085] FIG. 14 is depicts Human IgG immunohistochemistry images of TfR KI mice brain biopsies following administration of exemplary anti-Ap / anti-TfR bispecific antibodies to assess brain exposure using MSD.

[0086] FIG. 15 is a graph depicting the Human serum pre-existing anti-drug antibody assessment (Absorbance, OD450) for exemplary anti-Ap / anti-TfR bispecific antibody and three control antibodies. Binding of exemplary anti-Ap / anti-TfR bispecific antibody was determined using an Ap-binding ELISA.- 22 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01DETAILED DESCRIPTION

[0087] The present disclosure provides, in part, bispecific antibodies capable of binding beta amyloid (A ) and transferrin receptor 1 (TfR). Related polypeptides, polynucleotides, vectors, cells, compositions, methods of making the bispecific antibodies, and methods of delivering the compositions are also provided. The disclosure also provides methods of using the anti-Ap / anti-TfR bispecific antibodies described herein. The present disclosure also relates, in part, to the treatment of neurological and / or neurodegenerative diseases comprising the use of anti-Ap / anti-TfR bispecific antibodies described herein or compositions comprising the same. Examples of a neurological and / or neurodegenerative disease includes, but is not limited to, Alzheimer’s disease, Parkinson’s disease Down's syndrome, amyloidosis disorders, hereditary cerebral hemorrhage with amyloidosis Dutch type, Lewy body dementia, frontotemporal dementia, Guam Parkinson-Dementia complex, ALS (amyotrophic lateral sclerosis), Creutzfeldt Jacob disease, HIV-related dementia, motor neuropathy, Huntington’s disease, progressive supranuclear palsy, multiple sclerosis, spinal muscular atrophy, muscular dystrophy, spinal cord injury, stroke, ophthalmological conditions, acute or chronic optic neuritis, psychiatric disorders, Tourette’s disease brain injury, brain tumors, epilepsy, cerebral amyloid angiopathy, inflammatory cerebral amyloid angiopathy, cerebral amyloidoma, and any other amyloid-related disease. Alzheimer’s disease, abbreviated herein as AD, is a dementia that can be identified by clinical diagnosis and established by markers of the disease. AD is a continuum having certain operationally defined stages of disease progression. AD pathology begins prior to the onset of clinical symptoms. For example, amyloid plaques, one marker of AD pathology, form 10-20 years prior to the onset of AD dementia. The currently recognized stages of AD include preclinical, prodromal, mild, moderate, and severe. These stages may be further divided into subcategories based on the severity of symptoms and measures of AD progression Among other things, the present disclosure relates to the treatment of Alzheimer’s disease comprising the use of anti-Ap / anti-TfR bispecific antibodies described herein or compositions comprising the same.DEFINITIONS

[0088] Unless otherwise defined herein, technical and scientific terms used in the present description have the meanings that are commonly understood by those of ordinary skill in the art. For purposes of interpreting this specification, the following description of terms will apply and- 23 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01whenever appropriate, terms used in the singular will also include the plural and vice versa In the event that any description of a term set forth conflicts with any document incorporated herein by reference, the description of the term set forth below shall control.

[0089] The term ‘‘antibody” as used herein refers to an immunoglobulin molecule, or a molecule comprising a fragment of an immunoglobulin molecule, that recognizes and binds a target through at least one antigen-binding site. “Antibody” as used herein in the broadest sense and encompasses various antibody structures, including “antibody fragments” and “antigenbinding fragments.” Thus, as used herein, the term “antibody” includes, but is not limited to, recombinant antibodies, monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, bispecific antibodies, multispecific antibodies, diabodies, tribodies, tetrabodies, single chain Fv (scFv) antibodies, and antibody fragments as long as they exhibit the desired antigen-binding activity.

[0090] The term “intact antibody” or “full-length antibody” as used herein refers to an antibody having a structure substantially similar to a native antibody structure. This includes, for example, an antibody comprising two light chains each comprising a variable region and a light chain constant region (CL) and two heavy chains each comprising a variable region and at least heavy chain constant regions CHI, CH2, and CH3 and a hinge region between CHI and CH2 regions.

[0091] The term “antigen-binding fragment”, as used herein refers to a molecule other than an intact antibody that comprises a portion of an antibody and an antigen-binding site. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv, single chain antibody molecules (e.g., scFv, sc(Fv)2,), disulfide-linked scFv (dsscFv), diabodies, tribodies, tetrabodies, minibodies, dual variable domain antibodies (DVD), single variable domain antibodies (e.g., camelid antibodies), and multispecific antibodies formed from antibodyfragments.

[0092] The term “monoclonal antibody” as used herein refers to a substantially homogenous antibody population involved in the highly specific recognition and binding of a single antigenic determinant or epitope. The term “monoclonal antibody” as used herein encompasses intact and full-length monoclonal antibodies as well as antibody fragments (e.g., Fab, Fab', F(ab')2, Fv), single chain antibodies (e.g., scFv), fusion proteins comprising an antibody fragment, and any other modified immunoglobulin molecule comprising at least one- 24 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01antigen-binding site. Furthermore, “monoclonal antibody” as used herein refers to such antibodies made by any number of techniques, including but not limited to, hybridoma production, phage library display, recombinant expression, and transgenic animals.

[0093] The term “chimeric antibody” refers to an antibody in which a portion of the heavy and / or light chain is derived from a first source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0094] The term “humanized antibody” as used herein refers to an antibody that comprises a human heavy chain variable region and a light chain variable region wherein the native CDR amino acid residues are replaced by residues from corresponding CDRs from a nonhuman antibody (e.g., mouse, rat, rabbit, or nonhuman primate), wherein the nonhuman antibody has the desired specificity, affinity, and / or activity. In some embodiments, one or more framework region amino acid residues of the human heavy chain or light chain variable regions are replaced by corresponding residues from nonhuman antibody. Furthermore, humanized antibodies can comprise amino acid residues that are not found in the human antibody or in the nonhuman antibody. In some embodiments, these modifications are made to further refine and / or optimize antibody characteristics In some embodiments, a humanized antibody comprises at least a portion of an immunoglobulin constant region (e.g., CHI, hinge, CH2, CH3, Fc), typically that of a human immunoglobulin

[0095] The term “human antibody” as used herein refers to an antibody that possesses an amino acid sequence that corresponds to an antibody produced by a human and / or an antibody that has been made using any of the techniques that are known to those of skill in the art for making human antibodies. These techniques include, but are not limited to, phage display libraries, yeast display libraries, transgenic animals, recombinant protein production, and B-cell hybridoma technology.

[0096] The terms “epitope” and “antigenic determinant” are used interchangeably herein and refer to that portion of an antigen or target capable of being recognized and bound by a particular antibody. When the antigen or target is a polypeptide, epitopes can be formed both from contiguous amino acids and noncontiguous amino acids juxtaposed by tertiary folding of the protein. Epitopes formed from contiguous amino acids (also referred to as linear epitopes) are typically retained upon protein denaturing, whereas epitopes formed by tertiary folding (also referred to as conformational epitopes) are typically lost upon protein denaturing. An epitope- 25 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01typically includes at least 3, and more usually, at least 5, 6, 7, or 8-10 amino acids in a unique spatial conformation. Epitopes can be predicted using any one of a large number of software bioinformatic tools available on the internet. X-ray crystallography or electron microscopy (e.g., cryo-electron microscopy) may be used to characterize an epitope on a target protein by analyzing the amino acid residue interactions of an antigen / antibody complex.

[0097] The term “specifically binds” or “binds” as used herein refers to an antibody that interacts more frequently, more rapidly, with greater duration, with greater affinity, or with some combination of the above to a particular antigen, epitope, protein, or target molecule than with alternative substances. An antibody that specifically binds an antigen can be identified, for example, by immunoassays, ELISAs, surface plasmon resonance (SPR), or other techniques known to those of skill in the art. In some embodiments, an antibody that specifically binds an antigen (e g., human TfRl) can bind related antigens (e.g., cyno TfRl). An antibody that specifically binds an antigen can bind the target antigen at a higher affinity than its affinity for a different antigen. The different antigen can be a related antigen. In some embodiments, an antibody that specifically binds an antigen can bind the target antigen with an affinity that is at least 20 times greater, at least 30 times greater, at least 40 times greater, at least 50 times greater, at least 60 times greater, at least 70 times greater, at least 80 times greater, at least 90 times greater, or at least 100 times greater, than its affinity for a different antigen. In some embodiments, an antibody that specifically binds a particular antigen binds a different antigen at such a low affinity that binding cannot be detected using an assay described herein or otherwise known in the art. In some embodiments, affinity is measured using SPR technology in a Biacore system as described herein or as known to those of skill in the art.

[0098] The terms “polypeptide” and “peptide” and “protein” are used interchangeably herein and refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid, including but not limited to, unnatural amino acids, as well as other modifications known in the art. It is understood that, because the polypeptides of this disclosure may be based upon antibodies, the- 26 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01term “polypeptide” encompasses polypeptides as a single chain and polypeptides of two or more associated chains.

[0099] The terms “polynucleotide” and “nucleic acid” and “nucleic acid molecule” are used interchangeably herein and refer to polymers of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase.

[0100] The terms “identical” or percent “identity” in the context of two or more nucleic acids or polypeptides, refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned (introducing gaps, if necessary) for maximum correspondence, not considering any conservative amino acid substitutions as part of the sequence identity. The percent identity may be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software that may be used to obtain alignments of amino acid or nucleotide sequences are well-known in the art. These include, but are not limited to, BLAST, ALIGN, Megalign, BestFit, GCG Wisconsin Package, and variants thereof In some embodiments, two nucleic acids or polypeptides of the disclosure are substantially identical, meaning they have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, and in some embodiments, at least 95%, 96%, 97%, 98%, 99% nucleotide or amino acid residue identity, when compared and aligned for maximum correspondence, as measured using a sequence comparison algorithm or by visual inspection. In some embodiments, identity exists over a region of the sequences that is at least about 10, at least about 20, at least about 20-40, at least about 40-60 nucleotides or amino acid residues, at least about 60-80 nucleotides or amino acid residues in length or any integral value there between. In some embodiments, identity exists over a longer region than 60-80 nucleotides or amino acid residues, such as at least about 80-100 nucleotides or amino acid residues, and in some embodiments, the sequences are substantially identical over the full length of the sequences being compared, for example, (i) the coding region of a nucleotide sequence or (ii) an amino acid sequence.

[0101] The phrase “conservative amino acid substitution” as used herein refers to a substitution in which one amino acid residue is replaced with another amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been- 27 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01generally defined in the art, including basic side chains (e.g, lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). For example, substitution of a phenylalanine for a tyrosine is considered to be a conservative substitution. Generally, conservative substitutions in the sequences of polypeptides and / or antibodies do not abrogate the binding of the polypeptide or antibody to the target binding site Methods of identifying nucleotide and amino acid conservative substitutions that do not eliminate binding are well-known in the art.

[0102] The term “vector’ as used herein means a construct that is capable of deli vering, and usually expressing, one or more gene(s) or sequence(s) of interest in a host cell. Examples of vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, plasmid, cosmid, or phage vectors, DNA or RNA expression vectors associated with cationic condensing agents, and DNA or RNA expression vectors encapsulated in liposomes.

[0103] The term “isolated” as used herein refers to a polypeptide, soluble protein, antibody, polynucleotide, vector, cell, or composition that is in a form not found in nature. An “isolated” antibody is substantially free of material from the cellular source from which it is derived. In some embodiments, isolated polypeptides, soluble proteins, antibodies, polynucleotides, vectors, cells, or compositions are those that have been purified to a degree that they are no longer in a form in which they are found in nature. In some embodiments, a polypeptide, soluble protein, antibody, polynucleotide, vector, cell, or composition that is isolated is substantially pure. A polypeptide, soluble protein, antibody, polynucleotide, vector, cell, or composition can be isolated from a natural source (e.g., tissue) or from a source such as an engineered cell line.

[0104] The term “substantially pure” as used herein refers to material that is at least 50% pure (i.e., free from contaminants), at least 90% pure, at least 95% pure, at least 98% pure, or at least 99% pure.

[0105] The term “pharmaceutically acceptable” as used herein refers to a substance approved or approvable by a regulatory agency or listed in the U. S. Pharmacopeia, European- 28 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01Pharmacopeia, or other generally recognized pharmacopeia for use in animals, including humans.

[0106] The terms “pharmaceutically acceptable excipient, carrier, or adjuvant” as used herein refer to an excipient, carrier, or adjuvant that can be administered to a subject, together with at least one antibody of the disclosure, and that is generally safe, non-toxic, and has no effect on the pharmacological activity of the therapeutic agent. In general, those of skill in the art and the U. S. FDA consider a pharmaceutically acceptable excipient, carrier, or adjuvant to be an inactive ingredient of any formulation.

[0107] The term “pharmaceutical composition” as used herein refers to a preparation that is in such form as to permit the biological activity of the antibody to be effective. A pharmaceutical formulation or composition generally comprises additional components, such as a pharmaceutically acceptable excipient, carrier, adjuvant, buffers, etc.

[0108] The term “effective amount” or “therapeutically effective amount” as used herein refers to an amount of an antibody of the disclosure that is required to reach the tissue of interest, or to an amount of a conjugate, a fusion protein or polypeptide, or a complex comprising an antibody of the di sclosure and a therapeutic agent that is suffici ent to reduce and / or ameliorate the severity and / or duration of (i) a disease, disorder or condition in a subject, and / or (ii) a symptom in a subject. The term also encompasses an amount of a conjugate necessary for the (i) reduction or amelioration of the advancement or progression of a given disease, disorder, or condition, (ii) reduction or amelioration of the recurrence, development, or onset of a given disease, disorder, or condition, and / or (iii) the improvement or enhancement of the prophylactic or therapeutic effect(s) of another agent or therapy (e.g., an agent other than the conjugates provided herein).

[0109] The term “therapeutic effect” as used herein refers to the effect and / or ability of an agent, e.g., an antibody, a conjugate, a fusion protein or polypeptide, or a complex comprising the antibody of the disclosure to reduce and / or ameliorate the severity and / or duration of (i) a disease, disorder, or condition in a subject, and / or (ii) a symptom in a subject. The term also encompasses the ability of an agent, e.g., a conjugate, to (i) reduce or ameliorate the advancement or progression of a given disease, disorder, or condition, (ii) reduce or ameliorate the recurrence, development, or onset of a given disease, disorder, or condition, and / or (iii) to- 29 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01improve or enhance the prophylactic or therapeutic effect(s) of another agent or therapy (e g., an agent other than the conjugates provided herein).

[0110] As used herein, reference to “about” or “approximately” a value or parameter includes (and describes) embodiments that are directed to that value or parameter. For example, a description referring to “about X” includes description of “X”. “About X” means + / - 10% of X. So, “about 10” means a value between 9 to 11.ANTI-Ap / ANTI-TFRl BISPECIFIC ANTIBODIES

[0111] The present disclosure provides, in part, bispecific antibodies capable of binding to a transferrin receptor or a fragment thereof and a beta-amyloid or a fragment thereof. In some embodiments, a bispecific antibody described herein is capable of binding to human transferrin receptor and human beta-amyloid. In some embodiments, a bispecific antibody comprises an anti-beta amyloid (AP) antibody or antigen-binding fragment thereof and an anti-TfR antibody or antigen-binding fragment thereof. In some embodiments, a bi specific antibody comprises an anti-Ap antibody and an anti-TfR antibody.AMYLOID BETA (AD OR ABET A)

[0112] Ap peptide is an important risk factor and has a central role in the onset and progression of neurological and / or neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Other exemplary neurological and / or neurodegenerative diseases include, but are not limited to, Down's syndrome, amyloidosis disorders, hereditary cerebral hemorrhage with amyloidosis Dutch type, Lewy body dementia, frontotemporal dementia, Guam Parkinson-Dementia complex, ALS (amyotrophic lateral sclerosis), Creutzfeldt Jacob disease, HIV-related dementia, motor neuropathy, Huntington’s disease, progressive supranuclear palsy, multiple sclerosis, spinal muscular atrophy, muscular dystrophy, spinal cord injury, stroke, ophthalmological conditions, acute or chronic optic neuritis, psychiatric disorders, Tourette’s disease brain injury', brain tumors, epilepsy, cerebral amyloid angiopathy, inflammatory cerebral amyloid angiopathy, cerebral amyloidoma, and any other amyloid-related diseases.

[0113] Ap is produced in normal individuals, but under some circumstances, this molecule aggregates leading to disease progression. Ap denotes peptides of 36 to 43 amino acids that are involved in forming amyloid plaques found in the brains of patients with neurological- 30 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01and / or neurodegenerative diseases such as Alzheimer’s disease. Similar plaques appear in some variants of Lewy body dementia and in inclusion body myositis. Ap also forms the aggregates that coat cerebral blood vessels in cerebral amyloid angiopathy. The Ap peptides are formed by cleavage of the amyloid precursor protein (APP) by the enzymes beta secretase and gamma secretase. Ap molecules can aggregate to form flexible soluble oligomers which may exist in several forms. Soluble oligomeric forms of the Ap peptide are thought to be causative agents in the development of Alzheimer's disease and / or other neurological diseases. Several A peptide alloforms exist, A 40 and A 42. The amino acid sequence of human Amyloid Peptide (1-40) is as follows: DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVV (SEQ ID NO:600). The amino acid sequence of human Amyloid Peptide (1-42) is as follows:DAEFRFIDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA (SEQ ID NO:601).TRANSFERRIN RECEPTOR (TFR)

[0114] Transferrin receptor, also known as CD71, is a transmembrane glycoprotein expressed in various sites of the human body at differing levels, whose function is to mediate cellular uptake of iron from a plasma glycoprotein, transferrin. Iron uptake from transferrin involves the binding of transferrin to the transferrin receptor, internalization of transferrin within an endocytic vesicle by receptor-mediated endocytosis and the release of iron from the protein by a decrease in endosomal pH. Ponka P, Lok CN. Int J Biochem Cell Biol. 1999 Oct;31 (10): 1111- 37 and Xiaopeng Mo, in Brain Targeted Drug Delivery System, 2019. Apotransferrin (i.e., non¬ iron conjugate) binds to TfR when bound to two Fe 3+ ions to form holotransferrin (i.e., iron conjugate). The complex of TfR and holotransferrin is translocated into the cell by receptor-mediated endocytosis. CD71 and transferrin dissociate in an endosomal environment, and transferrin moves into the cell while CD71 is recycled to the cell membrane. Thus, transferrin is thought to translocate into cells by proper binding to TfR and proper dissociation. The transferrin receptor system has been exploited for delivery of anticancer drugs and proteins, therapeutic genes into malignant cells, and to deliver other therapeutic agents across the blood brain barrier to the brain.

[0115] In humans and cynomolgus monkeys, two transferrin receptors, TfRl and TfR2 have been characterized. TfRl is a high affinity ubiquitously expressed receptor while- 31 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01expression of TfR2 is restricted to certain cell types and is unaffected by intracellular iron concentrations. TfR2 binds to transferrin with a 25-30 fold lower affinity than TfRl.

[0116] The sequences for human TfRl and cyno TfRl are as follows:Human TfRl (UniProtNo. P02786.2, SEQ IDNO:1)MMDQARSAFSNLFGGEPLSYTRF SLARQVDGDNSHVEMKLAVDEEENADNNTKANV TKPKRC SGSICYGTIAVIVFFLIGFMIGYLGYCKGVEPKTECERLAGTESPVREEPGEDFPAARRLYWDDLK RKLSEKLDSTDFTGTIKLLNENSYVPREAGSQKDENLALYVENQFREFKLSKVWRDQHFVKIQV KDSAQNSVIIVDKNGRLVYLVENPGGYVAYSKAATVTGKLVFIANFGTKKDFEDLYTPVNGSIVI VRAGKITFAEKVANAESLNAIGVLIYMDQTKFPIVNAELSFFGHAHIUTGDPYTPGFPSFNHTQFP PSRSSGLPNIPVQTISRAAAEKLFGNMEGDCPSDWKTDSTCRMVTSESKNVKLTVSNVLKEIKILN IFGVIKGFVEPDHYVVVGAQRDAWGPGAAKSGVGTALLLKLAQMFSDMVLKDGFQPSRSIIFAS WSAGDFGSVGATEWLEGYLSSLHLKAFTYINLDKAVLGTSNFKVSASPLLYTLIEKTMQNVKHP VTGQFLYQDSNWASKVEKLTLDNAAFPFLAYSGIPAVSFCFCEDTDYPYLGTTMDTYKELIERIP ELNKVARAAAEVAGQFVIKLTHDVELNLDYERYNSQLLSFVRDLNQYRADIKEMGLSLQWLYS ARGDFFRATSRLTTDFGNAEKTDRFVMKKINTDRVMRVEYHFLSPYVSPKESPFRHVFWGSGSHT LPALLENLKLRKQNNGAFNETLFRNQLALAIY’TIQGAANALSGDVWDIDNEFCyno TfR1 (UniProt No. G8F602; SEQ ID NO:2) MMDQARSAFSNLFGGEPLSYTRFSLARQVDGDNSHVEMKLAVDDEENADNNTKANGTKPKRC GGNICYGTIAVIIFFLIGFMIGYLGYCKGVEPKTECERLAGTESPAREEPEEDFPAAPRLYWDDLK RKLSEKLDTTDFTSTIKLLNENLYVPREAGSQKDENLALYIENQFREFKLSKVWRDQHFVKIQVK DSAQNSVIIVDKNGGLVYLVENPGGYVAYSKAATVTGKLVHANFGTKKDFEDLDSPVNGSIVIV RAGKITFAEKVANAESLNAIGVLIYMDQTKFPIVKADLSFFGHAHLGTGDPYTPGFPSFNHTQFPP SQSSGLPNIPVQTISRAAAEKLFGNMEGDCPSDWKTDSTCKMVTSENKSVKLTVSNVLKETKILN IFGVIKGFVEPDHYVVVGAQRDAWGPGAAKSSVGTALLLKLAQMFSDMVLKDGFQPSRSIIFAS WSAGDFGSVGATEWLEGYLSSLHLKAFTYINLDKAVLGTSNFKVSASPLLYTLIEKTMQDVKHP VTGRSLYQDSNWASKVEKLTLDNAAFPFLAYSGIPAVSFCFCEDTDYPYLGTTMDTYKELVERIP ELNKVARAAAEVAGQFVIKLTHDTELNLDYERYNSQLLLFLRDLNQYRADVKEMGLSLQWLYS ARGDFFRATSRLTTDFRNAEKRDKFVMKKLNDRVMRVEYYFLSPYVSPKESPFRHVFWGSGSH TLSALLESLKLRRQNNSAFNETLFRNQLALATWTIQGAANALSGDVWDIDNEF

[0117] Provided herein are bispecific antibodies that bind A and TfR. In some em bodiments, bi specific antibodies described herein bind to Ap or a fragment thereof and TfRl or a fragment thereof. In some embodiments, a bispecific antibody described herein is capable of binding to an amino acid sequence at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1 or 2, and an amino acid sequence at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 600 or 601.- 32 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0118] The present disclosure provides, among other things, abispecific anti-Ap / anti-TfR antibody with improved properties. In some embodiments, a bispecific antibody comprises an anti-Ap antibody or antigen-binding fragment thereof and an anti-TfRl antibody or antigen¬ binding fragment thereof.

[0119] In some embodiments, a bispecific antibody described herein comprises an anti- Ap antibody and an anti-TfRl antibody, wherein the anti-Ap is aducanumab, bapineuzumab, gantenerumab, solanezumab, donanemab, or lecanemab. In some embodiments, a bispecific antibody described herein comprises an anti-Ap antibody and an anti-TfRl antibody, wherein the anti-Ap is aducanumab In some embodiments, bispecific antibody described herein comprises an anti-Ap antibody and an anti-TfRl antibody, wherein the anti-Ap is bapineuzumab. In some embodiments, abispecific antibody described herein comprises an anti-Ap antibody and an anti-TfRl antibody, wherein the anti-Ap is gantenerumab. In some embodiments, a bispecific antibody described herein comprises an anti-Ap antibody and an anti-TfRl antibody, wherein the anti-Ap is solanezumab. In some embodiments, a bispecific antibody described herein comprises an anti-Ap antibody and an anti-TfRl antibody, wherein the anti-Ap is donanemab. In some embodiments, bispecific antibody described herein comprises an anti-Ap antibody and an anti-TfRl antibody, wherein the anti-Ap is lecanemab. In some embodiments, a bispecific antibody described herein comprising an anti-A antibody recognizes aggregated forms of Ap, including plaques.

[0120] Among other things, in some embodiments, a bispecific antibody comprises a recombinant antibody. In some embodiments, a bispecific antibody comprises a monoclonal antibody. In some embodiments, a bispecific antibody comprises a chimeric antibody. In some embodiments, a bispecific antibody comprises a humanized antibody. In some embodiments, a bispecific antibody comprises a human antibody. In some embodiments, a bispecific antibody comprises an IgA, IgD, IgE, IgG, or IgM antibody. In some embodiments, abispecific antibody comprises an IgG antibody. In some embodiments, a bispecific antibody comprises an IgGl antibody. In some embodiments, a bispecific antibody comprises an IgG2 antibody. In some embodiments, a bispecific antibody comprises an IgG3 antibody. In some embodiments, a bispecific antibody comprises an IgG4 antibody. In some embodiments, a bispecific antibody comprises a human kappa light chain. In some embodiments, a bispecific antibody comprises one or more human kappa light chains. In some embodiments, a bispecific antibody comprises a- 33 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01human kappa light chain constant region. In some embodiments, a bispecific antibody comprises a human lambda light chain. In some embodiments, a bi specific antibody comprises one or more human lambda light chains. In some embodiments, a bispecific antibody comprises a human lambda light chain constant region. In other embodiments, a bispecific antibody comprises two heavy chains and two human kappa light chains. In other embodiments, a bispecific antibody comprises an IgGl antibody and comprises a human kappa light chain constant region. In some embodiments, a bi specific antibody comprises an IgGl antibody and comprises a human lambda light chain constant region. In some embodiments, a bispecific antibody comprises a first antibody fragment comprising a first antigen-binding site and a second antibody fragment comprising a second antigen-binding site. In some embodiments, a first antigen-binding site and a second antigen-binding site target different antigens. In some embodiments, a bi specific antibody comprises a scFv. In some embodiments, a bi specific antibody comprises a disulfide-linked scFv. In some embodiments, a bispecific antibody comprises a monovalent antibody In some embodiments, a bispecific antibody comprises a bivalent antibody. In some embodiments, a bispecific antibody comprises a bivalent antibody, a monovalent antibody, or any combination thereof. In some embodiments, a bispecific antibody comprises a bivalent antibody and a monovalent antibody.

[0121] In some embodiments, a bispecific antibody comprises an anti-Ap recombinant antibody and / or an anti-TfRl recombinant antibody. In some embodiments, a bispecific antibody comprises an anti-Ap monoclonal antibody and / or an anti-TfRl monoclonal antibody In some embodiments, a bi specific antibody comprises an anti-Ap chimeric antibody and / or an anti-TfRl chimeric antibody. In some embodiments, a bispecific antibody comprises an anti-Ap humanized antibody and / or an anti-TfRl humanized antibody. In some embodiments, a bispecific antibody comprises an anti-Ap human antibody and / or an anti-TfRl human antibody. In some embodiments, a bi specific antibody comprises an IgA, IgD, IgE, IgG, or IgM anti-Ap antibody and / or an IgA, IgD, IgE, IgG, or IgM anti-TfRl antibody. In some embodiments, a bispecific antibody comprises an IgG anti-Ap antibody and / or an IgG anti-TfRl antibody. In some embodiments, a bispecific antibody comprises an IgGl anti-Ap antibody and / or an IgGl anti- TfRl antibody In some embodiments, a bi specific antibody comprises an IgG2 anti- Ap antibody and / or an IgG2 anti-TfRl antibody. In some embodiments, a bi specific antibody comprises an- 34 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01IgG3 anti-Ap antibody and / or an IgG3 anti-TfRl antibody. In some embodiments, a bispecific antibody comprises an IgG4 anti-Ap antibody and / or an IgG4 anti-TfRl antibody,

[0122] In some embodiments, a bispecific antibody as used herein is a recombinant antibody. In some embodiments, a bispecific antibody as used herein is a monoclonal antibody. In some embodiments, a bispecific antibody as used herein is a chimeric antibody, in some embodiments, a bispecific antibody as used herein is a humanized antibody. In some embodiments, a bi specific antibody as used herein is a human antibody.

[0123] In some embodiments, a bispecific antibody comprises an anti-Ap antibody that is a recombinant antibody and / or an anti-TfRl antibody that is a recombinant In some embodiments, a bispecific antibody comprises an anti-Ap antibody that is a monoclonal antibody and / or an anti-TfRl antibody that is a monoclonal antibody. In some embodiments, a bispecific antibody comprises an anti-Ap antibody that is a chimeric antibody and / or an anti-TfRl antibody that is a chimeric antibody. In some embodiments, a bispecific antibody comprises an anti-Ap antibody that is a humanized antibody and / or an anti-TfRl antibody that is a humanized antibody. In some embodiments, a bispecific antibody comprises an anti-Ap antibody that is a human antibody and / or an anti-TfRl antibody that is a human antibody.

[0124] In some embodiments, a bispecific antibody comprises an anti-Ap antibody that is a bivalent antibody and / or an anti- anti-TfRl antibody that is a bivalent antibody. In some embodiments, a bispecific antibody comprises an anti-Ap antibody that is a monovalent antibody and / or an anti-TfRl antibody that is a monovalent antibody. In some embodiments, a bispecific antibody comprises an anti-Ap antibody that is a monovalent antibody and an anti-TfRl antibody that is a bivalent antibody. In some embodiments, a bispecific antibody comprises an anti-Ap antibody that is a bivalent antibody and an anti-TfRl antibody that is a monovalent antibody.

[0125] In some embodiments, a bispecific antibody comprises a single chain antibody, an Fab fragment, an F(ab’)2 fragment, an Fab’ fragment, an Fsc fragment, an Fv fragment, an scFv, an sc(Fv)2, a diabody, or any combination thereof. In some embodiments, a bispecific antibody comprises a single chain antibody, an Fab fragment, an F(ab’)2 fragment, an Fab’ fragment, an Fsc fragment, an Fv fragment, an scFv, an sc(Fv)₂, or a diabody. In some embodiments, a bispecific antibody comprises an anti-Ap antibody that is a single chain antibody, an Fab fragment, an F(ab’)2 fragment, an Fab’ fragment, an Fsc fragment, an Fv fragment, an scFv, an sc(Fv)₂, or a diabody and an anti-TfRl antibody that is a single chain antibody, an Fab fragment,- 35 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01an F(ab’)2 fragment, an Fab’ fragment, an Fsc fragment, an Fv fragment, an scFv, an sc(Fv)?., or a diabody. In some embodiments, an interchain disulfide in a bispecific antibody is removed. In some embodiments, an interchain disulfide in a bispecific antibody comprising a first antigen binding fragment and / or a second antigen binding fragment (e.g., Fab) is removed. In some embodiments, a Fab or Fab’ comprises a variable heavy (VH) and a variable light domain (VL).

[0126] In some embodiments, a bispecific antibody is isolated. In some embodiments, a bispecific antibody is substantially pure.

[0127] In some embodiments, a bispecific antibody is a humanized antibody. Various methods for generating humanized antibodies are known in the art. In some embodiments, a humanized antibody comprises one or more amino acid residues that have been introduced into its sequence from a source that is non-human. In some embodiments, humanization is performed by substituting one or more non-human CDR sequences for the corresponding CDR sequences of a human antibody.

[0128] The choice of which human heavy chain variable region and / or light chain variable region are used for generating humanized antibodies can be made based on a variety of factors and by a variety of methods known in the art. In some embodiments, “best-fit” method is used where the sequence of the variable region of a non-human (e.g., rodent) antibody is screened against the entire library of known human variable region sequences. The human sequence that is most similar to that of the non-human (e.g., rodent) sequence is selected as the human variable region framework for the humanized antibody. In some embodiments, a particular variable region framework derived from a consensus sequence of all human antibodies of a particular subgroup of light or heavy chains is selected as the variable region framework. In some embodiments, a variable region framework sequence is derived from the consensus sequences of the most abundant human subclasses. In some embodiments, human germline genes are used as the source of variable region framework sequences.

[0129] Other methods for humanization include, but are not limited to, (i) a method called “superhumanization” that is described as the direct transfer of CDRs to a human germline framework, (ii) a method termed Human String Content (HSC) that is based on a metric of “antibody humanness”, (iii) methods based on generation of large libraries of humanized variants (including phage, ribosomal, and yeast display libraries), and (iv) methods based on framework region shuffling.- 36 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0130] In some embodiments, a bispecific antibody as used herein is a “human antibody”. Human antibodies, as used herein, can be prepared using various techniques known in the art. In some embodiments, human antibodies are generated from immortalized human B lymphocytes immunized in vitro. In some embodiments, human antibodies are generated from lymphocytes isolated from an immunized individual. In some embodiments, cells that produce an antibody directed against one or more target antigens can be generated and isolated. In some embodiments, a human antibody is selected from a phage library, where that phage library expresses human antibodies. Alternatively, phage display technology may be used to produce human antibodies and antibody fragments in vitro, from immunoglobulin variable region gene repertoires from unimmunized donors. Techniques for the generation and use of antibody phage libraries are well-known in the art. Once antibodies are identified, affinity maturation strategies known in the art, including but not limited to, chain shuffling and site-directed mutagenesis, may be employed to generate higher affinity human antibodies, as used herein. In some embodiments, as used herein, human antibodies are produced in transgenic mice that contain human immunoglobulin loci. Upon immunization these mice are capable of producing the full repertoire of human antibodies in the absence of endogenous immunoglobulin production.

[0131] In some embodiments, a bispecific antibody described herein has enhanced potency as compared to an individual antibody or to a combination of more than one antibody. In some embodiments, a bispecific antibody has reduced toxicity as compared to an individual antibody or to a combination of more than one antibody. It is known to those of skill in the art. that any therapeutic agent may have unique pharmacokinetics (PK) (e.g., circulating half-life). In some embodiments, a bispecific antibody has the ability to synchronize the PK of two active binding agents wherein the two individual binding agents have different PK profiles. In some embodiments, a bispecific antibody has the ability to concentrate the actions of two agents in a common area (e.g., tissue) in a subject. In some embodiments, a bispecific antibody has the ability to concentrate the actions of two agents to a common target (e.g., a specific cell type). In some embodiments, a bispecific antibody has the ability to target, the actions of two agents to more than one biological pathway or function. In some embodiments, a bispecific antibody has the ability to target two different cells and bring them closer together.

[0132] In some embodiments, a bi specific antibody has decreased toxicity and / or side effects. In some embodiments, abispecific antibody has decreased toxicity and / or side effects as- 37 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01compared to a mixture of the two individual antibodies or the antibodies as single agents. In some embodiments, a bispecific antibody has an increased therapeutic index. In some embodiments, a bispecific antibody has an increased therapeutic index as compared to a mixture of the two individual antibodies or the antibodies as single agents.

[0133] Several techniques for making bispecific antibodies are known by those skilled in the art. In some embodiments, bispecific antibodies comprise heavy chain constant regions with modifications in the amino acids that are part of the interface between the two heavy chains. These modifications are made to enhance heterodimer formation and generally reduce or eliminate homodimer formation. In some embodiments, bispecific antibodies are generated using a knobs-into-holes (KIH) strategy. In some embodiments, bispecific antibodies produced using the heterodimerization technology KIH comprise a first heavy chain comprising one or more knob mutations (HCknob) and a second heavy chain comprising one or more hole mutations (HChole). See., e.g., Ridgway et al. Protein Eng. 1996,9(7):617-21 and Klein et al. MAbs.2012;4(6):653-663.

[0134] In some embodiments, bispecific antibodies comprise light chain constant regions with modifications in the amino acids that are part of the interface between the two light chains. These modifications are made to reduce or eliminate light chain mispairing. See, e.g., Lewis et al. NatBiotech 2014;32(2): I91-98. In some embodiments, bispecific antibodies comprise an scFv that covalently links VH and VL and removes CHI and CL. In some embodiments, bispecific antibodies comprise an scFab or Fcab (see, e g., Wozniak-Knopp et al PEDS 2010;23(4):289-97), single-domain antibodies (e.g., with VHHs from camelid species or sharks), or Duet Mabs (see, e.g., Mazor et al. Mabs 2015;7(2):377-89).

[0135] In some embodiments, nucleotide sequences of human immunoglobulins light and heavy chains is given in: Kabat, E. A., et al, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991) unless a different numbering system is specified. Specifically, the Kabat EU index numbering system (EU numbering) (see Kabat, et al, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991)) is used for a light chain constant domain CL of kappa or lambda isotype and for a constant heavy chain domain (e.g. CHI, Hinge, CH2, CH3, CS). Amino acid positions in a light variable chain and a heavy variable chain, including CDRs of an antibody are defined by those skilled in the art using a variety of- 38 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01methods / systems These systems and / or definitions have been developed and refined over a number of years and include Kabat, Chothia, IMGT, AbM, Contact, and Union, The Kabat definition is based on sequence variability and is commonly used. The Chothia definition is based on the location of the structural loop regions. The IMGT system is based on sequence variability and location within the structure of the variable domain. The AbM definition is a compromise between Kabat and Chothia. The Contact definition is based on analyses of the available antibody crystal structures. An Exemplary system is a combination of Kabat and Chothia. Software programs (e.g., abYsis) are available and known to those of skill in the art for analysis of antibody sequence and determination of CDRs In some embodiments, CDR sequences include the union of all positions in the Union CDR definitions (Kabat, E. A., Wu, T. T., Perry, H. M., Gottesman, K S. & Foeller, C. (1991). Sequences of Proteins of Immunol ogical Interest, 5th edit. National Institutes of Health, Bethesda, MD) and the Chothia CDR definitions (Chothia, C & Lesk, A. M. J. Mol. Biol (1987) 196, 901-917) (Chothia, C. et al. Nature (1989) 342, 877-883) (Al-Lazikani, B„ Lesk, A. M. & Chothia, C. J. Mol. Biol (1997) 273, 927-948). This "union" definition of the CDRs is also known as the " Wolfguy" definition by Bujotzek et al. (Bujotzek Al, Dunbar J, LipsmeierF, Schafer W, Antes I, Deane CM, Georges G, (2015) " Prediction of VH-VL domain orientation for antibody variable domain modeling." Proteins Apr, 8 (4): 681-95, doi: 10.1002 / prot.24756)), In some embodiments, CDR definition is based on a combination of Kabat and Chothia definitions (Exemplary system). However, it will be understood that reference to a VH CDR or CDRs and / or a VL CDR or CDRs of a specific antibody will encompass all CDR definitions as known to those of skill in the art.ANTIBODY Z / ANTIBODY X BISPECIFIC ANTIBODIES

[0136] In some embodiments, bispecific antibodies can comprise intact antibodies and / or antibody fragments comprising antigen-binding sites. In some embodiments, bispecific antibodies can comprise intact anti-Ap antibody or antibody fragments comprising Ap antigenbinding sites and / or anti-TfR antibody or antibody fragments comprising TfR antigen-binding sites. In some embodiments, an anti-Ap antibody is aducanumab, bapineuzumab, gantenerumab, solanezumab, donanemab, or lecanemab. In some embodiments, an anti-Ap antibody is ANTIBODY Z. In some embodiments, an anti-Ap antibody is ANTIBODY Z parental, variant,- 39 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01and / or mutant. In some embodiments, an anti-TfR antibody is ANTIBODY X parental, variant, and / or mutant.

[0137] In some embodiments, a bispecific antibody described herein comprises six CDRs of ANTIBODY X parental antibody and / or six CDRs of ANTIBODY Z parental antibody disclosed herein based on the Wolfguy or Union definition. In some embodiments, a bispecific antibody described herein comprises six CDRs of ANTIBODY X parental antibody and / or six CDRs of ANTIBODY Z parental antibody disclosed herein based on the Chothia definition. In some embodiments, a bispecific antibody described herein comprises six CDRs of ANTIBODY X parental antibody and / or six CDRs of ANTIBODY Z parental antibody di sclosed herein based on the Kabat definition. In some embodiments, a bispecific antibody described herein comprises six CDRs of ANTIBODY X parental antibody and / or six CDRs of ANTIBODY Z parental antibody disclosed herein based on the AbM definition. In some embodiments, abispecific antibody described herein comprises six CDRs of ANTIBODY X parental antibody and / or six CDRs of ANTIBODY Z parental antibody disclosed herein based on the IMGT definition. In some embodiments, a bispecific antibody described herein comprises six CDRs of ANTIBODY X parental antibody and / or six CDRs of ANTIBODY Z parental antibody disclosed herein based on the Contact definition. In some embodiments, a bispecific antibody described herein compri ses six CDRs of any ANTIBODY X mutant antibody and / or six CDRs of any ANTIBODY Z mutant disclosed herein based on the Wolfguy or Union definition. In some embodiments, a bispecific antibody described herein comprises six CDRs of any ANTIBODY X mutant antibody and / or six CDRs of any ANTIBODY Z mutant disclosed herein based on the Chothia definition. In some embodiments, a bispecific antibody described herein comprises six CDRs of any ANTIBODY X mutant antibody and / or six CDRs of any ANTIBODY Z mutant disclosed herein based on the Kabat definition. In some embodiments, a bispecific antibody described herein comprises six CDRs of any ANTIBODY X mutant antibody and / or six CDRs of any ANTIBODY Z mutant disclosed herein based on the AbM definition. In some embodiments, a bispecific antibody described herein comprises six CDRs of any ANTIBODY X mutant antibody and / or six CDRs of any ANTIBODY Z mutant disclosed herein based on the IMGT definition. In some embodiments, bispecific antibody described herein comprises six CDRs of any ANTIBODY X mutant antibody and / or six CDRs of any ANTIBODY Z mutant disclosed herein based on the Contact definition- 40 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0138] Provided herein are anti-Ap / anti-TfR bispecific antibodies. In some embodiments, a bispecific antibody, comprises an anti-Ap antibody or antigen binding fragment thereof, and an anti-TfR antibody or antigen binding fragment thereof. Among other things, provided herein, are bispecific antibodies comprising a first antibody and a second antibody. In some embodiments, a bispecific antibody comprises a first antibody comprising an anti-Ap ANTIBODY Z and a second antibody comprising an anti-TfRl ANTIBODY X.

[0139] In some embodiments, a bispecific antibody comprises an ANTIBODY Z recombinant antibody and / or an ANTIBODY X recombinant antibody. In some embodiments, a bispecific antibody comprises an ANTIBODY Z monoclonal antibody and / or an ANTIBODY X monoclonal antibody. In some embodiments, a bispecific antibody comprises an ANTIBODY Z chimeric antibody and / or an ANTIBODY X chimeric antibody. In some embodiments, a bispecific antibody comprises an ANTIBODY Z humanized antibody and / or an ANTIBODY X humanized antibody. In some embodiments, a bispecific antibody comprises an ANTIBODY Z human antibody and / or an ANTIBODY X human antibody. In some embodiments, a bispecific antibody comprises an IgA, IgD, IgE, IgG, or IgM ANTIBODY Z antibody and / or an IgA, IgD, IgE, IgG, or IgM ANTIBODY X antibody. In some embodiments, a bispecific antibody comprises an IgG ANTIBODY Z antibody and / or an IgG ANTIBODY X antibody. In some embodiments, a bispecific antibody comprises an IgGl ANTIBODY Z antibody and / or an IgGl ANTIBODY X antibody. In some embodiments, a bispecific antibody comprises an IgG2 ANTIBODY Z antibody and / or an IgG2 ANTIBODY X antibody In some embodiments, a bispecific antibody comprises an IgG3 ANTIBODY Z antibody and / or an IgG3 ANTIBODY X antibody. In some embodiments, a bispecific antibody comprises an IgG4 ANTIBODY Z antibody and / or an IgG4 ANTIBODY X antibody. In some embodiments, a bispecific antibody comprises an IgGl, IgG2, IgG3, or IgG4 ANTIBODY Z antibody and an IgGl, IgG2, IgG3, or IgG4 ANTIBODY X antibody. In some embodiments, an IgGl, IgG2, IgG3, or IgG4 ANTIBODY Z antibody comprises one or more mutations. In some embodiments, an IgGl, IgG2, IgG3, or IgG4 ANTIBODY X antibody comprises one or more mutations. In some embodiments, one or more mutations comprise amino acid substitution(s) in a variable region of a bispecific antibody. In some embodiments, one or more mutations comprise amino acid substitution(s) in a constant region of a bispecific antibody (e.g., at position VH-K2I4R, VH-D356E, VH-L358M, VH-D356E, VH-L358M, VH-L145Q, VH-K147E, VH-S181E, VH-- 41 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01Y349C, VH-T366S, VH-L368A, VH-Y407V, VH-S354C, VH-T366W, VH-M428L, VH-N434S, VH-M428L, VH-N434S, VH-M252Y, VH-S254T, VH-T256E, VH-H433K, VH-N434F, VL-T129R, VL-T178R, VL-T180Q, VL-S32N, M252Y, S254T, T256E, M428L, N434S, H433K, N434F, N434A, N434S, T250Q, M428L, T256D, N286D, T307R, Q311V, A378V, L309D, and / or Q311H positions identified with EU numbering).

[0140] In some embodiments, a bispecific antibody comprises an ANTIBODY Z antibody that is a recombinant antibody and / or an ANTIBODY X antibody that is a recombinant. In some embodiments, a bispecific antibody comprises an ANTIBODY Z antibody that is a monoclonal antibody and / or an ANTIBODY X antibody that is a monoclonal antibody. In some embodiments, a bispecific antibody comprises an ANTIBODY Z antibody that is a chimeric antibody and / or an ANTIBODY X antibody that is a chimeric antibody. In some embodiments, a bispecific antibody comprises an ANTIBODY Z antibody that is a humanized antibody and / or an ANTIBODY X antibody that is a humanized antibody. In some embodiments, a bispecific antibody comprises an / ANTIBODY Z antibody that is a human antibody and / or an ANTIBODY X antibody that is a human antibody.

[0141] In some embodiments, a bi specific antibody comprises an ANTIBODY Z antibody that is a bivalent antibody and / or an anti- ANTIBODY X antibody that is a bivalent antibody. In some embodiments, a bispecific antibody comprises an ANTIBODY Z antibody that is a monovalent antibody and / or an ANTIBODY X antibody that is a monovalent antibody. In some embodiments, a bispecific antibody comprises an ANTIBODY Z antibody that is a monovalent antibody and an ANTIBODY X antibody that is a bivalent antibody. In some embodiments, a bispecific antibody comprises an ANTIBODY Z antibody that is a bivalent antibody and an ANTIBODY X antibody that is a monovalent antibody.

[0142] In some embodiments, a bispecific antibody comprises an ANTIBODY Z antibody that is a single chain antibody, an Fab fragment, an F(ab’)2 fragment, an Fab’ fragment, an Fsc fragment, an Fv fragment, an scFv, an sc(Fv)₂, or a diabody and an ANTIBODY X antibody that is a single chain antibody, an Fab fragment, an F(ab’)2 fragment, an Fab’ fragment, an Fsc fragment, an Fv fragment, an scFv, an sc(Fv)₂, or a diabody.

[0143] In some embodiments, a bispecific antibody described herein comprises a) a first heavy chain variable region (VH) comprising a first VH complementarity determining region (CDR)l, a first VH CDR2, and a first VH CDR3, and a first light chain variable region (VE)- 42 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01comprising a first VL CDR1, a first VL CDR2, and a first VL CDR3; and b) a second VH comprising a second VH CDR1, a second VH CDR2, and a second VH CDR3, and a second VL comprising a second VL CDR1, a second VL CDR2, and a second VL CDR3.

[0144] In some embodiments, abispecific antibody described herein comprises an ANTIBODY Z comprising a first heavy chain variable region (VH) comprising a first VH complementarity determining region (CDR)1, a first VH CDR2, and a first VH CDR3, and a first light chain variable region (VL) comprising a first VL CDR1, a first VL CDR2, and a first VL CDR3; and an ANTIBODY X comprising a second VH comprising a second VH CDR1, a second VH CDR2, and a second VH CDR3, and a second VL comprising a second VL CDR1, a second VL CDR2, and a second VL CDR3.

[0145] In some embodiments, a bi specific antibody comprises a variant of ANTIBODY Z parental antibody or of an ANTIBODY Z mutant antibody described herein which comprises one to thirty conservative amino acid substitutions. In some embodiments, a variant of a bispecific antibody comprises one to twenty-five conservative amino acid substitutions. In some embodiments, a variant of a bispecific antibody comprises one to twenty conservative amino acid substitutions. In some embodiments, a variant of a bispecific antibody comprises one to fifteen conservative amino acid substitutions. In some embodiments, a variant of a bispecific antibody comprises one to ten conservative amino acid substitution(s). In some embodiments, a variant of a bispecific antibody comprises one to five conservative amino acid substitution(s). In some embodiments, a variant of a bispecific antibody comprises one to three conservative amino acid substitution(s). In some embodiments, conservative amino acid substitution(s) is in a CDR of a bispecific antibody. In some embodiments, conservative amino acid substitution(s) is in a CDR of a bispecific antibody (e g., at position VH- A30T, VH-F60Y, VH-T66S, VH-K67N, VH- T71A, VL-Q29E, and / or VL-S32N, positions identified with AHo numbering). In some embodiments, conservative amino acid substitution(s) is not in a CDR of a bispecific antibody. In some embodiments, conservative amino acid substitution(s) is in a framework region of a bispecific antibody (e.g., at position VH-R17G and / or VH-T95S, positions identified with AHo numbering). In some embodiments, conservative amino acid substitution(s) is in a constant region of a bispecific antibody (e g., at position VH-K214R, VH-D356E, VH-L358M, VH-D356E, VH-L358M, VL-T129R, VL-T178R, and / or VL-T180Q, positions identified with EU numbering).- 43 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0146] In some embodiments, a bispecific antibody comprises a first VH CDRI, first VH CDR2, and / or first VH CDR3 selected from a VH CDRI, VH CDR2, and VH CDR3 from the ANTIBODY X parental antibody described herein. In some embodiments, a bispecific antibody comprises a first VH CDRI, first VH CDR2, and / or first VH CDR3 selected from a VH CDRI, VH CDR2, and VH CDR3 from an ANTIBODY X mutant antibody described herein.

[0147] In some embodiments, a bispecific antibody comprises a first VL CDRI, first VL CDR2, and / or first VL CDR3 selected from a VL CDRI, VL CDR2, and VL CDR3 from the ANTIBODY X parental antibody described herein. In some embodiments, a bispecific antibody comprises a first VL CDRI, first VL CDR2, and / or first VL CDR3 selected from a VL CDRI, VL CDR2, and VL CDR3 from an ANTIBODY X mutant antibody described herein.

[0148] In some embodiments, a bi specific antibody comprises a first VH CDRI, first VH CDR2, a first VH CDR3, first VL CDRI, first VL CDR2, and / or first VL CDR3 selected from a CDR described in Table A.

[0149] Table A describes the “parental” CDRs (according to the Union definition) of the reference ANTIBODY Z antibody as well as mutant CDRs present in ANTIBODY Z mutants described herein. Mutant amino acid positions are identified with Allo numbering (Honegger et al., J Mol Biol, 2001, 309(3):657-70). Where a mutant CDR is not present, the variable region compri ses the corresponding parental CDR. In some embodiments, a bi specific antibody comprises an anti-A[3 antibody that comprises at least one of the CDR mutations described in Table A (e g, 1-3, 1, 2, or 3 of the CDR mutations described in Table A), but otherwise contains the parental CDR sequences described in Table A. In some embodiments, a bispecific antibody comprises (i) one, two, and / or three mutant VH CDRs described in Table A, and / or (ii) one, two, and / or three mutant VL CDRs described in Table A, with all remaining CDRs selected from the parental CDRs depicted in Table A. In some embodiments, a bispecific antibody comprises (i) one, two, and / or three parental VH CDRs described in Table A, and / or (ii) one, two, and / or three parental VL CDRs described in Table A, with all remaining CDRs selected from the mutant CDRs depicted in Table A.- 44 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01Table A: Rabat CDRs for ANTIBODY Z Parental and Mutants.Parental CDRsVH CDRl VH CDR2 VH CDR3 VL CDRl VL CDR2 VL CDR3 GFAFSSYGMH VIWFDGTKKY DRGIGARRGP RASQSISSYLN AASSLQS QQSYSTPLT(SEQ ID YTDSVKG YYMDV (SEQ ID NO: 507) (SEQ ID (SEQ ID NO: 501) (SEQ ID (SEQ ID NO: 508) NO:509) NO: 502) NO: 503)Mutant CDRsMutation VH CDRl VH CDRl VH CDR3 VL CDRl VL CDR2 VL CDR3 VH- A30T / GFTFSSYGMH VIWYDGSNK RASESINSYLNF60Y / T66S / (SEQ ID YYADSVKG (SEQ ID NO: 519)K67N'T71A NO: 512) (SEQ ID / VL- NO:513)Q29E / S32N

[0150] In some embodiments, a bispecific antibody, comprises an anti-Ap antibody comprising a first heavy chain variable region (VH) comprising a first VH complementarity determining region (CDR)l, a first VH CDR.2, and a first VH CDR3, and a first light chain variable region (VL) comprising a first VL CDRl, a first VL CDR2, and a first VL CDR3, wherein: the first VH CDRl comprises the amino acid sequence of SEQ ID NO: 501 or 512; the first VH CDR2 comprises the amino acid sequence of SEQ ID NO: 502 or 513; and the first VH CDR3 comprises the amino acid sequence of SEQ ID NO: 503; the first VL CDRl comprises the amino acid sequence of SEQ ID NO: 507 or 519; the first VL CDR2 comprises the amino acid sequence of SEQ ID NO: 508; and the first VL CDR3 comprises the amino acid sequence of SEQ ID NO: 509; and an anti-TIR antibody or antigen binding fragment thereof.

[0151] In some embodiments, a bispecific antibody, comprises an anti-Ap antibody comprising a first heavy chain variable region (VH) comprising a first VH complementarity determining region (CDR)1, a first VH CDR2, and a first VH CDR3, and a first light chain variable region (VL) comprising a first VL CDRl, a first VL CDR2, and a first VL CDRS, wherein: the first VH CDRl comprises the amino acid sequence of SEQ ID NO: 501 or 512; the first VH CDR2 comprises the amino acid sequence of SEQ ID NO: 502 or 513; and the first VH CDR3 comprises the amino acid sequence of SEQ ID NO: 503; the first VL CDRl comprises the amino acid sequence of SEQ ID NO: 507 or 519, the first VL CDR2 comprises the amino acid sequence of SEQ ID NO: 508; and the first VL CDR3 comprises the amino acid sequence of SEQ ID NO: 509; and an ANTIBODY X.- 45 _13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0152] In some embodiments, a bispecific antibody comprises a second VH CDR1, second VH CDR2, and / or second VH CDR3 selected from a VH CDRI, VH CDR2, and VH CDR3 from the ANTIBODY X parental antibody described herein. In some embodiments, a bispecific antibody comprises a second VH CDR1, second VH CDR2, and / or second VH CDR3 selected from a VH CDRI, VH CDR2, and VH CDR3 from an ANTIBODY X mutant antibody described herein.

[0153] In some embodiments, a bi specific antibody comprises a second VL CDRI, second VL CDR2, and / or second VL CDR3 selected from a VL CDR1, VL CDR2, and VL CDR3 from the ANTIBODY X parental antibody described herein. In some embodiments, a bispecific antibody comprises a second VL CDR1, second VL CDR2, and / or second VL CDR3 selected from a VL CDRI, VL CDR2, and VL CDR3 from an ANTIBODY X mutant antibody described herein.

[0154] In some embodiments, a bispecific antibody comprises a second VH CDR1, second VH CDR2, a second VH CDR3, second VL CDRI, second VL CDR2, and / or second VL CDR3 selected from a CDR described in Table 1 or Table 2.Table 1 describes the “parental” CDRs (according to the Union definition) of the reference ANTIBODY X antibody as well as mutant CDRs present in ANTIBODY X mutants described herein. Mutant amino acid positions are identified with AHo numbering (Honegger et al., J Mol Biol, 2001, 309(3):657-70). Where a mutant CDR is not present, the variable region comprises the corresponding parental CDR. For instance, for VH-S40A / VL Parental, the VH comprises a mutant VH CDRI (S40A), parental VH CDR2, and parental VH CDR3, and the VL comprises parental VL CDRI, parental VL CDR2, and parental VL CDR3. In some embodiments, a bispecific antibody comprises an anti-TfRI antibody that comprises at least one of the CDR mutations described in Table 1 (e.g., 1-10, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the CDR mutations described in Table 1), but otherwise contains the parental CDR sequences described in Table 1. In some embodiments, a bispecific antibody comprises (i) one, two, and / or three mutant VH CDRs described in Table I, and / or (ii) one, two, and / or three mutant VL CDRs described in Table 1, with all remaining CDRs selected from the parental CDRs depicted in Table 1.- 46 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01Table 1: Union CDRs for ANTIBODY X Parental and Mutants.Parental CDRsVH CDR1 VH CDR2 VH CDR3 VL CDR1 VL CDR2 VL CDR3 GFTFSSYSMN SISSSSSYIYY KYRAGDFDY RASQSVSSSYLA GASNRAT QQQSSSPPT(SEQ ID NO:3) ADSVKG (SEQ ID NO: 5) (SEQ ID NO:6) (SEQ IDNO:7) (SEQ ID NO: 8)(SEQ ID NO:4)Mutant CDRsMutation VH CDR1 VH CDR2 VH CDR3 VL CDR1 VL CDR2 VL CDR3 VH-S40A / GUESS YAMNVL Parental (SEQ ID NO:9)VH-S60A / SISASSSYIYYVI. Parental ADSVKG (SEQID NO: 10)VH-Y67S / SISSSSSSIYYAVL Parental DSVKG (SEQID NO: 11)VH-Y110S / KSRAGDFDYVL Parental (SEQ IDNO: 12)VH-R1HS / KYSAGDFDYVL Parental (SEQ IDNO: 13)VH-AU2Y / KYRYGDFDYVL Parental (SEQ IDNO: 14)VH- SISASSSSIYYS60A / Y67S ADSVKG (SEQ / 'VI, IDNO:25)ParentalVH- SISASSSYIYY KYSAGDFDYS60A / R111 ADSVKG (SEQ (SEQ IDS / VI, ID NO: 10) NO: 13)ParentalVH Parental RASQSVSSNYL / VL-S39N A (SEQ IDNO: 15)VH Parental RASQSVSSSNLA / VL-Y40N (SEQ ID NO: 16)VI I Parental GASNRAT / VL-Y57S (SEQ ID NO: 7)VH Parental GASSRAT / VL-N69S (SEQ IDNO: 17)VH- S60A / SISASSSYIYY RASQSVSSNYLVL-S39N ADSVKG (SEQ A (SEQ IDID NO: 10) NO: 15)VH- S60A / SISASSSYIYY GASNRATVL-Y57S ADSVKG (SEQ (SEQ ID NO: 7)ID NO: 10)- 47 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0155] Table 2 describes the “parental” CDRs (according to the Kabat definition) of the ANTIBODY X antibody as well as mutant CDRs present in ANTIBODY X mutants described herein. Mutant amino acid positions are identified with AHo numbering. Where a mutant CDR is not present, VH or VL comprises the corresponding parental CDR. For instance, for VH-S40 A / VL Parental, the VH comprises a mutant VH CDR1 (S40A), parental VH CDR2, and parental VH CDR3, and the VL comprises parental VL CDR1, parental VL CDR2, and parental VL CDR3. In some embodiments, a bispecific antibody is a bi specific antibody that comprises at least one of the CDR mutations described in Table 2 (e.g., 1-10, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the CDR mutations described in Table 2), but otherwise contains the parental CDR sequences described in Table 2. In some embodiments, a bispecific antibody comprises (i) one, two, and / or three mutant VH CDRs described in Table 2, and / or (ii) one, two, and / or three mutant VL CDRs described in Table 2, with all remaining CDRs selected from the parental CDRs depicted in Table 2.- 48 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01Table 2: Rabat CDRs for ANTIBODY X Parental and Mutants.Parental CDRsVH CDR1 VH CDR2 VH CDR3 VL CDR1 VL CDR2 VL CDR3 SYSMN SISSSSSYIYYA KYRAGDFDY RASQSVSSSYL GASNRAT QQQSSSPPT(SEQ ID DSVKG (SEQ ID NO: 5) A (SEQ IDNO:7) (SEQ ID NO: 8) NO: 23) (SEQ IDNO:4) (SEQIDNO:6)Mutant CDRsMutation VH CDR1 VH CDR2 VH CDR3 VL CDR1 VL CDR2 VL CDR3 \ ■ PS 40A / SYAMN (SEQVL Parental ID NO:24)VH-S60A / STSASSSYIYYAVI, Parental DSVKG (SEQ IDNO: 10)VH-Y67S / SISSSSSSIYYAVI, Parental DSVKG (SEQ IDNO: 11)VH-Y110S, KSRAGDFDYVL Parental (SEQ ID NO: 12)VH-R111S / ' KYSAGDFDYVL Parental (SEQ ID NO: 13)VH-A 112Y / KYRYGDFDYVL Parental (SEQ ID NO: 14)VH- SISASSSSIYYAS60A / Y67S DSVKG (SEQ ID / VL NO:25)ParentalVH- SISASSSYIYYA KYSAGDFDYS60A / R111S DS VKG (SEQ ID (SEQ ID NO: 13) / VL NO: 10)ParentalVH Parental RASQSVSSNYL / VL-S39N A (SEQ IDNO: 15)VH Parental RASQSVSSSNL / VL-Y40N A (SEQ IDNO: 16)VII Parental GASNRAT / VL-Y57S (SEQ ID NO: 7)VH Parental GASSRAT / VL-N69S (SEQ IDNO: 17)VII- S60A / SISASSSYIYYA RASQSVSSNYLVL-S39N DSVKG (SEQ ID A (SEQ IDNO: 10) NO: 15)VH- S60A / SISASSSYIYYA GASNRATVL-Y57S DSVKG (SEQ ID (SEQ ID NO: 7)NO: 10)- 49 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0156] In some embodiments, a bispecific antibody comprises (i) a first VH CDR1, first VH CDR2, a first VH CDR3, first VL CDR1, first VL CDR2, and / or first VL CD 3 selected from a CDR described in Table A; and (ii) a second VH CDR1, second VH CDR2, a second VH CDR3, second VL CDR1, second VL CDR2, and / or second VL CDR3 selected from a CDR described in Table 1 or Table 2

[0157] In some embodiments, a bispecific antibody comprises (i) a first VH CDR1, a first VH CDR2, and / or a first VH CDR3 comprising or consisting of the amino acid sequences set forth in any one of SEQ ID NOs: 501-503, 512, and 513; (ii) a first VL CDR1, a first VL CDR2, and / or a first VL CDR3 comprising or consisting of the amino acid sequences set forth in any one of SEQ ID NOs: 507-509, and 519; (iii) a second VH CDR1, a second VH CDR2, and / or a second VH CDR3 comprising or consisting of the amino acid sequences set forth in any one of SEQ ID NOs: 3-5, 9-14, and 23-25; or (iv) a second VL CDR, a second VL CDR2, and / or a second VL CDR3 comprising or consisting of the amino acid sequences set forth in any one of SEQ ID NOs: 6-8 and 15-17.

[0158] In some embodiments, a bispecific antibody comprises (i) a first VH CDR1, a first VH CDR2, and / or a first VH CDR3 comprising or consisting of the amino acid sequences set forth in any one of SEQ ID NOs: 501-503, 512, and 513; (ii) a first VL CDR1, a first VL CDR2, and / or a first VL CDR3 comprising or consisting of the amino acid sequences set forth in any one of SEQ ID NOs: 507-509, and 519; (iii) a second VH CDR1, a second VH CDR2, and / or a second VH CDR3 comprising or consisting of the amino acid sequences set forth in any one of SEQ ID NOs: 3-5, 9-14, and 23-25; and (iv) a second VL CDR1, a second VL CDR2, and / or a second VL CDR3 comprising or consisting of the amino acid sequences set forth in any one of SEQ ID NOs: 6-8 and 15-17.

[0159] In some embodiments, a bispecific antibody is a variant of ANTIBODY Z parental antibody or of an ANTIBODY Z mutant antibody described herein which comprises one to thirty conservative amino acid substitutions. In some embodiments, a variant of a bispecific antibody comprises one to twenty-five conservative amino acid substitutions. In some embodiments, a variant of a bispecific antibody comprises one to twenty conservative amino acid substitutions. In some embodiments, a variant of a bispecific antibody comprises one to fifteen conservative amino acid substitutions. In some embodiments, a variant of a bispecific antibody comprises one to ten conservative amino acid substitution(s) In some embodiments, a variant of- 50 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01a bispecific antibody comprises one to five conservative amino acid substitution(s). In some embodiments, a variant of a bispecific antibody comprises one to three conservative amino acid substitution(s). In some embodiments, conservative amino acid substitution(s) is in a CDR of a bispecific antibody. In some embodiments, conservative amino acid substitution(s) is in a CDR of a bispecific antibody (e.g., at position, VH-A30, VH-F60, VH-T66, VH-K67, VH-T71, VL- Q29, and / or VL-S32 positions identified with AHo numbering). In some embodiments, conservative amino acid substitution(s) is in a CDR of a bispecific antibody. In some embodiments, conservative amino acid substitution(s) is in a CDR of a bispecific antibody (e.g., at position, VH-A30T, VH-F60Y, VH-T66S, VH-K67N, VH-T71A, VL-Q29E, and / or VL-S32N positions identified with AHo numbering). In some embodiments, conservative amino acid substitution(s) is not in a CDR of a bispecific antibody. In some embodiments, conservative amino acid substitution(s) is in a framework region of a bispecific antibody (e g., at position VH-R17, VH-T95, VL-T129, VL-T178, and / or VL-T180 at position, positions identified with AHo numbering). In some embodiments, conservative amino acid substitution(s) is not in a CDR of a bispecific antibody. In some embodiments, conservative amino acid substitution(s) is in a framework region of a bispecific antibody (e.g., at position VH-R17G, VH-T95S, VL-T129R, VL-T178R, and / or VL-T180Q at position, positions identified with AHo numbering).

[0160] In some embodiments, a bispecific antibody comprises a first VH comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table B and a first VL comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table C, where the VH and VL is not identical to the parental ANTIBODY Z VH and VL sequence. In some embodiments, variation imparted by the percent identity is not at the mutation position of the sequence set forth in Table B or Table C.

[0161] Table B describes the heavy chain variable region sequences of ANTIBODY Z parental and ANTIBODY Z mutants described herein. Table C describes the light chain variable regi on sequences of ANTIBODY Z parental and ANTIBODY Z mutants described herein. In both tables, mutant amino acid positions are identified with AHo numbering.- 51 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01Table B: Heavy Chain Variable Regions of ANTIBODY Z and Mutants.Parental SEQ ID NO SequenceVH-Parental SEQ ID QVQLVESGGGVVQPGRSLRLSCAASGFAFSSYGMHWVRQAPGKGLEWV NO: 504 AVIWFDGTKKYYTDSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCA RDRGIGARRGPYYMDVWGKGTTVTVSSMutant Name SEQ ID NO SequenceVH- A30T / SEQ ID QVQLVESGGGVVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWV F60Y / T66S / K67N7 NO:514 AVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAT71A RDRGIGARRGPYYMDWGKGTTVTVSSTable C: Light Chain Variable Regions of ANTIBODY Z and Mutants.Parental SEQ ID NO SequenceVL-Parental SEQ ID DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ NO:510 SGVPSRFSGSGSGTDFTLTTSSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK Mutant Name SEQ ID NO SequenceVL- SEQ ID DIQMTQSPSSLSASVGDRVTITCRASESINSYLNWYQQKPGKAPKLLIYAASSLQQ29E / S32N NO: 520 SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK

[0162] For example, in some embodiments, a bispecific antibody comprises a first VH comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 504 or 514 and a first VL comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 510 or 520, where the first VH is not identical to the parental ANTIBODY Z VH sequence and / or the first VL is not identical to the parental ANTIBODY Z VL sequence. For example, in some embodiments, a bispecific antibody comprises a first VH comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 504 or 514 and a first VL comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 510 or 520, where the first VH is identical to the parental ANTIBODY Z VH sequence and / or the first VL is not identical to the parental ANTIBODY Z VL sequence. In some embodiments, a bispecific antibody comprises a first VH comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 504 or 514- 52 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01and a first VL comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 510 or 520, where the first VH is not identical to the parental ANTIBODY Z VH sequence and / or the first VL is identical to the parental ANTIBODY Z VL sequence In some embodiments, variation imparted by the percent identity is at position VH-A30, VH-F60, VH- T66, VH-K67, and / or VH-T71 positions of the ANTIBODY Z VH (according to AHo numbering of SEQ ID NO: 504). In some embodiments, variation imparted by the percent identity is at position VL-Q29, and / or VL-S32 positions of the ANTIBODY Z VL (according to AHo numbering of SEQ ID NO: 510). In some embodiments, variation imparted by the percent identity is at position VH-A30T, VH-F60Y, VH-T66S, VH-K67N, and / or VH-T71A positions of the ANTIBODY Z VH (according to AHo numbering of SEQ ID NO: 504). In some embodiments, variation imparted by the percent identity is at position VL-Q29E, and / or VL-S32N positions of the ANTIBODY Z VL (according to AHo numbering of SEQ ID NO: 510).

[0163] In some embodiments, a bispecific antibody comprises a first VH comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 504 or 514 and a first VL comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 510 or 520, wherein the first VH and / or VL regions have one or more substitutions, deletions, and / or insertions. In some embodiments, first VH and first VL regions may have up to 25, up to 20, up to 15, up to 10, up to 5, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions and still bind beta-amyloid. In some embodiments, amino acid substitutions occur only in the framework region. Tn some embodiments, amino acid substitution(s) is / are conservative amino acid substitutions. In some embodiments, a first VH and a first VL regions may include 1 to 5 (1, 2, 3, 4, 5) amino acid deletions and / or additions and still bind beta-amyloid. In some embodiments, deletions and / or additions are made at the N- and / or C-terminus of the first VH and / or first VL regions. In some embodiments, one or more amino acid is deleted and / or added at the N and / or C-terminus of a first VH region. In some embodiments, one or more amino acid is deleted and / or added at the N and / or C-terminus of a first VL region.- 53 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0164] In some embodiments, a bispecific antibody comprises a) a first heavy chain variable region (VH) comprising a first VH complementarity determining region (CDR)1, a first VH CDR2, and a first VH CDR3, and a first light chain variable region (VL) comprising a first VL CDR1, a first VL CDR2, and a first VL CDR3, wherein: the first VH CDRl comprises the amino acid sequence of SEQ ID NO: 501 or 512; the first VH CDR2 comprises the amino acid sequence of SEQ ID NO: 502 or 513; and the first VH CDR3 comprises the amino acid sequence of SEQ ID NO: 503; the first VL CDR1 comprises the amino acid sequence of SEQ ID NO: 507 or 519; the first VL CDR2 comprises the amino acid sequence of SEQ ID NO: 508; and the first VL CDR3 comprises the amino acid sequence of SEQ ID NO: 509; and b) a second VH comprising a second VH CDR1, a second VH CDR2, and a second VH CDR3, and a second VL comprising a second VL CDRl, a second VL CDR2, and a second VL CDR3, wherein: the second VH CDR1 comprises the amino acid sequence GFTFSSYX1MN (SEQ ID NO: 18), wherein XI is S or A; the second VH CDR2 comprises the amino acid sequence SISX₂SSSX₃IYYADSVKG (SEQ ID NO:19), wherein X₂ is S or A, and wherein X₃ is Y or S; and the second VH CDR3 comprises the amino acid sequence KX4X5X6GDFDY (SEQ ID NO: 20), wherein X4 is Y or S, wherein X5 is R or S, and wherein X6 is A or Y; the second VL CDRl comprises the amino acid sequence RASQSVSSX7X8LA (SEQ ID NO: 21), wherein X7 is S or N, and wherein X8 is Y or N; the second VL CDR2 comprises the amino acid sequence GASX9RAT (SEQ ID NO: 22), wherein X9 is N or S; and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO: 8).

[0165] In some embodiments, a bi specific antibody comprises (i) the first VH is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 504; and (ii) the first VL is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 510.

[0166] In some embodiments, a bispecific antibody comprises (i) the first VH is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 514; and (ii) the first VL is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 520.

[0167] In some embodiments, a bi specific antibody comprises a second VH CDRl, a second VH CDR2, and a second VH CDR3 and a second VL CDRl, a second VL CDR2, and a second VL CDR3 from an ANTIBODY X parental antibody described herein. In some- 54 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01embodiments, a bispecific antibody comprises a second VH CDR1, a second VH CDR2, and a second VH CDR3 and a second VL CDR1, a second VL CDR2, and a second VL CDR3 from an ANTIBODY X mutant antibody described herein. In some embodiments, a bispecific antibody comprises a humanized version or humanized variant of an ANTIBODY X mutant antibody described herein.

[0168] In some embodiments, a bispecific antibody comprises a second VH comprising a second VH CDR1, a second VH CDR2, and a second VH CDR3, and a second VL comprising a second VL CDR1, a second VL CDR2, and a second VL CDR3, wherein: (a) the second VH CDR1 comprises the amino acid sequence GFTFSSYX₁MN (SEQ ID NOS:18) or the amino acid sequence SYX₁MN (SEQ ID NOS:26), wherein X₁ is S or A; (b) the second VH CDR2 comprises the amino acid sequence SISX₂SSSX₃IYYADSVKG (SEQ ID NOS:19), wherein X₂ is S or A, and wherein X₃ is Y or S; (c) the second VH CDR3 comprises the amino acid sequence KX₄X₅X₆GDFDY (SEQ ID NOS:20), wherein X₄ is Y or S, wherein X₅ is R or S, and wherein X₆ is A or Y; (d) the second VL CDR1 comprises the amino acid sequence RASQSVSSX₇X₈LA (SEQ ID NOS:21), wherein X₇ is S or N, and wherein X₈ is Y or N; (e) the second VL CDR2 comprises the amino acid sequence GASX₉RAT (SEQ ID NOS:22), wherein X₉ is N or S; and (f) the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NOS:8). In some embodiments, a bispecific antibody comprises or is a monovalent antibody and has a monovalent affinity (KD) for hTfRl of > 10 nM. In some embodiments, a bispecific antibody comprises or is a bivalent antibody and has a monovalent affinity (KD) of hTfRl of >10 nM. In some embodiments, a bispecific antibody comprises or is a bivalent antibody and has a monovalent affinity (KD) for hTfRl of >100 nM. In some embodiments, a bispecific antibody comprises or is a bivalent antibody and has a monovalent affinity (KD) for hTfRl of >1000 nM. In some embodiments, a bispecific antibody comprises or is a bivalent antibody and has a monovalent affinity (KD) for hTfR 1 of >100 nM or >1000nM. In some embodiments, valency and affinity of a bispecific antibody are targeted for optimal brain exposure.

[0169] In some embodiments, a bispecific antibody comprises a second VH CDRI, a second VH CDR2, and a second VH CDR3 and / or a second light chain variable region (VL) CDRI, a second VL CDR2, and a second VL CDR3 from an ANTIBODY X mutant antibody described herein. In some embodiments, a bispecific antibody comprises a second VH CDRI, a- 55 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01second VH CDR2, and a second VH CDR3 and a second VL CDR1, a second VL CDR2, and a second VL CDR3 from an ANTIBODY X mutant antibody described herein. In some embodiments, a bispecific antibody comprises a humanized version or humanized variant of an ANTIBODY X mutant antibody described herein.

[0170] In some embodiments, a bispecific antibody is a variant of ANTIBODY X parental antibody or of an ANTIBODY X mutant antibody described herein which comprises one to thirty conservative amino acid substitutions. In some embodiments, a variant of a bispecific antibody comprises one to twenty-five conservative amino acid substitutions. In some embodiments, a variant of a bispecific antibody comprises one to twenty conservative amino acid substitutions. In some embodiments, a variant of a bispecific antibody comprises one to fifteen conservative amino acid substitutions. In some embodiments, a variant of a bispecific antibody comprises one to ten conservative amino acid substitution(s). In some embodiments, a variant of a bispecific antibody comprises one to five conservative amino acid substitution(s). In some embodiments, a variant of a bispecific antibody comprises one to three conservative amino acid substitution(s) In some embodiments, conservative amino acid substitution(s) is in a CDR of a bispecific antibody. In some embodiments, conservative amino acid substitution(s) is in a CDR of a bispecific antibody (e.g., at position VH-S40, VH-S60, VH-Y67, VH-Y110, VH-R111, VH-A112, VL-S39, VL-Y40, and / or VL-N69, positions identified with AHo numbering). In some embodiments, conservative amino acid substitution(s) is not in a CDR of a bispecific antibody. In some embodiments, conservative amino acid substitution(s) is in a framework region of a bispecific antibody (e.g., at position VL-Y57 and / or at position VL-S83, positions identified with AHo numbering).

[0171] In some embodiments, a bispecific antibody comprises a second VH comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table 3 and a second VL comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table 4, where the second VH and VL is not identical to the parental ANTIBODY X VH and VI., sequence. In some embodiments, variation imparted by the percent identity is not at the mutation position of the sequence set forth in Table 3 or Table 4. For example, in some embodiments, a bispecific antibody comprises a second VH comprising- 56 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 101 and a second VL comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID N0:200, where the second VH is not identical to the parental ANTIBODY X VH sequence, and wherein the second VH comprises an S40A substitution (according to AHo numbering of SEQ ID NO: 100). In some embodiments, variation imparted by the percent identity is not at position Y57 and / or S83 of the ANTIBODY X VL (according to AHo numbering of SEQ ID NO:200). In some embodiments, second VL comprises Y57 (or a conservative substitution thereof, e.g., Y57S) and / or S83 (or a conservative substitution thereof) (according to AHo numbering of SEQ ID NO:200)

[0172] Table 3 describes the heavy chain variable region sequences of ANTIBODY X parental and several ANTIBODY X mutants described herein. Table 4 describes the light chain variable region sequences of ANTIBODY X parental and several ANTIBODY X mutants described herein. In both tables, mutant amino acid positions are identified with AHo numbering for variable regions and EU numbering for constant regions.- 57 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01Table 3: Heavy Chain Variable Regions of ANTIBODY X and Mutants.Parental SEQ ID NO SequenceVH-Parental 100 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVS SISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARKY RAGDFDYWGQGTLVTVSSMutant Name SEQ ID NO SequenceVH-S40A 101 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLEWVS SISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARKYRAGDFDYWGQGTLVTVSS VH-S60A 102 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVS SISASSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARKY YR AGDFD Y WGQGTL VTVS S VH-Y67S 103 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVS SISSSSSSIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARKY RAGDFDYWGQGTLVTVSS VH-Y1 IOS 104 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVS SISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARKS RAGDFDYWGQGTLVTVSS VH-R111S 105 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVS SISSSSSYIYYADSVXGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARKY SAGDFDYWGQGTLVTVSS VH-A112Y 106 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVS SISSSSSY1YYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARKY RYGDFDYWGQGTLVTVSS VH-S60A / Y67S 107 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVS SISASSSSIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARKY RAGDFDYWGQGTLVTVSS VH-S60A / R11 IS 108 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISASSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARKYYSAGDFDYWGQGTLVTVSSTable 4: Light Chain Variable Regions of ANTIBODY X and Mutants.Parental SEQ ID NO SequenceVL-Parental 200 EIVMTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASN RATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQQSSSPPTFGGGTKVEIK Mutant Name SEQ ID NO SequenceVL-S39N 201 EIVMTQSPGTLSLSPGERATLSCRASQSVSSNYLAWYQQKPGQAPRLLIYgasn RATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQQSSSPPTFGGGTKVEIK VL-Y40N 202 EIVMTQSPGTLSLSPGERATLSCRASQSVSSSNLAWYQQKPGQAPRLLIYGASN RATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQQSSSPPTFGGGTKVEIK VL-Y57S 203 EIVMTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLISGASNR ATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQQSSSPPTFGGGTKVEIK VL-N69S 204 EIVMTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQQSSSPPTFGGGTKVEIK- 58 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0173] In some embodiments, a bispecific antibody comprises a second VH comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 100. In some embodiments, a bispecific antibody comprises a second VL comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID N0:200. In some embodiments, a bispecific antibody comprises a second VH comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 100 and a second VL comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID N0:200. In some embodiments, variation imparted by the percent identity is not at position Y57 and / or S83 of the ANTIBODY X VL (according to AHo numbering of SEQ ID NO:200). In some embodiments, second VL comprises Y57 (or a conservative substitution thereof, e g., Y57S) and / or S83 (or a conservative substitution thereof) (according to AHo numbering of SEQ ID NO:200). In some embodiments, a bispecific antibody comprises a second VH comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 100 and a second VL comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:200, wherein the second VH and / or VL regions have one or more substitutions, deletions, and / or insertions. In some embodiments, second VH and second VL regions may have up to 25, up to 20, up to 15, up to 10, up to 5, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions and still bind TfR. In some embodiments, amino acid substitutions occur only in the framework region. In some embodiments, amino acid substitution(s) is / are conservative amino acid substitutions. In some embodiments, a second VH and a second VL regions may include 1 to 5 (1, 2, 3, 4, 5) amino acid deletions and / or additions and still bind TfR. In some embodiments, deletions and / or additions are made at the N- and / or C-terminus of the second VH and / or second VL regions. In some embodiments, one or more amino acid is deleted and / or added at the N and / or C -terminus of a second VH region. In some- 59 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01embodiments, one or more amino acid is deleted and / or added at the N and / or C -terminus of a second VL region,

[0174] In some embodiments, a bispecific antibody comprises a second heavy chain variable region comprising an amino acid sequence that has the three VH CDRs of the ANTIBODY X parental antibody described herein and which has at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 100 and a second light chain variable region comprising an amino acid sequence that has the three VL CDRs of the ANTIBODY X parental antibody described herein and which has at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:200. In some embodiments, variation imparted by the percent identity is not at position Y57 and / or S83 of the ANTIBODY X VL (according to AHo numbering of SEQ ID NO:200). In some embodiments, a second VL comprises Y57 (or a conservative substitution thereof, e.g., Y57S) and / or S83 (or a conservative substitution thereof) (according to AHo numbering of SEQ ID NO:200).

[0175] In some embodiments, a bi specific antibody comprises a second heavy chain variable region comprising an amino acid sequence that has the three VH CDRs of any ANTIBODY X mutant antibody described herein and which has at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the VH sequences set forth in Table 3 and a second light chain variable region comprising an amino acid sequence that has the three VL CDRs of any ANTIBODY X mutant antibody described herein and which has at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table 4. In some embodiments, variation imparted by the percent identity is not at position Y57 and / or S83 of the ANTIBODY X VL (according to AHo numbering of SEQ ID NO:200). In some embodiments, a second VL comprises Y57 (or a conservative substitution thereof, e.g, Y57S) and / or S83 (or a conservative substitution thereof) (according to AHo numbering of SEQ ID NO:200).

[0176] In some embodiments of a bispecific antibody:second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID- 60 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO: 5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8), wherein second VL comprises a Y57S conservative substitution,second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8), wherein second VL comprises the amino acid sequence of SEQ ID NO:203;second VH CDR1 comprises the amino acid sequence GFTFSSYAMN (SEQ ID NO:9); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO:10); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);- 61 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7), and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8), wherein second VL comprises a Y57S conservative substitution;second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8), wherein second VL comprises the amino acid sequence of SEQ ID NO: 203;second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSNYLA (SEQ ID NO: 15); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISSSSSSIYYADSVKG (SEQ ID NO:11); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KSRAGDFDY (SEQ ID NO: 12); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6);- 62 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:7);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYSAGDFDY (SEQ ID NO: 13); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:7); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:7);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRYGDFDY (SEQ ID NO: 14); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:7); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7), and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:7);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:7); second VH CDR2 comprises the amino acid sequence SISASSSSIYYADSVKG (SEQ ID NO:25 ); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:7); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:7); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:7); second ATI CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NOTO); second VH CDR3 comprises the amino acid sequence KYSzAGDFDY (SEQ ID NO:13), second VL CDR1 comprises the amino acid sequence RASQSA'SSSYLA (SEQ ID NO:7); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:7);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:7); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSATCG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:7); second VL CDR1 comprises the amino acid sequence RASQSVSSNYLA (SEQ ID NO: 15);- 63 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSNLA (SEQ ID NO: 16), second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8); orsecond VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASSRAT (SEQ ID NO: 17); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NOR). In some embodiments, second VL comprises Y57 (or a conservative substitution thereof, e.g., Y57S) and / or S83 (or a conservative substitution thereof) (according to AHo numbering of SEQ ID NO:200).

[0177] In some embodiments of a bispecific antibody:second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NOR); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NOR); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NOR);second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NOR); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NOR); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NOR), wherein second VL comprises a Y57S conservative substitution;- 64 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8), wherein second VL comprises the amino acid sequence of SEQ ID NO:203;second VH CDR1 comprises the amino acid sequence SYAMN (SEQ ID NO:24); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4), second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO: 5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); second VH CDR3 comprises the amino acid sequence KYR AGDFDY (SEQ ID NO:5), second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL, CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO: 5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8), wherein second VL comprises a Y57S conservative substitution;second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO: 5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3- 65 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:81 wherein second VL comprises the amino acid sequence of SEQ ID NO:203,second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL. CDRI comprises the amino acid sequence RASQSVSSNYLA (SEQ ID NO: 15); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDRI comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSSIYYADSVKG (SEQ ID NO: 11); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDRI comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8 );second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KSRAGDFDY (SEQ ID NO: 12); second VL CDRI comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDRI comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYSAGDFDY (SEQ ID NO:13); second VL. CDRI comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6), second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDRI comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRYGDFDY (SEQ ID NO: 14); second VL CDRI comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 6); second VL- 66 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISASSSSIYYADSVKG (SEQ ID NO:25); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:7); second VL CDRl comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:7); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:7);second VH CDRl comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); second VH CDR3 comprises the amino acid sequence KYSAGDFDY (SEQ ID NO: 13); second VL CDRl comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino ac d sequence QQQSSSPPT (SEQ ID NO: 8);second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO: 5); second VL CDRl comprises the amino acid sequence RASQSVSSNYLA (SEQ ID NO: 15); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);second VH CDRl comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:7); second VL CDRl comprises the amino acid sequence RASQSVSSSNLA (SEQ ID NO: 16); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:7); orsecond VH CDRl comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:7); second VL CDRl comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:7); second VL CDR2 comprises the amino acid sequence GASSRAT (SEQ ID NO: 17); and second VL CDR3- 67 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8). In some embodiments, second VL comprises Y57 (or a conservative substitution thereof, e.g., Y57S) and / or S83 (or a conservative substitution thereof) (according to AHo numbering of SEQ ID NO:200).

[0178] In some embodiments of a bispecific antibody: second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8). In some embodiments, second VL comprises Y57 (or a conservative substitution thereof, e.g., Y57S) and / or S83 (or a conservative substitution thereof) (according to AHo numbering of SEQ ID NO:200).

[0179] In some embodiments of a bispecific antibody: second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO: 5); second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8). In some embodiments, second VL comprises Y57 (or a conservative substitution thereof, e.g., Y57S) and / or S83 (or a conservative substitution thereof) (according to AHo numbering of SEQ ID NO:200).

[0180] In some embodiments of a bispecific antibody:second VH comprises the amino acid sequence of SEQ ID NO: 100 and second VL comprises the amino acid sequence of SEQ ID NO:200;second VH comprises the amino acid sequence of SEQ ID NO: 101 and second VL comprises the amino acid sequence of SEQ ID NO:200;second VH comprises the amino acid sequence of SEQ ID NO: 102 and second VL comprises the amino acid sequence of SEQ ID NO:200;second VH comprises the amino acid sequence of SEQ ID NO: 102 and second VL comprises the amino acid sequence of SEQ ID NO:201;- 68 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01second VH comprises the amino acid sequence of SEQ ID NO: 102 and second VL comprises the amino acid sequence of SEQ ID NO:203,second VH comprises the amino acid sequence of SEQ ID NO: 103 and second VL comprises the amino acid sequence of SEQ ID NO:200;second VH comprises the amino acid sequence of SEQ ID NO: 104 and second VL comprises the amino acid sequence of SEQ ID NO:200;second VH comprises the amino acid sequence of SEQ ID NO: 105 and second VL comprises the amino acid sequence of SEQ ID NO:200;second VH comprises the amino acid sequence of SEQ ID NO: 106 and second VL comprises the amino acid sequence of SEQ ID NO:200;second VH comprises the amino acid sequence of SEQ ID NO: 107 and second VL comprises the amino acid sequence of SEQ ID NO:200;second VH comprises the amino acid sequence of SEQ ID NO: 108 and second VL comprises the amino acid sequence of SEQ ID NO:200;second VH comprises the amino acid sequence of SEQ ID NO: 100 and second VL comprises the amino acid sequence of SEQ) ID NO:201,second VH comprises the amino acid sequence of SEQ ID NO: 100 and second VL comprises the amino acid sequence of SEQ ID NO:202;second VH comprises the amino acid sequence of SEQ ID NO: 100 and second VL comprises the amino acid sequence of SEQ ID NO:203; orsecond VH comprises the amino acid sequence of SEQ ID NO: 100 and second VL comprises the amino acid sequence of SEQ ID NO:204.

[0181] In some embodiments, a bispecific antibody comprises a second VH comprising SEQ ID NO: 100 and a second VL comprising SEQ ID NO:200. In some embodiments, a bispecific antibody comprises a second VH consisting of SEQ ID NO: 100 and a second VL consisting of SEQ ID NO:200.

[0182] In some embodiments, a bispecific antibody comprises (i) a first VH comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table B; (ii) a first VL comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the- 69 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01amino acid sequences set forth in Table C; (iii) a second VH comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table 3; or (iv) a second VL comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table 4.

[0183] In some embodiments, a bi specific antibody comprises (i) a first VH comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table B; (ii) a first VL comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table C; (iii) a second VH comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table 3; and (iv) a second VL comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table 4.

[0184] In some embodiments, a bispecific antibody comprises (i) a first VH comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 504 and 514; (ii) a first VL comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 510 and 520; (iii) a second VH comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 100-108; or (iv) a second VL comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 200-204.

[0185] In some embodiments, a bi specific antibody comprises (i) a first VH comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in- 70 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01SEQ ID NOs: 504 and 514; (ii) a first VL comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 510 and 520; (iii) a second VH comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 100-108; and (iv) a second VL comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 200-204.CONSTANT REGIONS OF ANTI-Ap / ANTI-TFRl BISPECIFIC ANTIBODIES

[0186] In some embodiments, a variable region of a bispecific antibody described herein is fused to a constant region. A constant region has a constant heavy chain (CH) domain (e.g., CHI, hinge, CH2, and / or CH3 domain(s) or any combination thereof) and a constant light chain (CL) domain. In some embodiments, a CH domain is from an IgGl molecule or an IgG4 molecule. In some embodiments, a CH domain is from an IgGl molecule. In some embodiments, a CH domain is from an IgG2 molecule, an IgG3 molecule, or an IgG molecule. In some embodiments, a first VH and / or a second VH of a bispecific antibody described herein can be fused to any one of the following constant heavy chain (CH) constructs as shown in Table 5 below. In some embodiments, a first VL and / or a second VL of the bispecific antibody described herein can be fused to any one of the following constant light chain (CL) constructs as shown in Table 5 below. In some embodiments, a hinge region is any hinge region known in the art. In some embodiments, a hinge region is naturally occurring, e.g., from a naturally occurring IgGl, IgG2, IgG3, or IgG4 molecule. In other embodiments, a hinge region contains modification(s) relative to a naturally occurring hinge

[0187] In some embodiments, a bi specific antibody of the disclosure is one in which at least one or more of the constant regions has been modified or deleted. In some embodiments, a bispecific antibody may comprise one or more modifications to a heavy chain constant domain (CHI, CH2 or CH3) and / or to a light chain constant region (CL). In some embodiments, a bispecific antibody may comprise one or more modifications to a first heavy chain constant domain (CHI, CH2 or CH3) and / or to a first light chain constant region (CL). In some- 71 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01embodiments, a bispecific antibody may comprise one or more modifications to a second heavy chain constant domain (CHI, CH2 or CH3) and / or to a second light chain constant region (CL).

[0188] In some embodiments, a bispecific antibody may comprise one or more modifications to a first heavy chain constant domain (CHI, CH2 or CH3), a first light chain constant region (CL), a second heavy chain constant domain (CHI, CH2 or CH3), and / or to a second light chain constant region (CL). In some embodiments, a heavy chain constant region of the modified antibody comprises at least one human constant region. In some embodiments, a heavy chain constant region of the modified antibody comprises more than one human constant region. In some embodiments, a VH is fused to any CHI construct known in the art, and a VL is fused to any CL known in the art. In some embodiments, a constant light chain (CL) of the constructs is a naturally occurring human Kappa constant region. In some embodiments, modifications to the constant region comprise additions, deletions, or substitutions of one or more amino acids in one or more regions. In some embodiments, one or more regions are parti lly or entirely deleted from the constant regions of a modified antibody. In some embodiments, the entire CH2 and CH3 domains have been removed from a bispecific antibody In some embodiments, a deleted constant region is replaced by a short amino acid spacer that provides some of the molecular flexibility typically imparted by the absent constant region. In some embodiments, a modified antibody comprises a CHI domain directly fused to the hinge region of a bispecific antibody. In some embodiments, a modified bispecific antibody comprises a Fab fused to the bottom of a Fc

[0189] In some embodiments, a bispecific antibody of the disclosure contains a linker (e.g., a linker as shown in Table 5 below). In some embodiments, a linker is positioned between a Fc region and a Fab region of a bispecific antibody of the disclosure. In some embodiments, a linker is positioned between a human IgGl Fc region and a Fab region of a bispecific antibody of the present disclosure. In some embodiments, a bispecific antibody comprises a linker between a first heavy chain and a second heavy chain. In some embodiments, a bispecific antibody comprises a linker between a constant region in a first heavy chain and a variable region in a second heavy chain. In some embodiments, a bispecific antibody comprises one or more linkers described in Table 5,- 72 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01Table 5: Constant Region, Hinge Sequences, and Linker Sequences.Domain SequenceIgGl or IgG4 CHIIgGl CHI (no hinge) A STKGPS VFPLAPS SKSTSGGTAALGCL VKDYFPEPVTVS WNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT(SEQ ID NO: 300)KVDKKVIgGl CHI (with hinge underlined) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSWTX'TSSSLGTQIYTCNV'NHKPSNT (SEQ ID NO: 301)KVDKKVEPKSCDKTHTCPPIgGl CHI (no hinge) ASTKGPSVTPLAPSSKSTSGGTAALGCL VKDYFPEPVTVS WNSGAL (SEQ ID NO: 302) TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT KVDKRVIgGl CHI (with hinge underlined) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT(SEQ ID NO: 303)KVDKRVESKYGPPCPIgGl CHI (no hinge) ASTKGPS VFPLAPS SKSTSGGTAALGCL VKDYFPEPVTVS WNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT(SEQ ID NO: 304) KVDKKVIgGl CHI (with hinge underlined) A STKGPS VFPLAPS SKSTSGGTAALGCL VKDYFPEPVTVS WN SGAL (SEQ ID NO: 305) TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT KVDKKVEPKSCIgG4 CHI (no hinge) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGAL (SEQ ID NO: 306) TSGVTITFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNT KVDKRVIgG4 CHI (with lunge underlined) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGAL (SEQ ID NO: 307) TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNT KVDKRVESFc hlgGl agly DelPG KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH (SEQ ID NO: 308) EDPEVKFNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL TKNQVSLTCLVKGFYPSDTAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSFc hlgGl.agly DelG KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH (SEQ ID NO: 309) EDPEVKFNWYVDGVEVHNAKI’KPREEQYQSIYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL TKNQVSLTCLVKGFYPSDLAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPFc hlgGl.agly KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVT)GVEVHNAKTKPREEQYQSTYRVVSVLTVLHQD (SEQ ID NO: 310) WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGHingeFc hlgGl.agly DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVS HEDPEVKFNWYVDGVTVTINAKTKPREEQYQSTYRVVSVLTVLHQ(SEQ ID NO: 311) DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNWSCSVMHEALHNHYTQKSLSLSPGHingeFc hlgGl.agly (KnobS) DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQ(SEQ ID NO: 312) DWLNGKEYKCKVSNKALPAPTEKTTSKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG- 73 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01Fc hlgGl.agly(KnobS) KTHTCPPCPAPELI> GGPS\7FLFPPKPKDTI. MISRTPEVTCW\7DVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYQSTYRWSVLTVLHQD(SEQ ID NO: 313) WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDE LTKNQVSIAVCIA^KGFYPSDIAXTWESNGQPENNYKTTPPVLDSDG SFFLYSKI., TVT)KSRWQQGNy7FSCS\7MHEAI., HNHYTQKSLSI.. SPG HingeFc hlgGl.agly(HoleS) KTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPE VTCV VVD VSH EDPEVKFNWYVDGVEVHNAKTKPREEQYQS'FYRV\7SVLTVLHQD (SEQ ID NO: 314) WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDEL TKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGHinge regionIgGl hinge A (SEQ ID NO: 315) EPKSCDKTHTCPPCPAPELLGGPIgGl hinge B (SEQ ID NO: 316) EPKSCDKTHTCPPIgGl hinge C (SEQ ID NO: 317) EPKSCIgG4 hinge D (SEQ ID NO: 318) ESKYGPPCPPCPAPEFLGGPIgG4 hinge E (SEQ ID NO: 319) ESKYGPPCPIgG4 hinge F ESIgGl hinge G (SEQ ID NO: 320) EPKSIgGl hinge H (SEQ ID NO: 321) EPKSCDIgGl hinge I (SEQ ID NO: 322) EPKSCDKIgGl hinge J (SEQ ID NO: 323) EPKSCDKTIgGl hinge K (SEQ ID NO: 324) EPKSCDKTHIgGl hinge L (SEQ ID NO: 325) EPKSCDKTHTIgGl hinge M (SEQ ID NO: 326) EPKSCDKTHTCIgGl hinge N (SEQ ID NO: 327) EPKSCDKTHTCPIgGl hinge 0 (SEQ ID NO: 328) EPKSCDKTHTCPPCIgGl hinge P (SEQ ID NO: 329) EPKSCDKTHTCPPCPIgGl hinge Q (SEQ ID NO: 330) EPKSCDKTHTCPPCPAIgGl hinge R (SEQ ID NO: 331) EPKSCDKTHTCPPCPAPIgGl hinge S (SEQ ID NO: 332) EPKSCDKTHTCPPCPAPEIgGl hinge T (SEQ ID NO: 333) EPKSCDKTHTCPPCPAPELIgGl hinge U (SEQ ID NO: 334) EPKSCDKTHTCPPCPAPELLIgGl lunge V (SEQ ID NO: 335) EPKSCDKTHTCPPCPAPELLGIgGl hinge W (SEQ ID NO: 336) EPK SCDKTHTCPPCPAPELLGGIgG4 hinge X ESKIgG4 hinge Y (SEQ ID NO: 337) ESKYIgG4 lunge Z (SEQ ID NO: 338) ESKYGIgG4 hinge ZA (SEQ ID NO: 339) ESKYGPIgG4 hinge ZB (SEQ ID NO: 340) ESKYGPP- 74 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01IgG4 hinge ZC (SEQ ID NO: 341) ESKYGPPClgG4 hinge ZD (SEQ ID NO: 342) ESKYGPPCPPIgG4 hinge ZE (SEQ ID NO: 343) ESKYGPPCPPCIgG4 lunge ZF (SEQ ID NO: 344) ESKYGPPCPPCPIgG4 hinge ZG (SEQ ID NO: 345) ESKYGPPCPPCPAIgG4 hinge ZH (SEQ ID NO: 346) ESKYGPPCPPCP APIgG4 hinge ZI (SEQ ID NO: 347) ESKYGPPCPPCP APEIgG4 lunge ZJ (SEQ ID NO: 348) ESKYGPPCPPCP APEFIgG4 hinge ZK (SEQ ID NO: 349) ESKYGPPCPPCP APEFLIgG4 hinge ZL (SEQ ID NO: 350) ESKYGPPCPPCP APEFLGIgG4 hinge ZM (SEQ ID NO: 351) ESKYGPPCPPCP APEFLGGIgG4 lunge ZN (SEQ ID NO: 352) ESKYGPPCPPCP APEFLGGPCL domainHuman kappa CL (SEQ ID NO: RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDN ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT353)HQGLSSPVTKSFNRGECHuman kappa CL (A ( 214) RTVAAPSVFIFPPSDEQLKSGTASV7VCLLNNFATREAKVQWKVDN (SEQ ID NO: 354) ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGELinkerLinkers SLinkerSGz SGGLinkgerSG4(SEQ ID NO: 355) SGGGGLinkerSG4SG4(SEQ ID NO: 356) SGGGGSGGGGLinkerSG4SG4SG4(SEQ ID NO: SGGGGSGGGGSGGGG357)LinkerG3SG5(SEQ ID NO: 358) GGGSGGGGGLinkerG4SG4SG4S (SEQ ID NO: GGGGSGGGGSGGGGS359)LinkerG4SG4S (SEQ ID NO: 361) GGGGSGGGGSLinkerG4S (SEQ ID NO: 362) GGGGSLinkeiTG TG

[0190] Other exemplary constant regions, e.g., hinge regions, that can be combined with a bispecific antibody variable regions described herein include but are not limited to the hinge regions described in Peters SJ, et al. J Biol Chem 2012 Jul 13;287(29):24525-33; and Heads JT, et al. Protein Sei. 2012 Sep;21(9): 1315-22; incorporated herein by reference in their entirety.13278272v 1Attomey Docket No. 2011256-2654 / P1939PCT01

[0191] In some embodiments, a bispecific antibody comprises a first heavy chaindescribed in Table D. In some embodiments, a bispecific antibody comprises a first light chain described in Table D. In some embodiments, a bispecific antibody comprises a first heavy chain described in Table D and a first light chain described in Table D.Table D: Heavy Chains and Light Chains of ANTI BODY Z and Mutants.Name SEQ ID NO SequenceANTIBODY Z 603 QVQLVESGGGWQPGRSLRLSCAASGFATSSYGMHWVRQAPGKGLEWVAVIWF HC1 parent DGTKKYYTDSVKGRFFISRDNSKNTLYLQMNl'LRAEDTAVYYCARDRGIGARRG PYYMDAAVGKGTTVTVSSASTKGPSATPLAPSSKSTSGGTAALGCLVKDYFPEPVT VStVNSGAETSGVHTFPAVEQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSIY'RVVSVLTVLHQDWLNGKE YTCCKVSNTCALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPP\T, DSDGSFFL / FSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPG ANTIBODY Z 604 QVQLVESGGGWQPGRSLRLSCAASGFAFSSYGMHWVRQAPGKGLEWVAVIWF HC2 parent DGTKKYYTDSVKGRFnSRDNSKNTLYLQMNTLRAEDTAVYYCARDRGIGARRG PYYMDVWGKGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VT)KKVEPKSCDKTHTCPPCPAPELLGGPS\TLFPPKPKDTLMISRTPEVTCVVVDV Sf-IEDPEVKFNVvA’VDGVEVH?sAKTKPREEQYNSTYRVVSVLTVLJ-! OD\VL. NGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSL SLSPG ANTIBODY Z 605 QVQLVESGGGVVQPGRSLRLSCAASGFAFSSYGMHWVRQAPGKGLEWVAVIWF HC3 parent DGTKKYYTDSVKGRFTISRDNSKNl’LYLQMNTLRAEDTAVYYCARDRGIGARRG PYYMDVWGKGTTVTVSSASTKGPSVFPLAPSSKSTSGGTA / ALGCLYKDYTPEPVT VSWNSGALTSGVHTFPAY^QSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTK VDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMTSRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTX7LHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVE\W. SNGQPENNYKTTPP\TDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPG ANTIBODY Z 606 QVQLVESGGGVVQPGRSLRLSCAASGFAFSSYGMHWVRQAPGKGLEWVAVIWF mutant 1 DGTKKYYTDS\7KGRFTISRDNSKNTI., YT., QMNTLRAEDTAVYYCARDRGIGARRG HC holeC PYYMDVWGKGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCQVEDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYELSSVVTVPSSSLGTQTYICNVNHKPSNTK WKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDV SHEDPEVXFNWYVDGVEVHNAKTKPREEQYNSTYRWSVI. TVI. HQDWI. NGKE YKCKVSNKALPAPIEKTTSKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFY PSD1AVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG- 76 - 13278272vlAttorney Docket No. 2011256-2654 / P1939PCT01Name SEQ ID NO SequenceANTIBODY Z 607 QVQLVESGGGVVQPGGSLRLSCAASGFITSSYGMHWVRQAPGKGLEWVAVIWY mutant 2 DGSNKYYADSV’KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRGIGARRG HC boleC PYYMDVVVGKGTTVTVSSASTKGPSVFPL. APSSKSTSGGTA ALGCQVEDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYELSSWTV'PSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFN\W\7DG\7E\TINAKTKPREEQYNSTYRVVSVLTVLIIQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYP SDTAVEWESNGQPENTTYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPG ANTIBODY Z 608 QVQLXTiSGGGWQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWY mutant 2 DGSNKYYADSVKGRFTTSRDNSKNTLYLQMNSLRAEDTAVYYCARDRGIGARRG HC holeC (LS) PYYMDVWGKGTrVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCQV'EDYFPEPVT VSWNSGALTSGVHTFPA\7LQSSGLYELSSWT\T> SSSLGTQTYICN\TNHKPSNTK vDKK\'T. PKSCDKTHTCPPCPAPE. L. L. GGPSVFLFPPKPKDTLM! SF< TPEVTCVvVDV SHEDPEVXFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKnSKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYP SDLAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLH EALHSHYTQKSLSLSPG ANTIBODY Z 609 QVQLVESGGGWQPGRSLRLSCAASGFAFSSYGMHWVRQAPGKGLEWVAVIWF mutant 1 DGTKKYYTDSVKGRFT1SRDNSKNTLYLQMNTLRAEDTAVYYCARDRG1GARRG HC knobC PYYMDVWGKGTTVTVSSASTKGPSVFPLA. PSSKSTSGGTAALGCQVEDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYELSSVVTVPSSSLGTQTY1CNVNHKPSNTK WKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM1SRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVY'TUPCREEMTKNQVSLWCLA'KGFY PSDLAAT. WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSP ANTIBODY Z 610 QVQLVESGGGVVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWY mutant 2 DGSNKYY AD S VKGRFT1SRDN SKNTLYLQMN SLR AEDTAVYYC ARDRGIGARRG HC knobC PYYMDVWGKGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCQVEDYFPEPVT VSWNSGALTSGATITFPAV’LQSSGLYELSSWTV’PSSSLGTQTYTCNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPEIJ> GGPS\TLFPPKPKDTI.. MISRTPE\7TC\'rV\7DV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKl’lSKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSP ANTIBODY Z 611 QVQLVESGGGVVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWY mutant 2 DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRGIGARRG HC knobC (LS) PYYMDVWGKGTTVTX^SSASTKGPSVFPLAPSSKSTSGGTAALGCQVEDYFPEPVT VSWNSGALTSGWTFPAVLQSSGLYELSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDK'rHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFN\\YAT)G\H\TINAKTKPREEQYNSTYRVVSVLTVTJ-IQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTI. PPCRDELTKNQVSLWCIA / KGFY' PSDIAVE^SNGQPENNYKTTPPXT> DSDGSFH> YSKLTVDKSRWQQGN\TSCSVI-HEALHSHYTQKSLSLSP13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01Name SEQ ID NO SequenceANTIBODY Z 700 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQS parent LC GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIKRTVAAP SVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWVDNALQSGNSQESXTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC ANTIBODY Z 701 DIQMTQSPSSLSASVGDRWITCRASQSISSYLNWYQQKPGKAPKLLTYAASSLQS mutant 1 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVFJKRTVAAP LC SVFIFPPSDEQLKSGRASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSRLQLSKADYEKHKVYACEVOTQGLSSPVIKSFNRGEC ANTIBODY Z 702 DIQMTQSPSSLSASVGDRVTrTCRASESINSYLNWT'QQKPGKAPKLLlYAASSLQS mutant 2 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVE1KRTVAAP LC SVFIFPPSDEQLKSGRASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSRLQLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0192] In some embodiments, a bi specific antibody comprises a second heavy chain described in Table 6. In some embodiments, a bispecific antibody comprises a second light chain described in Table 6. In some embodiments, a bi specific antibody comprises a second heavychain described in Table 6 and a second light chain described in Table 6.Table 6: Heavy Chains and Light Chains of ANTIBODY X and Mutants.Name SEQ ID NO SequenceANTIBODY X 400 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSS SYiYYADSVKGFtFTlSRDNAKNSLYL. QYfNSLRAEDTAVYYCARKYRAGDFDYVv HC GQGTLVTVSSASTKGPSWPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTSGWTFPA\T, QSSGLYSLSSWTYTSSSLGTQTYTCN\TsHKPSNTKVT2KKVEPK SCDKTHTCPPCPAPELLGGPSYTLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEYTC FNWYVDGVEWINAKTKPRFEQYQSTYRVVSVI. TVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYT[., PPSRDELTKNQVSLTCLVKGFYPSD1AVEWE SNGQPENNYKTTPPVI> DSDGSFFI> YSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPG ANTIBODY X 401 EIVMTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQK. PGQAPRLL1YGASNRA TGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQQSSSPPTFGGGTKVEIKRTVAA LC PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC ANTIBODY X 402 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSTSSSS Fab fragment SY1YYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARKYRAGDFDYW GQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK. DYFPEPVTVSWNSGA HC LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH- 78 - 13278272v 1Attomey Docket No. 2011256-2654 / P1939PCT01Name SEQ ID NO SequenceANTIBODY X 403 KTHTCPPCPAPELLGGPSVFLFPPKPKDILMISRTPEVrCVVVDVSHEDPEVKFNW YVDGVEVHNAKTI< PREEQYQSrnARVVSVLTVLHQDWLNGKEYKCKVSNKALP Fc-Fab bivalent APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG HC QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGGGGSGGGGSEVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVR QAPGKGLEWVSSISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAV YYCARKYRAGDFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSyWSGALTSGVTITFPAVLQSSGLYSLSSVX'TVPSSSLGTQTYTCNV NHKPSNTKVDKKVEPKSC ANTIBODY X 404 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSS SYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARKYRAGDFDYWFab-Fc GQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA monovalent LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY1CNVNHKPSNTKVDKKVEPK SCDKTHTCPPCPAPELLGGPSV'FLFPPKPKDTL. MISRTPEVTCVVVTDVSHEDPEV’K HC1 (knob) FNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPG ANTIBODY X 405 KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYQSTYRVVSVTTVLHQDWLNGKEYKCKVSNKALPFc-Fab APIEK’nSKAKGQPREPQY'YTLPPSRDELTKNQVSLWCLVKGFYPSDIAY’EWESNG monovalent QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVTSCSVMHEAITINHYTQK SLSLSPGGGGSGGGGSEVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVR HC1 (knob)QAPGKGLEWVSSISSSSSYIYYADSV'KGRFTISRDNAKNSLYI-. QMNSLRAEDTAV Y^CARKYRAGDFDYWGQGTIA'TVSSASTKGPSyTPLAPSSKSTSGGTAAI. GCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NHKPSNTKVDKKVEPKSCFc (hole) 406 KTHTCPPCPAPELLGGPSV'FLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYI’LPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPG ANTIBODY X 407 ETVMTQSPGTLSLSPGERATLSCRASQSVSSNYLAWXXK> KPGQAPRELIYGASNR (VL-S39N) ATGIPDRFSGSGSGTDFTL. TISRIT. PEDFAVYYCQQQSSSPPTFGQGTKV'EIKRTVA APSVFIFPPSDEELKSGTASVQCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ LC DSKDSTYSLSSELTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC ANTIBODY X 412 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSS S442C HC SYIYYADSVKGRFTISIU9NAKNSLYLQMNSLRAEDTAVYYCARKYRAGDFDYW GQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVXDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVTSSSLGTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNW YVDGVEVI-1NAKTKPREEQFQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPS SIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVNniEALHNHYTQKSLCLSPG- 79 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01Name SEQ ID NO SequenceANTIBODY X 413 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSS monovalent SYIYYADSVKGRFT1SRDNAKNSLYLQMNSLRAEDTAVYYCARKYRAGDFDYW GQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALS442CHC1 TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEFLGGPSVTLFPPKPKD1LMISRTPEVTCVVVDVSQEDPEVQFNW (knob)YVDGVEVHNAKTKPREEQFQSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPS SIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQ PENNYKTTPPyTDSDGSFFLYSKLTXnDKSRWQQGNWSCSVMHEALHNHYTQKS LSLSPG ANTIBODY X 414 KYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFN WY'VDGVEVHNAKTKPREEQFQSTYRWSVLTVLHQDWLNGKEYKCKVSNKGL monovalent PSSIEKTISKAKGQPREPQWTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESN S442C HC2 GQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVTSCSVlVlHEALHNHYTQ (hole) KSLCLSPG

[0193] In some embodiments, a bispecific antibody comprises a first heavy chaindescribed in Table D and / or a first light chain described in Table D, and a second heavy chain described in Table 6 and / or a second light chain described in Table 6. In some embodiments, a bispecific antibody comprises a first heavy chain described in Table D and a first light chain described in Table D, and a second heavy chain described in Table 6 and a second light chain described in Table 6.

[0194] In some embodiments, a bispecific antibody comprises (i) a first heavy chaincompri sing at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table D; (ii) a first light chain comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table D; (iii) a second heavy chaincomprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table 6; or (iv) a second light chain comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table 6.

[0195] In some embodiments, a bispecific antibody comprises (i) a first heavy chain comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table D; (ii) a first light chain comprising at least 75%, at least 80%, at least 85%, at - 80 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table D; (iii) a second heavy chain comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table 6; and (iv) a second light chain comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in Table 6

[0196] In some embodiments, a bispecific antibody comprises (i) a first heavy chain comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 603-611; (ii) a first light chain comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 700-702; (iii) a second heavy chain comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 400, 402, 403-406, and 412-414, or (iv) a second light chain comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 401 and 407.

[0197] In some embodiments, a bispecific antibody comprises (i) a first heavy chain comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 603-611; (ii) a first light chain comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 700-702; (iii) a second heavy chain comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 400, 402, 403-406, and 412-414; and (iv) a second light chain comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 401 and 407.- 81 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0198] In some embodiments, a bispecific antibody comprises a heavy chain described in Table 7. In some embodiments, a bispecific antibody comprises alight chain described in Table7. In some embodiments, a bispecific antibody comprises a heavy chain described in Table 7 and a light chain described in Table 7.Table 7: Heavy Chains and Light Chains of ANTIBODY Z / ANTIBODY X Bispecific Antibodies.Name SEQ ID NO SequenceANTIBODY Z 800 QVQLXT. SGGGVVQPGRSLRLSCAASGFAFSSYGMHWVRQAPGKGLEWVAVIWF mutant DGTKKYYTDSWGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARDRGIGARRG PYYAroW'GKGTTVTVSSASTKGPSWPLAPSSKSTSGGTAALGCQVEDYFPEPVT 1 / ANTIBODY VS\VNSGALXSGVHTFr< AVLQSSGi.. YELSSVVTVPSSSl. GTQTYiCNVNHKPSNTK X (S60A) VT)KRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTI., MISRTPEVTC\WVDV SHEDPEVXFNWYWGWATlNAKTKPREEQYNSTYPvVVS\T, TVLHQDWLNGKE HC yXCKVSNKALPAPIEKTISKAKGQPREPQVYTITPCREEMTKNQVSLWCLVKGFY PSDIAXTWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGGGGSGGGGSEVQLVESGGGLVKPGGSLRLSCAASG FTFSSYSMNWVRQAPGKGLEWVSSISASSSYIYYADSVKGRFTISRDNAKNSLYL QMNSLRAEDTAVYYCARKYRAGDFD YWGQGTL VTVSSASTKGPSVFPRAPSSKS TSGGTAALGCLVRDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTY1CNVNHKPSNTKVDKKVEPKSCDANTIBODY Z 801 QVQLYESGGGVVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWY DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRGIGARRGmutant PYYMDVWGKGTTVTVSSASTKGPSVFPLAPSSKSTSGGTA / ALGCQVEDYFPEPVT 2 / ANTIBODY VSWNSGALTSGVHTFPAVLQSSGLYELSSVVTVPSSSLGTQTYICNVNHKPSNTK VT)KK\TiPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV X (S60A) SHEDPEVTCFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE HC YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFY PSDLAVEWESNGQPF. NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHE ALHNHYTQKSL SLSPGGGG SGGG G SEVQLVESGGGL VKPGG SLRLSCAASG FTFSSYSMNW VRQ APGKGLEWVS SIS A SSS YIYYAD S VKGRFTISRDN AKNSLYL QMNSLRAEDT AVYYC ARKYRAGDFD YWGQGTL VTVS S A STKGPS VFPR APS SKS TSGGTAALGCLVTIDYTTEPVTVSWNSGALTSGXTITFPAVLQSSGLYSLSSVVTVP SSSLGTQTYICNVNHKPSNTK\T)KKVEPKSCDANTIBODY Z 802 QVQLVESGGGVVQPGGSLRLSCAASGFITSSYGMHWVRQAPGKGLEWVAVIWY DGSNKYYAD S VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARDRGIGARRGmutant 2 PYYMDVWGKGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCQVEDYFPEPVT (LS) / ANT1BO VSWNSGALTSGVHTFPAVLQSSGLYELSSVVIVPSSSLGTQTYICNVNHKPSNTK DY X (S60A) VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR'rPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSl'YRVVSVLTVLHQDWLNGKE HC YKCKVSNKALPAPIEKTISKAKGQPREPQVYILPPCRDELTKNQVSLWCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVL HEALHSHYTQKSLSLSPGGGGSGGGGSEVQLVESGGGLVKPGGSLRLSCAASGFT FSSYSMNWVRQAPGKGLEWVSSISASSSYIYYADSXTCGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARKYRAGDFD YWGQGTL VTVSSASTKGPSVFPRAPSSKSTS GGTAALGCLVRDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVTTIKPSNTKWKKVEPKSCD- 82 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0199] In some embodiments, a bispecific antibody comprises a first heavy chain and / or a second heavy chain comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 400, 402, 403-406, 412-414, 603-611, and 800-802.

[0200] In some embodiments, a bispecific antibody comprises a first light chain and / or a second light chain comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 401, 407, and 700-702

[0201] In some embodiments, a bispecific antibody comprises (i) a first heavy chain and / or a second heavy chain comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 400, 402, 403-406, 412-414, 603-611, and 800-802; and (ii) a first light chain and / or a second light chain comprising at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to any one of the amino acid sequences set forth in SEQ ID NOs: 401, 407, and 700-702.

[0202] In some embodiments, a bispecific antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises or consists of the amino acid sequences set forth in any one of SEQ ID N0s:800-802.

[0203] In some embodiments, a bi specific antibody comprises one or more amino acid sequences set forth in any one of SEQ ID Nos: 400-407, 412-414, 603-611, 700-702, and 800-802

[0204] In some embodiments, a bispecific antibody comprises a Fab fragment. In some embodiments, a bispecific antibody comprises a Fab fragment, wherein the Fab fragment comprises the amino acid sequences set forth in any one of SEQ ID NOs:401 and 402.

[0205] In some embodiments, a bi specific antibody comprises a Fab-Fc. In some embodiments, a bispecific antibody comprises a Fab-Fc, wherein the Fab-Fc comprises the amino acid sequences set forth in SEQ ID NOs:401, 404, and 406. In some embodiments, a- 83 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01bispecific antibody comprises a Fab-Fc, wherein the Fab-Fc comprises the amino acid sequences set forth in SEQ ID NOs: 400 and 401.

[0206] In some embodiments, a bi specific antibody comprises an Fc-Fab. In some embodiments, a bispecific antibody comprises an Fc-Fab, wherein the Fc-Fab comprises the amino acid sequences set forth in SEQ ID NOs:401, 405, and 406 In some embodiments, a bispecific antibody comprises an Fc-Fab, wherein the Fc-Fab comprises the amino acid sequences set forth in SEQ ID NOs: 401 and 403.

[0207] In some embodiments, a bi specific antibody comprises a first heavy chain having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity' to a first heavy chain sequence identified herein, wherein the bispecific antibody has a first VH and first VL identical to VH and VL of ANTIBODY Z. In some embodiments, a bispecific antibody comprises a first light chain having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to a first light chain sequence identified herein, wherein the bispecific antibody has a first VH and first VL. identical to VH and VL of ANTIBODY Z. In some embodiments, a bispecific antibody comprises a first heavy chain having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to a first heavy chain sequence identified herein and a first light chain having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to a first light chain sequence identified herein, wherein the bispecific antibody has a first VH and first VL identical to VH and VL of ANTIBODY Z.

[0208] In some embodiments, a bispecific antibody comprises a first heavy chain having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to a first heavy chain sequence identified herein, wherein the bispecific antibody does not have a first VH and first VL identical to VH and VL of ANTIBODY Z In some embodiments, a bispecific antibody comprises a first light chain having at least 80%, at least 85%, at least 90%, or at least 95% sequence i dentity to a first light chain sequence identified herein, wherein the bi specific antibody does not have a first VH and first VL identical to VH and VL of ANTIBODY Z. In some embodiments, a bispecific antibody comprises a first heavy chain having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to a first heavy chain sequence identified herein and a first light chain having at least 80%, at least 85%, at least 90%, or at least 95% sequence i dentity to a first light chain sequence identified herein, wherein the bi specific antibody does not have a first VH and first VL identical to VH and VL of ANTIBODY Z.- 84 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0209] In some embodiments, a bispecific antibody comprises a first heavy chain having an amino acid sequence that has one, two, or three, or more modifications (e.g., substitutions, deletions, or insertions) compared to a first heavy chain sequence identified herein, wherein the bispecific antibody has a first VH and first VL identical to VH and VL of ANTIBODY Z. In some embodiments, a bispecific antibody comprises a first light chain having an amino acid sequence that has one, two, or three, or more modifications (e.g., substitutions, deletions, or insertions) compared to a first light chain sequence identified herein, wherein the bispecific antibody has a first VH and first VL identical to VH and VL of ANTIBODY Z. In some embodiments, a bispecific antibody comprises a first heavy chain having an amino acid sequence that has one, two, or three, or more modifications (e.g., substitutions, deletions, or insertions) compared to a first heavy chain sequence identified herein and a first light chain having an amino acid sequence that has one, two, or three, or more modifications (e.g., substitutions, deletions, or insertions) compared to a first light chain sequence identified herein, wherein the bispecific antibody has a first VH and first VL identical to VH and VL of ANTIBODY Z

[0210] In some embodiments, a bispecific antibody comprises a first heavy chain having an amino acid sequence that has one, two, or three, or more modifications (e.g., substitutions, deletions, or insertions) compared to a first heavy chain sequence identified herein, wherein the bispecific antibody does not have a first VH and first VL identical to the VH and VL of ANTIBODY Z. In some embodiments, a bispecific antibody comprises a first light chain having an amino acid sequence that has one, two, or three, or more modifications (e.g, substitutions, deletions, or insertions) compared to a first light chain sequence identified herein, wherein the bispecific antibody does not have a first VH and first VH identical to the VH and AT of ANTIBODY Z. In some embodiments, a bispecific antibody comprises a first heavy chain having an amino acid sequence that has one, two, or three, or more modifications (e.g., substitutions, deletions, or insertions) compared to a first heavy chain sequence identified herein and a first light chain having an amino acid sequence that has one, two, or three, or more modifications (e.g., substitutions, deletions, or insertions) compared to a first light chain sequence identified herein, wherein the bispecific antibody does not have a first VH and first VL identi cal to the VH and VL of ANTIBODY Z

[0211] In some embodiments, a bi specific antibody comprises a second heavy chain having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to a second- 85 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01heavy chain sequence identified herein, wherein the bispecific antibody has a second VH and second VL identical to the VH and VL of ANTIBODY X. In some embodiments, a bispecific antibody comprises a second light chain having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to a second light chain sequence identified herein, wherein the bispecific antibody has a second VH and second VL identical to first VH and VL of ANTIBODY X. In some embodiments, a bispecific antibody comprises a second heavy chain having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to a second heavy chain sequence identified herein and a second light chain having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to a second light chain sequence identified herein, wherein the bispecific antibody has a second VH and second VL identical to the VH and VL of ANTIBODY X.

[0212] In some embodiments, a bispecific antibody comprises a second heavy chain having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to a second heavy chain sequence identified herein, wherein the bispecific antibody does not have a second VH and second VL identical to the VH and VL of ANTIBODY X. In some embodiments, a bispecific antibody comprises a second light chain having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to a second light chain sequence identified herein, wherein the bispecific antibody does not have a second VH and second VL identical to the VH and VL of ANTIBODY X. In some embodiments, a bispecific antibody comprises a second heavy chain having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to a second heavy chain sequence identified herein and a second light chain having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to a second light chain sequence identified herein, wherein the bispecific antibody does not have a second VH and second VL identical to the VH and VL of ANTIBODY X.

[0213] In some embodiments, a bi specific antibody comprises a second heavy chain having an amino acid sequence that has one, two, or three, or more modifications (e.g., substitutions, deletions, or insertions) compared to a second heavy chain sequence identified herein, wherein the bispecific antibody has a second VH and second VL identical to the VH and VL of ANTIBODY X. In some embodiments, abispecific antibody comprises a second light chain having an amino acid sequence that has one, two, or three, or more modifications (e.g., substitutions, deletions, or insertions) compared to a second light chain sequence identified- 86 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01herein, wherein the bispecific antibody has a second VH and second VL identical to the VH and VL of ANTIBODY X. In some embodiments, a bi specific antibody comprises a second heavy chain having an amino acid sequence that has one, two, or three, or more modifications (e.g., substitutions, deletions, or insertions) compared to a second heavy chain sequence identified herein and a second light chain having an amino acid sequence that has one, two, or three, or more modifications (e.g., substitutions, deletions, or insertions) compared to a second light chain sequence identified herein, wherein the bispecific antibody has a second VH and second VL identical to the VH and VL of ANTIBODY X.

[0214] In some embodiments, a bispecific antibody comprises a second heavy chain having an amino acid sequence that has one, two, or three, or more modifications (e.g., substitutions, deletions, or insertions) compared to a second heavy chain sequence identified herein, wherein the bispecific antibody does not have a second VH and second VL identical to the VH and VL of ANTIBODY X. In some embodiments, a bispecific antibody comprises a second light chain having an amino acid sequence that has one, two, or three, or more modifications (e.g., substitutions, deletions, or insertions) compared to a second light chain sequence identified herein, wherein the bispecific antibody does not have a second VH and second VL identical to the VH and VL of ANTIBODY X. In some embodiments, a bi specific antibody comprises a second heavy chain having an amino acid sequence that has one, two, or three, or more modifications (e.g., substitutions, deletions, or insertions) compared to a second heavy chain sequence identified herein and a second light chain having an amino acid sequence that has one, two, or three, or more modifications (e.g., substitutions, deletions, or insertions) compared to a second light chain sequence identified herein, wherein the bispecific antibody does not have a second VH and second VL identical to the VH and VL of ANTIBODY X.

[0215] In some embodiments, a ANTIBODY X discontinuous epitope is formed by residues Q285, T286, K287, P289, E343, D352, C353, P354, S355, K358, D360, S361, R364 from the apical domain and S492, D560, T561, and R579 from the protease-like domain of hu TfRl (SEQ ID NO.l). In some embodiments, a bispecific antibody binds to the same epitope as ANTIBODY X. In some embodiments, a bispecific antibody binds to one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17) amino acids of the ANTIBODY X epitope (e.g., one or more of residues Q285, T286, K287, P289, E343, D352, C353, P354, S355, K358, D360, S361, R364, S492, D560, T561, and R579 of hu TfRl (SEQ ID NO:!)). In some embodiments, a- 87 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01bispecific antibody binds to one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17) amino acids of the ANTIBODY X epitope (e.g., one or more of residues T286, K287, E343, D352, C353, P354, S355, K358, D360, S361, R364, S492, D560, T561, and R579 of hu TfRl (SEQ ID NO: 1)). In some embodiments, a bispecific antibody comprises or is a monovalent antibody and has a monovalent affinity (KD) for hTfRl of >10 nM. In some embodiments, a bispecific antibody comprises or is a bivalent antibody and has a monovalent affinity (KD) of >10 nM. In some embodiments, a bispecific antibody comprises or is a bivalent antibody and has a monovalent affinity (KD) for hTfRl of >100 nM. In some embodiments, a bispecific antibody comprises or is a bivalent antibody and has a monovalent affinity (KD) for hTfRl of >1000 nM. In some embodiments, a bispecific antibody comprises or is a bivalent antibody and has a monovalent affinity (KD) for hTfRl of >100 nM or >1000nM. In some embodiments, valency and affinity of a bispecific antibody are targeted for optimal brain exposure and / or high apparent affinity to high molecular weight aggregates of human Ap>.

[0216] The present disclosure further embraces additional variants and equivalents that are substantially homologous to the recombinant, monoclonal, chimeric, humanized, and human antibodies, or antibody fragments thereof, described herein. In some embodiments, it is desirable to modulate the binding affinity of a bispecific antibody. In some embodiments, it is desirable to modulate biological properties of a bispecific antibody, including but not limited to, specificity, thermostability, expression level, effector function(s), glycosylation, immunogenicity, and / or solubility. Those skilled in the art. will appreciate that amino acid changes may alter post-translational processes of an antibody, such as changing the number or position of glycosylation sites or altering membrane anchoring characteristics.

[0217] Effector function of antibodies can be modulated by amino acid mutations and / or domain substitutions (e.g., including but not limited to those described in Dumet et al. MABS 2019; 11 ( 8): 1341 -50, and those described in Wilkinson et al., 2021, PLoS One.16(12):e0250954, e.g., any of the amino acid alterations in Table 4 therein, e g., the “LALA” double mutation (human IgGl L234A / L235A) and the “LALAPG” triple mutation (human IgGl L234A / L235A / P329G)). Additional characteristics such as pharmacokinetics (e.g., Dall’acqua et al J of Immunology 2002;169 (9) 5171-80), glycosyl tion, immunogenicity, solubility, and stability can be engineered by modification of Fc by mutations or substitutions. In addition, novel antigen specificity can be engineered into constant domains to create new paratopes (e.g.,- 88 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01Wozniak-Knopp et al. PEDS 2010;23(4):289-97). The affinity or avidity of a Fab may be modulated by changing the linkages between domains of antibodies such as removing the Fab from the top portion of a bispecific antibody and linking the Fab to the Fc C -terminus by a linker of any length from zero to 40 amino acids and fusing into the N-terminus of either a VH or VL domain of a Fab creating an “upside-down” antibody with potentially modulated affinity or avidity for binding to antigen, and modulated effector function (e.g., Weber et al. Cell Reports 2018;22:149-62).

[0218] Variations may be a substitution, deletion, or insertion of one or more nucleotides encoding a bispecific antibody or polypeptide that results in a change in the amino acid sequence as compared with the native antibody or polypeptide sequence. In some embodiments, amino acid substitutions are the result of replacing one amino acid with another amino acid having similar structural and / or chemical properties, such as the replacement of a leucine with a serine, e.g., conservative amino acid replacements. Insertions or deletions may optionally be in the range of about 1 to 5 amino acids. In some embodiments, substitution, deletion, or insertion includes less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions, or less than 2 amino acid substitutions relative to the parent molecule In some embodiments, variations in the amino acid sequence that are biologically useful and / or relevant may be determined by systematically making insertions, deletions, or substitutions in the sequence and testing the resulting variant proteins for activity as compared to the parent protein.

[0219] In some embodiments, variants may include addition of amino acid residues at the amino- and / or carboxyl -terminal end of a bi specific antibody or polypeptide. The length of additional amino acids residues may range from one residue to a hundred or more residues. In some embodiments, a variant comprises an N-terminal methionyl residue. In some embodiments, variant comprises an additional polypeptide / protein (e.g., Fc region) to create a fusion protein. In some embodiments, a variant is engineered to be detectable and may comprise a detectable label and / or protein (e.g., a fluorescent tag or an enzyme).

[0220] In some embodiments, a cysteine residue not involved in maintaining the proper conformation of a bispecific antibody is substituted or deleted to modulate the bispecific antibody’s characteristics, for example, to improve oxidative stability and / or prevent aberrant- 89 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01disulfide crosslinking and / or facilitate attachment of an agent Conversely, in some embodiments, one or more cysteine residues are added to create disulfide bond(s) to improve stability.

[0221] In some embodiments, a bispecific antibody described herein comprises an anti-Ap antibody or an anti-A Fab, and an anti-TfR antibody or an anti-TfR Fab. In some embodiments, a bi specific antibody described herein comprises an anti-Ap antibody and an anti- TfR antibody. In some embodiments, a bispecific antibody described herein comprises an anti-Ap Fab and an anti-TfR Fab. In some embodiments, a bispecific antibody described herein comprises an anti-Ap antibody and an anti-TfR Fab. In some embodiments, a bispecific antibody described herein comprises an anti-Ap Fab and an anti-TfR antibody. In some embodiments, a bispecific antibody described herein comprises one or more mutations. In some embodiments, a bispecific antibody comprises one or more mutations in an anti-Ap antibody. In some embodiments, a bispecific antibody comprises one or more mutations in an anti-Ap Fab In some embodiments, a bispecific antibody comprises one or more mutations in an anti-TfR antibody. In some embodiments, a bispecific antibody comprises one or more mutations in an anti-TfR Fab. In some embodiments, a bispecific antibody comprises one or more mutations in the amino acid sequence of a constant region CHI, CH2, CH3, CL, or any combination thereof. In some embodiments, a bispecific antibody comprises a CHI: L128R mutation, a CHI: K147R mutation, a CL: Q124E mutation, a CL: VI33Q mutation, and / or a CL: T178E mutation. In some embodiments, a bispecific antibody comprises an anti-TfR antibody or an anti-TfR Fab comprising a CHI: L145Q mutation, a CHI: K147E mutation, a CHI: S181E mutation, a CL: T129R mutation, a CL: T178R mutation, and / or a CL: T180Q mutation. In some embodiments, a bispecific antibody comprises an anti-TfR antibody or an anti-Tf Fab comprising a CHI:L145Q mutation, a CHI: K147E mutation, a CHI: S181E mutation, a CL: T129R mutation, a CL: T178R mutation, and a CL: T180Q mutation to promote proper light-chain pairing. In some embodiments, a bispecific antibody comprises one or more mutations in a Fc region. In some embodiments, a bispecific antibody comprises one or more mutations in a Fc region to reduce effector function. In some embodiments, a bispecific antibody comprises one or more mutations in aFc region comprising a N297Q mutation. In some embodiments, a bispecific antibody comprises a N297Q mutation in a Fc region to reduce Fc effector function through aglycosylation. In some embodiments, a bispecific antibody comprises one or more mutations in- 90 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01a Fc region comprising L234A, L235A, P329G, or any combination thereof. In some embodiments, a bispecific antibody comprises one or more mutations to promote hetero-Fc formation. In some embodiments, a bispecific antibody comprises one or more knob-in-hole mutations. In some embodiments, a bispecific antibody comprising a monovalent anti-TfR antibody comprises one or more mutations to promote hetero-Fc formation for the bispecific antibody (e.g. knob-in-hole mutations).

[0222] In some embodiments, a bi specific antibody of the present disclosure has an extended half-life in vivo. In some embodiments, a bispecific antibody comprises one or more amino acid modifications to increase half-life. In some embodiments, a bispecific antibody having an increased half-life can be generated by introducing one or more amino acid modifications (i.e., substitutions, insertions or deletions) into an IgG constant domain, or FcRn binding fragment thereof. See, e.g., International Publication No. WO 98 / 23289; International Publication No. WO 97 / 34631; and U. S. Patent No. 6,277,375, each of which is hereby incorporated by reference in its entirety. In some embodiments, one or more of the following non-limiting examples of glycosylation-reducing amino acid substitutions may be useful in increasing antibody half-life: M252Y, S254T, T256E, N297A, L234A, L235A, C220, C226S, C229S, P238S, C226S, C229S, E323P, L234V, L235A, G237A, L234F, N297G, L235E, P329G, P331 S, M428L, N434S, or any combination thereof, according to EU numbering. In some embodiments, mutations M428L and N434S can be useful in increasing half-life of an antibody and improving its binding affinity to FcRn relative to an unmodified antibody (see, e.g., Zalevsky et al., 2010., Nat Biotechnol. 28(2): 157 -159). In some embodiments, a bispecific antibody of the present disclosure comprises one or more mutations that can be useful in increasing half-life relative to an unmodified antibody. In some embodiments, mutations that can modify half-life of a bispecific antibody described herein includes, but not limited to M252Y, S254T, T256E, H433K, N434F, T250Q, M428L, M428V, N434S, N434A, T256D, N286D, T307R, Q31 IV, A378V, L309D, Q311H, S254T, V308P, or any combination thereof. In some embodiments, mutations that can modify half-life of a bispecific antibody described herein includes, but not limited to M252Y / S254T / T256E, M428L / N434S, H433K / N434F, T250Q / M428L, M428L / N434A, M428L, N434S, N434A,T256D / N286D / T307R / Q311 V / A378V, L309D / Q311H / N434S, S254T / V308P / N434A, or any combination thereof.- 91 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0223] In some embodiments, a bispecific antibody of the present disclosure comprises variant hinge regions incapable of forming disulfide linkages between identical heavy chains (e.g., reduce homodimer formation). In some embodiments, bispecific antibodies comprise heavy chains with changes in amino acids that result in altered electrostatic interactions. In some embodiments, bispecific antibodies comprise heavy chains with changes in amino acids that result in altered hydrophobic / hydrophilic interactions.

[0224] In some embodiments, a bi specific antibody of the present disclosure is “deimmunized”. The deimmunization of bispecific antibodies generally consists of introducing specific amino acid mutations (e.g., substitutions, deletions, additions) that result in removal of predicted T-cell epitopes without significantly reducing the binding affinity or other desired characteristics of the antibody.

[0225] In some embodiments, a bi specific antibody described herein has one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) modifications to enable attachment of the bispecific antibody to an agent as described below.

[0226] The variant bispecific antibodies or polypeptides described herein may be generated using methods known in the art, including but not limited to, site-directed mutagenesis, alanine scanning mutagenesis, and PCR mutagenesis.

[0227] In some embodiments, a bispecific antibody described herein is chemically modified. In some embodiments, a bispecific antibody has been chemically modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, and / or linkage to a cellular ligand or other protein. Any of numerous chemical modifications may be carried out by known techniques.

[0228] Generally speaking, antigen-antibody interactions are non-covalent and reversible, formed by a combination of hydrogen bonds, hydrophobic interactions, electrostatic and van der Waals forces. When describing the strength of an antigen-antibody complex, the terms affinity and / or avidity are often used. The binding of an antibody to its antigen is a reversible process, and the affinity of the binding is typically reported as an equilibrium dissociation constant (KD). KD is the ratio of an antibody dissociation rate (koff, also referred to herein as kd) (how quickly it dissociates from its antigen) to the antibody association rate (kon) (how quickly it binds to its antigen). In some embodiments, KD values are determined by measuring the kon and koff rates of a specific antibody / antigen interaction and then using a ratio- 92 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01of these values to calculate the KD value In some embodiments. KD values are used to evaluate and rank the strength of individual antibody / antigen interactions. The lower the KD of an antibody, the higher the affinity of the antibody for its target. In some embodiments, affinity is measured using SPR technology in a Biacore system. Avidity gives a measure of the overall strength of an antibody-antigen complex. It is dependent on three major parameters: (i) affinity of the antibody for the target, (ii) valency of both the antibody and antigen, and (iii) structural arrangement of the parts that interact.

[0229] In some embodiments, a bispecific antibody described herein has a monovalent affinity (KD) for hTfRl of > 10 nM (e.g., >25 nM, >50 nM, > 100 nM, >500 nM, >5000 nM, >1 uM, >2 uM, >10 nM to 100 nM, >10 nM to 1000 nM, >10 nM to 2000 nM, >10nM to 5000 nM, >10 M: to 10000 nM, 100 M to 1000 nM, 100 nM: to 5000 nM, 100 nM to 5000 nM, 100 M: to 500 nM, 500 nM to 1 uM, 50 nM to 1 uM, 100 nM to 1 uM, 500 nM to 10 uM, or 1 uM to 10 uM) and / or an off rate (kd) of >= 0.01 / s. In some embodiments, a bispecific antibody is monovalent or multivalent (e.g., bivalent). In some embodiments, a bispecific antibody described herein is a multivalent (e.g., bivalent) antibody and has a monovalent affinity of >100 nM. In some embodiments, a bispecific antibody described herein is a multivalent (e.g., bivalent) antibody and has a monovalent affinity of >1000 nM. In some embodiments, a bispecific antibody described herein is a multivalent (e.g., bivalent) antibody and has a monovalent affinity of 100 nM to 1000 nM. In some embodiments, a bispecific antibody described herein is a multivalent (e.g., bivalent) antibody and has a monovalent affinity of 100 nM to 10000 nM In some embodiments, a bispecific antibody described herein is a multivalent (e.g., bivalent) antibody and has a monovalent affinity of 100 nM to 5000 nM. In some embodiments, a bispecific antibody described herein is a monovalent antibody and has a monovalent affinity for hTfRl of > 10 nM.

[0230] In some embodiments, a bispecific antibody described herein binds with high apparent affinity to high molecular weight aggregates, presumably fibrils, of human Ap.METHODS OF MAKING ANTI-Ap / ANTI-TFR1 BISPECIFIC ANTIBODIES

[0231] Among other things, the present disclosure provides methods of making bispecific antibodies described herein. In some embodiments, bispecific antibodies described herein can be made using suitable methods known in the art. In some embodiments, components of bispecific- 93 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01antibodies are linked by covalent interactions. In some embodiments, conjugates are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HC1), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl) hexanedi amine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as l,5-difluoro-2,4-dinitrobenzene). In some embodiments, components of bispecific antibodies described herein can be conjugated (e g, via a linker).

[0232] In some embodiments, a free cysteine is introduced into the constant region of a bispecific antibody described herein to facilitate conjugation to an anti-Ap antibody. Suitable free cysteine substitutions are known in the art, such as, e g., those described in Zhou et al., Pharmaceuticals. 2021, 4(7):672 (see, e.g., Table 1), which is incorporated by reference herein in its entirety.

[0233] In some embodiments, components of bispecific antibodies described herein can be linked by a method described in Ohri et al,, Bioconjugate Chem. 2018, 29, 473-485, Yamazoe et al., Bioconjugate Chemistry 2020 31 (4), 1199-1208, Shen et al., Nat Biotechnol. 2012 Jan 22;30(2): 184-9, Dimasi et al., Mol. Pharmaceutics 2017, 14, 1501-1516, Stimmel et al., JBC, 275(39):30445-30450, and Sussman et al., Protein Engineering, Design & Selection, 2017, 31(2):47-54, each of which is incorporated by reference herein in its entirety.

[0234] In some embodiments, a bispecific antibody described herein is conjugated to a detectable substance or molecule that allows the bispecific antibody to be used for diagnosis and / or detection. A detectable substance can include, but is not limited to, enzymes, such as horseradish peroxidase, alkaline phosphatase, beta-galactosidase, and acetylcholinesterase, prosthetic groups, such as biotin and flavine(s); fluorescent materials, such as, umbelliferone, fluorescein, fluorescein isothiocyanate (FITC), rhodamine, tetramethylrhodamine isothiocyanate (TRITC), dichlorotriazinylamine fluorescein, dansyl chloride, cyanine (Cy3), and phycoerythrin; bioluminescent materials, such as luciferase; radioactive materials, such as212Bi,14C,57Co,51Cr.67Cu, ”F,68Ga,67Ga,153Gd,159Gd,68Ge,3H,166Ho,131I,1251,123I,121I,115In,113In,112In,111In,140La,177Lu,54Mn,99Mo,32P,103Pd,149Pm,142Pr,186Re,188Re,105Rh,97Ru,35S,47Sc,75Sc,153Sm,113Sn,117Sn,85Sr,99mTc,201Ti,133Xe,90Y,169Yb.l7’Yb.63Zn; positron emitting metals; and magnetic metal ions.- 94 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0235] In some embodiments, a bispecific antibody described herein is a fusion protein. Fusion proteins comprising a bispecific antibody described herein can be made using suitable methods known in the art. Such a fusion protein can include a fusion of an anti-Ap antibody or antigen-biding fragment thereof (including bispecific, multispecific, or multivalent anti-Ap antibodies) with an anti-TfRl antibody or antigen-biding fragment thereof (including bispecific, multispecific, or multivalent anti-TfRl antibodies). In one instance, avidin can be added to the C -terminus of the heavy chain to produce a fusion protein as described in Candelaria PVet al. Front Immunol. 2021; 12:607692. The fusion protein may be further conjugated or complexed to a second molecule or drug, such as a biotinylated drug, as described in Daniels TR, et al.Biochim Biophys Acta. 2012; 1820(3):291-317.

[0236] In some embodiments, complexes comprising a bispecific antibody described herein can be made using any suitable method known in the art In some embodiments, components of the complex are linked by non-covalent interactions. Such compounds comprise a bispecific antibody of the present disclosure complexed with another agent, e.g., therapeutic agent, or complexed with a lipid or nanoparticle which has a therapeutic polypeptide or protein.

[0237] Bispecific antibodies described herein can be produced by any suitable method known in the art. Such methods range from direct protein synthesis methods to constructing a DNA sequence encoding polypeptide sequences and expressing those sequences in a suitable host. In some embodiments, a DNA sequence is constructed using recombinant technology by isolating or synthesizing a DNA sequence encoding a wild-type protein of interest. Optionally, the sequence can be mutagenized by site-specific mutagenesis to provide functional variants thereof. In some embodiments, a DNA sequence encoding a polypeptide of interest is constructed by chemical synthesis using an oligonucleotide synthesizer. Oligonucleotides can be designed based on the amino acid sequence of the desired polypeptide and selecting those codons that are favored in the host cell in which the recombinant polypeptide of interest wil l be produced. Standard methods can be applied to synthesize a polynucleotide sequence encoding an isolated polypeptide of interest. For example, a complete amino acid sequence can be used to construct a back-translated gene. Further, a DNA oligomer containing a nucleotide sequence coding for the particular isolated polypeptide can be synthesized. For example, several small oligonucleotides coding for portions of the desired polypeptide can be synthesized and then- 95 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01ligated. The individual oligonucleotides typically contain 5' or 3' overhangs for complementary’ assembly.

[0238] Once assembled (by synthesis, site-directed mutagenesis, or another method), a polynucleotide sequence encoding a particular polypeptide of interest can be inserted into an expression vector and operatively linked to an expression control sequence appropriate for expression of the protein in a desired host. Proper assembly can be confirmed by nucleotide sequencing, restriction enzyme mapping, and / or expression of a biologically active polypeptide in a suitable host. As is well-known in the art, in order to obtain high expression levels of a transfected gene in a host, the gene must be operatively linked to transcriptional and translational expression control sequences that are functional in the chosen expression host.

[0239] In some embodiments, a recombinant expression vector is used to amplify and express DNA encoding a bi specific antibody against human Ap and human TfRl. For example, a recombinant expression vector can be a replicable DNA construct that includes synthetic or cDNA-derived DNA fragments encoding a polypeptide chain of a bispecific antibody operatively linked to suitable transcriptional and / or translational regulatory elements derived from mammalian, microbial, viral or insect genes A transcriptional unit generally comprises an assembly of (1) a genetic element or elements having a regulatory role in gene expression, for example, transcriptional promoters or enhancers, (2) a structural or coding sequence that is transcribed into mRNA and translated into protein, and (3) appropriate transcription and translation initiation and termination sequences. Regulatory elements can include an operator sequence to control transcription. The ability to replicate in a host, usually conferred by an origin of replication, and a selection gene to facilitate recognition of transformants can also be included. DNA regions are “operatively linked” when they are functionally related to each other. For example, DNA for a signal peptide (secretory leader) is operatively linked to DNA for a polypeptide if it is expressed as a precursor that participates in the secretion of the polypeptide; a promoter is operatively linked to a coding sequence if it controls the transcription of the sequence; or a ribosome binding site is operatively linked to a coding sequence if it is positioned so as to permit translation. In some embodiments, structural elements intended for use in yeast expression systems include a leader sequence enabling extracellular secretion of translated protein by a host cell. In some embodiments, in situations where recombinant protein is expressed without a leader or transport sequence, a polypeptide may include an N-terminal- 96 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01methionine residue This residue can optionally be subsequently cleaved from the expressed recombinant protein to provide a final product.

[0240] The choice of an expression control sequence and an expression vector generally depends upon the choice of host. A wide variety of expression host / vector combinations can be employed. Useful expression vectors for eukaryotic hosts include, for example, vectors comprising expression control sequences from SV40, bovine papilloma virus, adenovirus, and cytomegalovirus. Useful expression vectors for bacterial hosts include known bacterial plasmids, such as plasmids from A. coli, including pCRl, pBR322, pMB9 and their derivatives, and wider host range plasmids, such as M13 and other filamentous single-stranded DNA phages

[0241] In some embodiments, a bispecific antibody of the present disclosure is expressed from one or more vectors. In some embodiments, a first heavy chain polypeptide is expressed by one vector and a first light chain polypeptide is expressed by a second vector. In some embodiments, a first heavy chain polypeptide and a first light chain polypeptide are expressed by one vector. In some embodiments, a second heavy chain polypeptide is expressed by a third vector and a second light chain polypeptide is expressed by a fourth vector In some embodiments, a second heavy chain polypeptide and a second light chain polypeptide are expressed by one vector. In some embodiments, a first heavy chain polypeptide, a first light chain polypeptide, a second heavy chain polypeptide, and a second light chain polypeptide are expressed by one vector. Thus, the present disclosure provides vectors encoding a bispecific antibody described herein. In one embodiment, a vector encodes a first heavy chain polypeptide of a bi specific antibody described herein. In one embodiment, a vector encodes a first light chain polypeptide of a bispecific antibody described herein. In one embodiment, a vector encodes a first heavy chain polypeptide and a first light chain polypeptide of a bispecific antibody described herein. In one embodiment, a vector encodes a second heavy chain polypeptide of a bispecific antibody described herein. In one embodiment, a vector encodes a second light chain polypeptide of a bispecific antibody described herein. In one embodiment, a vector encodes a second heavy chain polypeptide and a second light chain polypeptide of a bi specific antibody described herein. In one embodiment, a vector encodes a first heavy chain polypeptide, a first light chain polypeptide, a second heavy chain polypeptide and a second light chain polypeptide of a bi specific antibody described herein.- 97 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0242] Suitable host cells for expression of a bispecific antibody include prokaryotes, yeast cells, insect cells, or higher eukaryotic cells under the control of appropriate promoters. Prokaryotes include gram-negative or gram-positive organisms, for example E. coli or Bacillus. Higher eukaryotic cells include established cell lines of mammalian origin as described herein. Cell-free translation systems may also be employed. Appropriate cloning and expression vectors for use with bacterial, fungal, yeast, and mammalian cellular hosts, as well as methods of protein production, including antibody production are well-known in the art.

[0243] Various mammalian culture systems may be used to express recombinant polypeptides. Expression of recombinant proteins in mammalian cells may be desirable because these proteins are generally correctly folded, appropriately modified, and biologically functional. Examples of suitable mammalian host cell lines include, but are not limited to, COS-7 (monkey kidney-derived), L-929 (murine fibroblast-derived), Cl 27 (murine mammary tumor-derived), 3T3 (murine fibroblast-derived), CHO (Chinese hamster ovary-derived), HeLa (human cervical cancer-derived), BHK (hamster kidney fibroblast-derived), HEK-293 (human embryonic kidney- derived) cell lines and variants thereof. Mammalian expression vectors can comprise nontranscribed elements such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, and other 5' or 3' flanking non-transcribed sequences, and 5' or 3' non¬ translated sequences, such as necessary ribosome binding sites, a polyadenylation site, splice donor and acceptor sites, and transcriptional termination sequences.

[0244] Expression of recombinant proteins in insect cell culture systems (e.g., baculovirus) also offers a robust method for producing correctly folded and biologically functional proteins. Baculovirus systems for production of heterologous proteins in insect cells are well-known to those of skill in the art.

[0245] Thus, the present disclosure provides cells comprising a bispecific antibody described herein. The present disclosure also provides cells comprising one or more polynucleotides encoding a bispecific antibody described herein or one or more vectors encoding a bispecific antibody described herein. In one embodiment, a cell comprises a polynucleotide encoding a bispecific antibody described herein. In one embodiment, a cell comprises a first polynucleotide encoding a first heavy chain of a bispecific antibody described herein and a second polynucleotide encoding a first light chain of a bispecific antibody described herein. In one embodiment, a cell comprises a polynucleotide encoding a first heavy chain and a first light- 98 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01chain of a bispecific antibody described herein. In one embodiment, a cell comprises a third polynucleotide encoding a second heavy chain of a bi specific antibody described herein and a fourth polynucleotide encoding a second light chain of a bispecific antibody described herein. In one embodiment, a cell comprises a polynucleotide encoding a second heavy chain and a second light chain of a bispecific antibody described herein. In one embodiment, a cell comprises a polynucleotide encoding a first heavy chain, a first light chain, a second heavy chain, and a second light chain of a bi specific antibody described herein.

[0246] In one embodiment, a cell comprises a vector encoding a bispecific antibody described herein In one embodiment, a cell comprises a first vector encoding a first heavy chain of a bispecific antibody described herein, a second vector encoding a first light chain of a bispecific antibody described herein, a third vector encoding a second heavy chain of a bispecific antibody described herein, and / or a fourth vector encoding a second light chain of a bispecific antibody described herein. In one embodiment, a cell comprises a first vector encoding a first heavy chain of a bispecific antibody described herein and a second vector encoding a first light chain of a bispecific antibody described herein. In one embodiment, a cell comprises a vector encoding a first heavy chain and a first light chain of a bispecific antibody described herein. In one embodiment, a cell comprises a third vector encoding a second heavy chain of a bispecific antibody described herein and a fourth vector encoding a second light chain of a bi specific antibody described herein. In one embodiment, a cell comprises a vector encoding a second heavy chain and a second light chain of a bispecific antibody described herein.

[0247] In some embodiments, cells produce bispecific antibodies described herein. In some embodiments, cells produce an anti-Ap / anti-TfR bispecific antibody. In some embodiments, cells produce a bispecific antibody that binds human Ap and human TfRl. In some embodiments, cells produce a bispecific antibody that binds cyno Ap and cyno TfRl. In some embodiments, cells produce a bispecific antibody that binds human Ap and cyno A. In some embodiments, cells produce a bispecific antibody that binds human TfRl and cyno TfRl. In some embodiments, a cell is a prokaryotic cell (e.g., E. coli). In some embodiments, a cell is a eukaryotic cell. In some embodiments, a cell is a mammalian cell. In some embodiments, a cell is a hybridoma cell.

[0248] Proteins produced by a host cell can be purified according to any suitable method. Standard methods include chromatography (e.g., ion exchange, affinity, and sizing column- 99 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01chromatography), centrifugation, differential solubility, or by any other standard technique for protein purification. Affinity tags such as hexa-histidine (SEQ ID NO:360), maltose binding domain, influenza coat sequence, and glutathione-S-transferase can be attached to the protein to allow easy purification by passage over an appropriate affinity column. Affinity chromatography used for purifying immunoglobulins include, but are not limited to, Protein A, Protein G, and Protein L chromatography. Isolated proteins can be physically characterized using techniques known to those of skill in the art, including but not limited to, proteolysis, size exclusion chromatography (SEC), mass spectrometry (MS), nuclear magnetic resonance (NMR), isoelectric focusing (IEF), high performance liquid chromatography (HPLC), and x-ray crystallography. The purity of isolated proteins can be determined using techniques known to those of skill in the art, including but not limited to, SDS-PAGE, SEC, capillary gel electrophoresis, IEF, and capillary isoelectric focusing (cIEF).

[0249] In some embodiments, supernatants from expression systems that secrete recombinant protein into culture media are first concentrated using a commercially available protein concentration filter, for example, an Amicon® or Millipore Pellicon® ultrafiltration unit. Following the concentration step, the concentrate can be applied to a suitable purification matrix. In some embodiments, an anion exchange resin is employed, for example, a matrix or substrate having pendant di ethylaminoethyl (DEAE) groups. The matrices can be acrylamide, agarose, dextran, cellulose, or other types commonly employed in protein purification. In some embodiments, a cation exchange step is employed. Suitable cation exchangers include various insoluble matrices comprising sulfopropyl or carboxymethyl groups. In some embodiments, a hydroxyapatite media is employed, including but not limited to, ceramic hydroxyapatite (CHT). In some embodiments, one or more reverse-phase HPLC steps employing hydrophobic RP-HPLC media, e.g., silica gel having pendant methyl or other aliphatic groups, are employed to further purify a recombinant protein. In some embodiments, hydrophobic interaction chromatography (HIC) is used to separate recombinant proteins based on their hydrophobicity. FIIC is a useful separation technique for purifying proteins while maintaining biological activity due to the use of conditions and matrices that operate under less denaturing conditions than some other techniques. Some or all of the foregoing purification steps, in various combinations, can be employed to provide a homogeneous recombinant protein.- 100 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0250] In some embodiments, a bispecific antibody of this disclosure comprises an Fab that can be generated by first making a full monoclonal Ab followed by digesting the monoclonal antibody by chemical or enzymatic cleavage (e.g., pepsin, papain, or ficin digestion) to yield a F(ab’)2 fragment, followed by reduction of those fragments to yield Fab fragments. Such techniques are known in the art. See, e.g., Victor C-G et al., Biosensors and Bioelectronics, 2016 (85): 32-45.

[0251] Alternatively, a bi specific antibody of this disclosure is made by recombinant synthesis of F(ab')₂ antibody fragments, followed by chemical reduction of these fragments to yield Fab units.POLYNUCLEOTIDES

[0252] In some embodiments, the disclosure encompasses polynucleotides comprising polynucleotides that encode a polypeptide (e.g, a bispecific antibody) described herein The term “polynucleotides that encode a polypeptide’’ encompasses a polynucleotide that includes only coding sequences for the polypeptide as well as a polynucleotide that includes additional coding and / or non-coding sequences. Polynucleotides of the disclosure can be in the form of RNA or in the form of DNA. DNA includes cDNA, genomic DNA, and synthetic DNA; and can be double¬ stranded or single-stranded, and if single stranded can be the coding strand or non-coding (antisense) strand. In some embodiments, a polynucleotide comprises a polynucleotide (e.g., a nucleotide sequence) encoding a first heavy chain of a bispecific antibody described herein. In some embodiments, a polynucleotide comprises a polynucleotide (e.g., a nucleotide sequence) encoding a first light chain of a bispecific antibody described herein. In some embodiments, a polynucleotide comprises a polynucleotide (e.g., a nucleotide sequence) encoding a second heavy chain of a bispecific antibody described herein. In some embodiments, a polynucleotide comprises a polynucleotide (e.g., a nucleotide sequence) encoding a second light chain of a bispecific antibody described herein.

[0253] In some embodiments, a polynucleotide comprises a polynucleotide (e g., a nucleotide sequence) encoding a first heavy chain of a bispecific antibody described herein and a polynucleotide (e.g., a nucleotide sequence) encoding a first light chain of a bispecific antibody. In some embodiments, a polynucleotide comprises a polynucleotide (e.g,, a nucleotide sequence)- 101 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01encoding a second heavy chain of a bispecific antibody described herein and a polynucleotide (e.g., a nucleotide sequence) encoding a second light chain of a bispecific antibody.

[0254] In some embodiments, a polynucleotide comprises a polynucleotide (e.g., a nucleotide sequence) encoding a first heavy chain of abispecific antibody described herein, a polynucleotide (e.g., a nucleotide sequence) encoding a first light chain of a bispecific antibody, a polynucleotide (e.g., a nucleotide sequence) encoding a second heavy chain of a bispecific antibody described herein, and a polynucleotide (e.g., a nucleotide sequence) encoding a second light chain of a bispecific antibody.

[0255] In some embodiments, a polynucleotide comprises a polynucleotide (e.g., a nucleotide sequence) encoding a polypeptide comprising a second VH amino acid sequence depicted in Table 3. In some embodiments, a polynucleotide comprises a polynucleotide (e.g., a nucleotide sequence) encoding a polypeptide comprising a second VL amino acid sequence depicted in Table 4. In some embodiments, a polynucleotide comprises a polynucleotide (e.g., a nucleotide sequence) encoding a polypeptide comprising a second VH amino acid sequence depicted in Table 3 and a polypeptide comprising a second VL amino acid sequence depicted in Table 4. In some embodiments, a polynucleotide comprises a polynucleotide (e.g., a nucleotide sequence) encoding a polypeptide comprising a heavy chain amino acid sequence depicted in Table 6. In some embodiments, a polynucleotide comprises a polynucleotide (e.g., a nucleotide sequence) encoding a polypeptide comprising a light chain amino acid sequence depicted in Table 6. In some embodiments, a polynucleotide comprises a polynucleotide (e.g., a nucleotide sequence) encoding a polypeptide comprising a heavy chain amino acid sequence depicted in Table 6 and a polypeptide comprising a light chain amino acid sequence depicted in Table 6

[0256] Polynucleotide variants can contain alterations in the coding regions, non-coding regions, or both. In some embodiments, a polynucleotide variant contains alterations that produce silent substitutions, additions, or deletions, but does not alter the properties or activities of the encoded polypeptide. In some embodiments, a polynucleotide variant comprises silent substitutions that results in no change to the amino acid sequence of the polypeptide (due to the degeneracy of the genetic code). In some embodiments, a polynucleotide variant comprises one or more mutated codons comprising one or more (e.g., 1, 2, or 3) substitutions to the codon that change the amino acid encoded by that codon. Methods for introducing one or more substitutions into a codon are known in the art, such as, e.g., PCR mutagenesis and site-directed mutagenesis.- 102 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01Polynucleotide variants can be produced for a variety of reasons, for example, to optimize codon expression for a particular host (e.g., change codons in the human mRNA to those preferred by a bacterial host such as E. coli). In some embodiments, a polynucleotide variant comprises at least one silent mutation in a non-coding or a coding region of the sequence.

[0257] In some embodiments, a polynucleotide variant is produced to modulate or alter expression (or expression levels) of the encoded polypeptide. In some embodiments, a polynucleotide variant is produced to increase expression of the encoded polypeptide. In some embodiments, a polynucleotide variant is produced to decrease expression of the encoded polypeptide. In some embodiments, a polynucleotide variant has increased expression of the encoded polypeptide as compared to a parental polynucleotide sequence. In some embodiments, a polynucleotide variant has decreased expression of the encoded polypeptide as compared to a parental polynucleotide sequence.

[0258] In some embodiments, a polynucleotide comprises the coding sequence for a polypeptide (e.g., an antibody) fused in the same reading frame to a polynucleotide that aids in expression and secretion of a polypeptide from a host cell (e.g., a leader sequence that functions as a secretory sequence for controlling transport of a polypeptide). The polypeptide can have the leader sequence cleaved by the host cell to form a “mature"’ form of the polypeptide.

[0259] In some embodiments, a polynucleotide comprises the coding sequence for a polypeptide (e.g., an antibody) fused in the same reading frame to a marker or tag sequence. For example, in some embodiments, a marker sequence is a hexa-histidine (SEQ ID NO.360) tag (HIS-tag) that allows for efficient purification of the polypeptide fused to the marker. In some embodiments, a marker sequence is a hemagglutinin (HA) tag derived from the influenza hemagglutinin protein when a mammalian host (e.g., COS-7 cells) is used. In some embodiments, a marker sequence is a FLAG™ tag. In some embodiments, a marker is used in conjunction with other markers or tags.

[0260] In some embodiments, polynucleotides are isolated. In some embodiments, polynucleotides are substantially pure.VECTORS AND CELLS

[0261] Vectors and cells comprising each and every one of the polynucleotides described herein are also provided. In some embodiments, an expression vector comprises a polynucleotide- 103 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01molecule encoding abispecific antibody described herein In some embodiments, an expression vector comprises a polynucleotide molecule encoding a polypeptide that is part of a bispecific antibody described herein. In some embodiments, an expression vector comprises a polynucleotide molecule encoding a first heavy chain polypeptide of a bispecific antibody described herein. In some embodiments, an expression vector comprises a polynucleotide molecule encoding a first light chain polypeptide of a bispecific antibody described herein. In some embodiments, an expression vector comprises a polynucleotide molecule encoding a second heavy chain polypeptide of a bispecific antibody described herein. In some embodiments, an expression vector comprises a polynucleotide molecule encoding a second light chain polypeptide of a bispecific antibody described herein. In some embodiments, an expression vector comprises a polynucleotide molecule encoding a first heavy chain polypeptide and a first light chain polypeptide of a bispecific antibody described herein In some embodiments, an expression vector comprises a polynucleotide molecule encoding a second heavy chain polypeptide and a second light chain polypeptide of a bispecific antibody described herein. In some embodiments, an expression vector comprises a polynucleotide molecule encoding a first and / or second heavy chain polypeptide and a first and / or second light chain polypeptide of a bi specific antibody described herein.

[0262] In some embodiments, a host cell comprises an expression vector comprising the polynucleotide molecule encoding a bispecific antibody described herein. In some embodiments, a host cell comprises an expression vector comprising the polynucleotide molecule encoding a polypeptide that is part of a bi specific antibody described herein. In some embodiments, a host cell comprises a polynucleotide molecule encoding a bispecific antibody described herein. In some embodiments, a host cell comprises an expression vector comprising a polynucleotide molecule encoding a first heavy chain polypeptide of abispecific antibody described herein. In some embodiments, a host cell comprises an expression vector comprising a polynucleotide molecule encoding a second heavy chain polypeptide of a bispecific antibody described herein. In some embodiments, a host cell comprises an expression vector comprises a polynucleotide molecule encoding a first light chain polypeptide of a bispecific antibody described herein. In some embodiments, a host cell comprises an expression vector comprises a polynucleotide molecule encoding a second light chain polypeptide of a bispecific antibody described herein. In some embodiments, a host cell comprises an expression vector comprises a first polynucleotide- 104 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01encoding a first heavy chain polypeptide and a second polynucleotide a first light chain polypeptide of a bi specific antibody described herein In some embodiments, a host cell comprises an expression vector comprises a first polynucleotide encoding a second heavy chain polypeptide and a second polynucleotide a second light chain polypeptide of a bispecific antibody described herein. In some embodiments, a host cell comprises: (ii) a first expression vector comprising a polynucleotide molecule encoding a first heavy chain polypeptide of a bispecific antibody described herein, (ii) a second expression vector comprising a polynucleotide molecule encoding a first light chain polypeptide of a bispecific antibody described herein, (iii) a third expression vector comprising a polynucleotide molecule encoding a second heavy chain polypeptide of a bispecific antibody described herein, and (iv) a fourth expression vector comprising a polynucleotide molecule encoding a second light chain polypeptide of a bispecific antibody described herein. In some embodiments, an isolated cell comprises a first expression vector comprising a first nucleotide sequence encoding a first polypeptide comprising a first VH of a bispecific antibody described herein operably linked to a promoter, and a second expression vector comprising a second nucleotide sequence encoding a second polypeptide comprising a first VL of a bispecific antibody operably linked to a promoter, and a third expression vector comprising a third nucleotide sequence encoding a third polypeptide comprising a second VH of a bispecific antibody operably linked to a promoter, and a fourth expression vector comprising a fourth nucleotide sequence encoding a fourth polypeptide comprising a second VL of a bispecific antibody operably linked to a promoterANALYSIS OF PHYSICAL / CHEMICAL PROPERTIES OF ANTI-A0 / ANTI-TFR1 BISPECIFIC ANTIBODIES

[0263] Bispecific antibodies of the present disclosure may be analyzed for their physical / chemical properties and / or biological activities by various methods known in the art. In some embodiments, a bispecific antibody is tested for its ability to bind TfRlhuman TfRl and / or c no TfRl). In some embodiments, a bi specific antibody is tested for its ability to bind Ap (e.g., Ap-40). Binding assays include, but are not limited to, SPR (e.g., Biacore), ELISA, and flow cytometry'. In some embodiments, a bispecific antibody is tested for its ability to inhibit, reduce, or block binding of transferrin to its TfRl receptor. In some embodiments, a bispecific antibody is tested for its ability to inhibit, reduce, or block TfRl activity. In some embodiments, a bispecific antibody is tested for its ability to internalize with TfRl and induce increased- 105 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01internalization of TfRl. In some embodiments, a bispecific antibody is tested for its ability to inhibit, reduce, or block formation of plaques. In some embodiments, a bi specific antibody is tested for its ability to disintegrate P-amyloid plaques. In addition, bispecific antibodies described herein may be evaluated for solubility, stability, thermostability, viscosity, expression levels, expression quality, and / or purification efficiency.

[0264] In some embodiments, assays are provided for identifying how a bispecific antibody described herein affects TfRl activity. In some embodiments, assays are provided for identifying how a bispecific antibody described herein affects aggregation of A3. In some embodiments, SPR, ELISA, or FACS assays are used to assess the ability of a bispecific antibody to block binding of TfRl to Tf. In some embodiments, cytotoxicity assays are used to assess the ability of a bispecific antibody described herein to affect natural killer (NK) cell activity In some embodiments, proliferation assays are used to assess the ability of a bispecific antibody described herein to affect T-cell activity.

[0265] In some embodiments, a bispecific antibody described herein is an antagonist of human Ap and human TfRl. In some embodiments, terms “inhibiting”, “inducing”, “reducing”, “increasing”, “enhancing” are relati ve to levels / activity in the absence of treatment with a bispecific antibody. In some embodiments, terms “inhibiting”, “inducing”, “reducing”, “increasing”, “enhancing” are relative to levels / activity prior to treatment with a bispecific antibody.PHARMACEUTICAL COMPOSITIONS

[0266] The present disclosure provides compositions comprising a bispecific antibody described herein In some embodiments, a composition comprises a bi specific antibody comprising an anti-Ap antibody and an anti-TfRl antibody. The present disclosure also provides pharmaceutical compositions comprising a bispecific antibody described herein and a pharmaceutically acceptable vehicle.

[0267] Formulations are prepared for storage and / or use by combining a bispecific antibody of the present disclosure with a pharmaceutically acceptable vehicle (e.g., a carrier or excipient). Those of skill in the art generally consider pharmaceutically acceptable carriers, excipients, and / or stabilizers to be inactive ingredients of a formulation or pharmaceutical composition.- 106 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01

[0268] Suitable pharmaceutically acceptable vehicles include, but are not limited to, nontoxic buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens, such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol; low molecular weight polypeptides (e.g., less than about 10 amino acid residues); proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; carbohydrates such as monosaccharides, disaccharides, glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium, metal complexes such as Zn-protein complexes; and non-ionic surfactants such as TWEEN or polyethylene glycol (PEG). (Remington: The Science and Practice of Pharmacy, 22ndEdition, 2012, Pharmaceutical Press, London.). In some embodiments, a formulation is in the form of an aqueous solution. In some embodiments, a formulation is lyophilized or in an alternative dried form.

[0269] In some embodiments, a therapeutic formulation of the present disclosure can be in unit dosage form. Such formulations include tablets, pills, capsules, powders, granules, solutions or suspensions in water or non-aqueous media, or suppositories. In solid compositions such as tablets the principal active ingredient is mixed with a pharmaceutical carrier Conventional tableting ingredients include corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and diluents (e.g., water). These can be used to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure, or a non-toxic pharmaceutically acceptable salt thereof. The solid preformulation composition is then subdivided into unit dosage forms of a type described above. The tablets, pills, etc. of the formulation or composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner composition covered by an outer component. Furthermore, the two components can be separated by an enteric layer that serves to resist disintegration and permits the inner component to pass intact through the stomach or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such- 107 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01materials include a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate,

[0270] In some embodiments, a bispecific antibody of the present disclosure may be formulated in any suitable form for delivery to a target cell / tissue. In some embodiments, a bispecific antibody can be formulated as a liposome, microparticle, microcapsule, albumin microsphere, microemulsion, nano-particle, nanocapsule, or macroemulsion. In some embodiments, a pharmaceutical formulation includes a bispecific antibody of the present disclosure complexed with liposomes. Methods to produce liposomes are known to those of skill in the art. For example, some liposomes can be generated by reverse phase evaporation with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphati dyl ethan ol ami ne (PEG-PE),

[0271] In some embodiments, a bispecific antibody is formulated as a sustained-release preparation. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing an agent, where the matrices are in the form of shaped articles (e.g., films or microcapsules). Sustained-release matrices include but are not limited to polyesters, hydrogels such as poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol), polylactides, copolymers ofL-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(- )-3-hydroxybutyric acid.

[0272] The pharmaceutical compositions or formulations of the present disclosure can be administered in any number of ways for either local or systemic treatment. In some embodiments, administration is topical by epidermal or transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. In some embodiments, administration is pulmonary by inhalation or insufflation of powders or aerosols, including by nebulizer, intratracheal, and intranasal. In some embodiments, administration is oral. In some embodiments, administration is parenteral including intravenous, intraarterial, intratumoral, subcutaneous, intraperitoneal, intramuscular (e.g., injection or infusion), or intracranial (e.g., intrathecal or intraventricular). In some embodiments, administration is by intravenous injection or intravenous infusion. In some embodiments, administration is by intramuscular injection. In some embodiments, administration is intrathecal (e.g., intrathecal administration via injection- 108 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01directly into the intrathecal space or injection into a port for intrathecal delivery). In some embodiments, administration subcutaneous. In some embodiments, a composition comprising bispecific antibodies of the present disclosure is administered intravenously to the human subject. In some embodiments, a composition comprising bispecific antibodies of the present disclosure is administered subcutaneously to the human subject.

[0273] Various delivery systems are known and can be used to administer a bispecific antibody described herein. In some embodiments, a bispecific antibody or a composition described herein is delivered in a controlled release or sustained release system. In some embodiments, a pump is used to achieve controlled or sustained release. In some embodiments, polymeric materials are used to achieve controlled or sustained release of a bispecific antibody described herein. Examples of polymers used in sustained release formulations include, but are not limited to, poly 2-hydroxy ethyl methacrylate, polymethyl methacrylate, polyacrylic acid, polyethylene-co-vinyl acetate, polymethacrylic acid, polyglycolides (PLG), polyanhydrides, poly N-vinyl pyrrolidone, polyvinyl alcohol (PVA), polyacrylamide, polyethylene glycol (PEG), polylactides (PLA), polylactide-co-glycolides (PLGA), and polyorthoesters. Any polymer used in a sustained release formulation should be inert, free of leachable impurities, stable on storage, sterile, and biodegradable.Additional delivery systems can be used to administer a bispecific antibody described herein including, but not limited to, injectable drug delivery devices and osmotic pumps. Injectable drug delivery devices include, for example, hand-held devices (e g., autoinjectors) or wearable devices. Different types of osmotic pump systems may include single compartment systems, dual compartment systems, and multiple compartment systems.METHODS OF USING ANTI-Ap / ANTI-TFRl BISPECIFIC ANTIBODIES

[0274] The present di sclosure provides, among other things, methods of using bispecific antibodies described herein and / or compositions comprising the same. In some embodiments, the present disclosure provides methods of administering bispecific antibodies described herein and / or compositions comprising the same, to a subject. In some embodiments, the present disclosure also provides methods of treating a disease in a subject comprising bispecific antibodies described herein and / or compositions comprising the same. In some embodiments, bispecific antibodies of the present disclosure can be used in the treatment of neurological and / or- 109 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01neurodegenerative diseases In some embodiments, bispecific antibodies of the present disclosure are used in the treatment of neurological and / or neurodegenerative diseases. In some embodiments, a bispecific antibody comprising an anti-Ap antibody and an anti-TfRl antibody is used in the treatment of neurological and / or neurodegenerative diseases. In some embodiments, a bispecific antibody comprising an ANTIBODY Z and an ANTIBODY X is used in the treatment of neurological and / or neurodegenerative diseases. In some embodiments, a bispecific antibody comprising: a) a first heavy chain variable region (VH) comprising a first VH complementarity determining region (CDR)l, a first VH CDR2, and a first VH CDR3, and a first light chain variable region (VL) comprising a first VL CDRl, a first VL CDR2, and a first VL CDR3, wherein the first VH CDRl comprises the amino acid sequence of SEQ ID NO: 501 or 512; the first VH CDR2 comprises the amino acid sequence of SEQ ID NO: 502 or 513; and the first VH CDR3 comprises the amino acid sequence of SEQ ID NO: 503; the first VL CDR1 comprises the amino acid sequence of SEQ ID NO: 507 or 519; the first VL CDR2 comprises the amino acid sequence of SEQ ID NO: 508; and the first VL CDR3 comprises the amino acid sequence of SEQ ID NO: 509; and b) a second VH comprising a second VH CDR1, a second VH CDR2, and a second VH CDR3, and a second VL comprising a second VL CDRl, a second VL CDR2, and a second VL CDR3, wherein the second VH CDRl comprises the amino acid sequence GFTFSSYX₁MN (SEQ ID NO:18), wherein X₁ is S or A; the second VH CDR2 comprises the amino acid sequence SISX₂SSSX₃IYYADSVKG (SEQ ID NO:19), wherein X₂ is S or A, and wherein X₃ is Y or S; and the second VH CDR3 comprises the amino acid sequence KX₄X₅X₆GDFDY (SEQ ID NO:20), wherein X₄ is Y or S, wherein X₅ is R or S, and wherein X₆ is A or Y; the second VL CDRl comprises the amino acid sequence RASQSVSSX₇X₈LA (SEQ ID NO:21), wherein X₇ is S or N, and wherein X₈ is Y or N; the second VL CDR2 comprises the amino acid sequence GASX₉RAT (SEQ ID NO:22), wherein X₉ is N or S; and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8) is used in the treatment of neurological and / or neurodegenerative diseases. In some embodiments, a neurological and / or neurodegenerative disease includes, but is not limited to, Alzheimer’s disease, Parkinson’s disease Down's syndrome, amyloidosis disorders, hereditary cerebral hemorrhage with amyloidosis Dutch type, Lewy body dementia, frontotemporal dementia, Guam Parkinson-Dementia complex, ALS (amyotrophic lateral sclerosis), Creutzfeldt Jacob disease, HIV-related dementia, motor neuropathy, Huntington’s disease, progressive supranuclear palsy, multiple- 110 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01sclerosis, spinal muscular atrophy, muscular dystrophy, spinal cord injury, stroke, ophthalmological conditions, acute or chronic optic neuritis, psychiatric disorders, Tourette’s disease brain injury, brain tumors, epilepsy, cerebral amyloid angiopathy, inflammatory cerebral amyloid angiopathy, cerebral amyloidoma, and any other amyloid-related disease. In some embodiments, a neurological disease is Alzheimer’s disease, Parkinson’s disease Down's syndrome, amyloidosis disorders, hereditary cerebral hemorrhage with amyloidosis Dutch type, Lewy body dementia, frontotemporal dementia, Guam Parkinson-Dementia complex, ALS (amyotrophic lateral sclerosis), Creutzfeldt Jacob disease, HIV-related dementia, motor neuropathy, Huntington’s disease, progressive supranuclear palsy, multiple sclerosis, spinal muscular atrophy, muscular dystrophy, spinal cord injury, stroke, ophthalmological conditions, acute or chronic optic neuritis, psychiatric disorders, Tourette’s disease brain injury, brain tumors, epilepsy, cerebral amyloid angiopathy, inflammatory cerebral amyloid angiopathy, cerebral amyloidoma, or any other amyloid -related disease. In some embodiments, a neurodegenerative disease is Alzheimer’s disease, Parkinson’s disease Down's syndrome, amyloidosis disorders, hereditary cerebral hemorrhage with amyloidosis Dutch type, Lewy body¬ dementia, frontotemporal dementia, Guam Parkinson-Dementia complex, ALS (amyotrophic lateral sclerosis), Creutzfeldt Jacob disease, HIV-related dementia, motor neuropathy, Huntington’s disease, progressive supranuclear palsy, multiple sclerosis, spinal muscular atrophy, muscular dystrophy, spinal cord injury, stroke, ophthalmological conditions, acute or chronic optic neuritis, psychiatric disorders, Tourette’s disease brain injury / , brain tumors, epilepsy, cerebral amyloid angiopathy, inflammatory cerebral amyloid angiopathy, cerebral amyloidoma, or any other amyloid-related disease.

[0275] In some embodiments, a bispecific antibody described herein can be used to transport an anti-Ap antibody across the blood brain barrier via transcytosis. In some embodiments, a bispecific antibody comprising an anti-Aβ antibody and an anti-TfR1 antibody is used to transport an anti-Ap antibody across the blood brain barrier via transcytosis. In some embodiments, a bispecific antibody comprising an ANTIBODY Z and an ANTIBODY X is used to transport an anti-Ap antibody across the blood brain barrier via transcytosis. In some embodiments, a bispecific antibody comprising: a) a first heavy chain variable region (VH) comprising a first VH complementarity determining region (CDR)1, a first VH CDR2, and a first VH CDR3, and a first light chain variable region (VL) comprising a first VL CDR1, a first VL- Ill - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01CDR2, and a first VL CDR3, wherein the first VH CDRI comprises the amino acid sequence of SEQ ID NO: 501 or 512; the first VH CDR2 comprises the amino acid sequence of SEQ ID NO: 502 or 513; and the first VH CDR3 comprises the amino acid sequence of SEQ ID NO: 503; the first VL CDR1 comprises the amino acid sequence of SEQ ID NO: 507 or 519; the first VL CDR2 comprises the amino acid sequence of SEQ ID NO: 508; and the first VL CDR3 comprises the amino acid sequence of SEQ ID NO: 509; and b) a second VH comprising a second VH CDR1, a second VH CDR2, and a second VH CDR3, and a second VL comprising a second VL CDR1, a second VL CDR2, and a second VL CDR3, wherein the second VH CDRI comprises the amino acid sequence GFTFSSYX₁MN (SEQ ID NO:18), wherein X₁ is S or A; the second VH CDR2 comprises the amino acid sequence SISX₂SSSX₃IYYADSVKG (SEQ ID NO:19), wherein X₂ is S or A, and wherein X₃ is Y or S; and the second VH CDR3 comprises the amino acid sequence KX4X5X6GDFDY (SEQ ID NO:20), wherein X4 is Y or S, wherein X5 is R or S, and wherein Xe is A or Y; the second VL CDR1 comprises the amino acid sequence RASQSVSSXvXsLA (SEQ ID NO:21), wherein X7 is S or N, and wherein Xx is Y or N; the second VL CDR2 comprises the amino acid sequence GASX₉RAT (SEQ ID NO:22), wherein X₉ is N or S; and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8) is used to transport an anti-Ap antibody across the blood brain barrier via transcytosis.

[0276] In some embodiments, a bispecific antibody described herein can be used to deliver an anti-Ap antibody in vivo to brain tissue.

[0277] In some embodiments, a bispecific antibody comprising an anti-Ap antibody and an anti-TfRl antibody is used to deliver an anti-Ap antibody in vivo to brain tissue.

[0278] In some embodiments, a bispecific antibody comprising an ANTIBODY Z and an ANTIBODY X is used to deliver an anti-Ap antibody in vivo to brain tissue.

[0279] In some embodiments, a bispecific antibody comprising: a) a first heavy chain variable region (VH) comprising a first VH complementarity determining region (CDR)l, a first VH CDR2, and a first VH CDR3, and a first light chain variable region (VL) comprising a first VL CDRI, a first VL CDR2, and a first VL CDR3, wherein the first VH CDR1 comprises the amino acid sequence of SEQ ID NO: 501 or 512; the first VH CDR2 comprises the amino acid sequence of SEQ ID NO: 502 or 513, and the first VH CDR3 comprises the amino acid sequence of SEQ ID NO: 503; the first VL CDR1 comprises the amino acid sequence of SEQ ID NO: 507 or 519; the first VL CDR2 comprises the amino acid sequence of SEQ ID NO: 508; and the first- 112 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01VL CDR3 comprises the amino acid sequence of SEQ ID NO: 509; and b) a second VH comprising a second VH CDRl, a second VH CDR2, and a second VH CDR3, and a second VL comprising a second VL CDR1, a second VL CDR2, and a second VL CDR3, wherein the second VH CDRl comprises the amino acid sequence GFTFSSYX₁MN (SEQ ID NO:18), wherein X₁ is S or A; the second VH CDR2 comprises the amino acid sequence SISX2SSSX3IYYADSVKG (SEQ ID NO: 19), wherein X2is S or A, and wherein Xs is Y or S; and the second VH CDR3 comprises the amino acid sequence KX4X5X6GDFDY (SEQ ID NO:20), wherein X4 is Y or S, wherein X5 is R or S, and wherein Xe is A or Y; the second VL CDRl comprises the amino acid sequence RASQSVSSXiXsLA (SEQ ID NO:21), wherein X7 is S orN, and wherein Xs is Y or N; the second VL CDR2 comprises the amino acid sequence GASX₉RAT (SEQ ID NO:22), wherein X₉ is N or S; and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8) is used to deliver an anti-Ap antibody in vivo to brain tissue.

[0280] In some embodiments, a bispecific antibody described herein can be used to deliver an anti-Ap antibody in vivo to brain tissue of a human subject. In some embodiments, a bispecific antibody comprising an anti-Ap antibody and an anti-TfRl antibody is used to deliver an anti-Ap antibody in vivo to brain tissue of a human subject.

[0281] In some embodiments, a bispecific antibody comprising an ANTIBODY Z and an ANTIBODY X is used to deliver an anti-Ap antibody in vivo to brain tissue of a human subject.

[0282] In some embodiments, a bispecific antibody comprising: a) a first heavy chain variable region (VH) comprising a first VH complementarity determining region (CDR)1, a first VH CDR2, and a first VH CDR3, and a first light chain variable region (VL) comprising a first VL CDRl, a first VL CDR2, and a first VL CDR3, wherein the first VH CDR1 comprises the amino acid sequence of SEQ ID NO: 501 or 512; the first VH CDR2 comprises the amino acid sequence of SEQ ID NO: 502 or 513; and the first VH CDR3 comprises the amino acid sequence of SEQ ID NO: 503; the first VL CDR1 comprises the amino acid sequence of SEQ ID NO: 507 or 519; the first VL CDR2 comprises the amino acid sequence of SEQ ID NO: 508; and the first VL CDR3 comprises the amino acid sequence of SEQ ID NO: 509; and b) a second VH comprising a second VH CDRl, a second VH CDR2, and a second VH CDR3, and a second VL comprising a second VL CDRl, a second VL CDR2, and a second VL CDR3, wherein the second VH CDRl comprises the amino acid sequence GFTFSSYXiMN (SEQ ID NO: 18),- 113 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01wherein Xi is S or A: the second VH CDR2 comprises the amino acid sequence SISX2SSSX3IYYADSVKG (SEQ ID NO: 19), wherein X2is S or A, and wherein X3 is Y or S; and the second VH CDR3 comprises the amino acid sequence KX4X5X6GDFDY (SEQ ID NO:20), wherein X4 is Y or S, wherein X5 is R or S, and wherein Xe is A or Y; the second VL CDRl comprises the amino acid sequence RASQSVSSX7X8LA (SEQ ID NO:21), wherein X7 is S or N, and wherein X8 is Y or N; the second VL CDR2 comprises the amino acid sequence GASX9RAT (SEQ ID NO:22), wherein X9 is N or S; and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8) is used to deliver an anti-Aβ antibody in vivo to brain tissue of a human subject.

[0283] In some embodiments, a bispecific antibody described herein can be used to reduce the amount of tau and / or Aβ in a human subject. In some embodiments, a bispecific antibody comprising an anti-Aβ antibody and an anti-TfR1 antibody is used to reduce the amount of tau and / or Aβ in a human subject.

[0284] In some embodiments, a bispecific antibody comprising an ANTIBODY Z and an ANTIBODY X is used to reduce the amount of tau and / or A in a human subject.

[0285] In some embodiments, a bi specific antibody comprising: a) a first heavy chain variable region (VH) comprising a first VH complementarity determining region (CDR)1, a first VH CDR2, and a first VH CDR3, and a first light chain variable region (VL) comprising a first VL CDRl, a first VL CDR2, and a first VL CDR3, wherein the first VH CDR1 comprises the amino acid sequence of SEQ ID NO: 501 or 512; the first VH CDR2 comprises the amino acid sequence of SEQ ID NO: 502 or 513; and the first VH CDR3 comprises the amino acid sequence of SEQ ID NO: 503; the first VL CDR1 comprises the amino acid sequence of SEQ ID NO: 507 or 519; the first VL CDR2 comprises the amino acid sequence of SEQ ID NO: 508; and the first VL. CDR3 comprises the amino acid sequence of SEQ ID NO: 509; and b) a second VH comprising a second VH CDRl, a second VH CDR2, and a second VH CDR3, and a second VL comprising a second VL CDRl, a second VL CDR2, and a second VL CDR3, wherein the second VH CDRl comprises the amino acid sequence GFTFSSYXiMN (SEQ ID NO.18), wherein Xi is S or A; the second VH CDR2 comprises the amino acid sequence SISX2SSSX3IYYADSVKG (SEQ ID NO: 19), wherein X2is S or A, and wherein X3 is Y or S; and the second VH CDR3 comprises the amino acid sequence KX4X5X6GDFDY (SEQ ID NO:20), wherein X4 is Y or S, wherein X5 is R or S, and wherein Xe is A or Y; the second VL- 114 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01CDRl comprises the amino acid sequence RASQSVSSXvXsLA (SEQ ID NO:21), wherein X? is S or N, and wherein Xs is Y or N; the second VL CDR2 comprises the amino acid sequence GASX₉RAT (SEQ ID NO:22), wherein X₉ is N or S; and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8) is used to reduce the amount of tau and / or Ap in a human subject.

[0286] In some embodiments, a bispecific antibody described herein can be used to deliver an anti-Ap antibody in vivo to brain tissue of a human subject having a neurological and / or neurodegenerative disease. In some embodiments, a bispecific antibody comprising an anti-Ap antibody and an anti-TfRl antibody is used to deliver an anti-Ap antibody in vivo to brain tissue of a human subject having a neurological and / or neurodegenerative disease. In some embodiments, a bi specific antibody comprising an ANTIBODY Z and an ANTIBODY X is used to deliver an anti-Ap antibody in vivo to brain tissue of a human subject having a neurological and / or neurodegenerative disease. In some embodiments, a bispecific antibody comprising: a) a first heavy chain variable region ( VH) comprising a first VH complementarity determining region (CDR)l, a first VH CDR2, and a first VH CDR3, and a first light chain variable region (VL) comprising a first VL CDRl, a first VL CDR2, and a first VL CDR3, wherein the first VH CDR1 comprises the amino acid sequence of SEQ ID NO: 501 or 512; the first VH CDR2 comprises the amino acid sequence of SEQ ID NO: 502 or 513; and the first VH CDR3 comprises the amino acid sequence of SEQ ID NO: 503; the first VL CDRl comprises the amino acid sequence of SEQ ID NO: 507 or 519; the first VL CDR2 comprises the amino acid sequence of SEQ ID NO: 508; and the first VL CDR3 comprises the amino acid sequence of SEQ ID NO: 509; and b) a second VH comprising a second VH CDRl, a second VH CDR2, and a second VH CDR3, and a second VL comprising a second VL CDR1, a second VL CDR2, and a second VL CDR3, wherein the second VH CDRl comprises the amino acid sequence GFTFSSYX₁MN (SEQ ID NO:18), wherein X₁ is S or A; the second VH CDR2 comprises the amino acid sequence SISX₂SSSX₃IYYADSVKG (SEQ ID NO:19), wherein X₂ is S or A, and wherein X₃ is Y or S, and the second VH CDR3 comprises the amino acid sequence KX4X5X6GDFDY (SEQ ID NO:20), wherein X4 is Y or S, wherein Xs is R or S, and wherein Xc, is A or Y; the second VL CDRl comprises the amino acid sequence RASQSVSSXTXSLA (SEQ ID NO:21), wherein X7 is S or N, and wherein Xs is Y or N; the second VL CDR2 comprises the amino acid sequence GASX₉RAT (SEQ ID NO:22), wherein X₉ is N or S; and the second VL- 115 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8) is used to deliver an anti-Ap antibody in vivo to brain tissue of a human subject having a neurological and / or neurodegenerative disease.

[0287] In some embodiments, a bi specific antibody described herein can be used to target brain tissue and transport an anti-Ap antibody across the blood brain barrier for the treatment of a neurological and / or neurodegenerative disease. In some embodiments, a bispecific antibody comprising an anti-Ap antibody and an anti-TfRl antibody is used to target brain tissue and transport an anti-Ap antibody across the blood brain barrier for the treatment of a neurological and / or neurodegenerati e disease In some embodiments, a bispecific antibody comprising an ANTIBODY Z and an ANTIBODY X is used to target brain tissue and transport an anti-Ap antibody across the blood brain barrier for the treatment of a neurological and / or neurodegenerative disease In some embodiments, a bispecific antibody comprising: a) a first heavy chain variable region (VH) comprising a first VH complementarity determining region (CDR)l, a first VH CDR2, and a first VH CDR3, and a first light chain variable region (XT) comprising a first VL CDR1, a first VL CDR2, and a first VL CDR3, wherein the first VH CDR1 comprises the amino acid sequence of SEQ ID NO: 501 or 512; the first VH CDR2 comprises the amino acid sequence of SEQ ID NO: 502 or 513; and the first VH CDR3 comprises the amino acid sequence of SEQ ID NO: 503; the first XT, CDR1 comprises the amino acid sequence of SEQ ID NO: 507 or 519; the first VL CDR2 comprises the amino acid sequence of SEQ ID NO: 508; and the first VL CDR3 comprises the amino acid sequence of SEQ ID NO: 509; and b) a second VH comprising a second VH CDR1, a second VH CDR2, and a second VH CDR3, and a second XT comprising a second XL CDR1, a second XT CDR2, and a second XT CDR3, wherein the second VH CDR1 comprises the amino acid sequence GFTFSSYX₁MN (SEQ ID NO:18), wherein X₁ is S or A; the second XTI CDR2 comprises the amino acid sequence SISX2SSSX3IYXXADSVXG (SEQ ID NO: 19), wherein X2 is S or A, and wherein X3 is Y or S; and the second XTI CDR3 comprises the amino acid sequence KX4X5X6GDFDY (SEQ ID NO:20), wherein X i is Y or S, wherein X5 is R or S, and wherein Xe is A or Y; the second XT CDR1 comprises the amino acid sequence RASQSVSSX7XTA (SEQ ID NO:21), wherein X? is S or N, and wherein Xs is Y or N; the second XT CDR2 comprises the amino acid sequence GASX₉RAT (SEQ ID NO:22), wherein X₉ is N or S; and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8) is used to target brain- 116 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01tissue and transport an anti-Ap antibody across the blood brain barrier for the treatment of a neurological and / or neurodegenerative disease. Exemplary' neurological and / or neurodegenerative diseases include, but are not limited to, Alzheimer’s disease, Parkinson’s disease, Down's syndrome, amyloidosis disorders, hereditary cerebral hemorrhage with amyloidosis Dutch type, Lewy body dementia, frontotemporal dementia, Guam Parkinson-Dementia complex, ALS (amyotrophic lateral sclerosis), Creutzfeldt Jacob disease, HIV-related dementia, motor neuropathy, Huntington’s disease, progressive supranuclear palsy, multiple sclerosis, spinal muscular atrophy, muscular dystrophy, spinal cord injury, stroke, ophthalmological conditions, acute or chronic optic neuritis, psychiatric disorders, Tourette’s disease brain injury, brain tumors, epilepsy, cerebral amyloid angiopathy, inflammatory cerebral amyloid angiopathy, cerebral amyloidoma, and any other amyloid-related diseases.

[0288] In some embodiments, a bi specific antibody described herein can be used to treat Alzheimer’s disease in a human subject. In some embodiments, a bispecific antibody comprising an anti-Ap antibody and an anti-TfRl antibody is used to treat Alzheimer’s disease in a human subject In some embodiments, a bispecific antibody comprising an ANTIBODY Z and an ANTIBODY X is used to treat Alzheimer’s disease in a human subject. In some embodiments, a bispecific antibody comprising: a) a first heavy chain variable region (VH) comprising a first VH complementarity determining region (CDR)1, a first VH CDR2, and a first VH CDR3, and a first light chain variable region (AT) comprising a first AT CDR1, a first AT CDR2, and a first AT CDR3, wherein the first ATI CDR1 comprises the amino acid sequence of SEQ ID NO: 501 or 512; the first VH CDR2 comprises the amino acid sequence of SEQ ID NO: 502 or 513; and the first VH CDR3 comprises the amino acid sequence of SEQ ID NO: 503; the first AT CDR1 comprises the amino acid sequence of SEQ ID NO: 507 or 519; the first AT CDR2 comprises the amino acid sequence of SEQ ID NO: 508; and the first AT CDR3 comprises the amino acid sequence of SEQ ID NO: 509; and b) a second VH comprising a second VH CDR1, a second ATI CDR2, and a second ATI CDR3, and a second AT comprising a second AT CDR1, a second VL CDR2, and a second AT CDR3, wherein the second VH CDR1 comprises the amino acid sequence GFTFSSYX₁MN (SEQ ID NO:18), wherein X₁ is S or A; the second ATI CDR2 comprises the amino acid sequence SISX2SSSX3IYYADSATCG (SEQ ID NO: 19), wherein X2 is S or A, and wherein Xs is Y or S; and the second VH CDR3 comprises the amino acid sequence KX4X5X6GDFDT7(SEQ ID NO:20), wherein X4 is Y or S, wherein Xs is R or S, and wherein Xe- 117 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01is A or Y; the second VL CDR1 comprises the amino acid sequence RASQSVSSX? XsLA (SEQ ID NO:21), wherein X7 is S or N, and wherein Xs is Y or N; the second VL CDR2 comprises the amino acid sequence GASX₉RAT (SEQ ID NO:22), wherein X₉ is N or S; and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8) is used to treat Alzheimer’s disease in a human subject. In some embodiments, Alzheimer’s disease is latent, preclinical, or asymptomatic Alzheimer’s disease, early Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease, mild Alzheimer’s disease dementia, mild cognitive impairment due to Alzheimer’s disease, mid-stage Alzheimer’s disease, or late-stage Alzheimer’s disease In some embodiments, a bispecific antibody described herein can be used to treat abnormal accumulation or deposition of Ap in the central nervous system in a human subject. In some embodiments, a bispecific antibody described herein can be used to treat mild cognitive impairment in a human subject. In some embodiments, a human subject has Alzheimer's disease. In some embodiments, a human subject has p-tau tangles, p-tau threads, and / or p-tau neuritic plaques, optionally wherein the human subject has neocortical p-tau tangles, neocortical p-tau threads, and / or neocortical p-tau neuritic plaques.

[0289] In some embodiments, a bi specific antibody described herein reduces Ap in a human subject. In some embodiments...

Claims

Attorney Docket No. 2011256-2654 / P1939PCT01WHAT IS CLAIMED IS:

1. A bispecific antibody comprising:a) a first heavy chain variable region (VH) comprising a first VH complementarity determining region (CDR)l, a first VH CDR2, and a first VH CDR3, and a first light chain variable region (VL) comprising a first VL CDR1, a first VL CDR2, and a first VL CDR3, wherein:the first VH CDR1 comprises the amino acid sequence of SEQ ID NO: 501 or 512; the first VH CDR2 comprises the amino acid sequence of SEQ ID NO: 502 or 513; and the first VH CDR3 comprises the amino acid sequence of SEQ ID NO: 503,the first VL CDR1 comprises the amino acid sequence of SEQ ID NO: 507 or 519; the first VL CDR2 comprises the amino acid sequence of SEQ ID NO: 508; and the first VL CDR3 comprises the amino acid sequence of SEQ ID NO: 509, andb) a second VH comprising a second VH CDR1, a second VH CDR2, and a second VH CDR3, and a second VL comprising a second VL CDR1, a second VL CDR2, and a second VL CDR3, wherein:the second VH CDRI comprises the amino acid sequence GFTFSSYX₁MN (SEQ ID NO:18), wherein X₁ is S or A; the second VH CDR2 comprises the amino acid sequence SISX2SSSX3IYYADSVKG (SEQ ID NO: 19), wherein X2is S or A, and wherein X3is Y or S; and the second VH CDR3 comprises the amino acid sequence KX4X5X6GDFDY (SEQ ID NO: 20), wherein X4 is Y or S, wherein X5 is R or S, and wherein X6 is A or Y;the second VL CDR1 comprises the amino acid sequence RASQSVSSXrXsLA (SEQ ID NO: 21), wherein X7 is S or N, and wherein Xs is Y or N; the second VL CDR2 comprises the amino acid sequence GASX9RAT (SEQ ID NO: 22), wherein X9 is N or S; and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO: 8)2. The bispecific antibody of claim 1, wherein:(i) the first VH is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 504; and the first VL is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 510; or- 177 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01(ii) the first VH is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 514; and the first VL is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 520.

3. The bispecific antibody of claim 1, wherein:(i) the first heavy chain is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 603-611; and / or (ii) the first light chain is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 700-702.

4. The bi specific antibody of claim 1, wherein at least one of the second VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 are selected from the mutant CDRs depicted in Table 1, and any of the second VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, or VL CDRS that are not selected from the mutant CDRs depicted in Table 1 are selected from the parental CDRs depicted in Table 1.

5. The bispecific antibody of claim 1, wherein:(i) one of the second VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, or VL CDR3 is selected from the mutant CDRs depicted in Table 1 and five of the second VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 are selected from the parental CDRs depicted in Table 1;(ii) two of the second VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 are selected from the mutant CDRs depicted in Table 1 and four of the second VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 are selected from the parental CDRs depicted in Table 1;(iii) three of the second VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 are selected from the mutant CDRs depicted in Table 1 and three of the second VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 are selected from the parental CDRs depicted in Table 1;- 178 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01(iv) four of the second VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 are selected from the mutant CDRs depicted in Table 1 and two of the second VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 are selected from the parental CDRs depicted in Table 1; or(v) five of the second VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 are selected from the mutant CDRs depicted in Table 1 and one of the second VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, or VL CDR3 is selected from the parental CDRs depicted in Table 1.

6. The bispecific antibody of claim 1, wherein:(i) the second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); the second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); the second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 6); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);(ii) the second VII CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); the second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); the second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);(iii) the second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); the second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); the second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8), wherein the second VL comprises a Y57S conservative substitution;- 179 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01(iv) the second VH CDR1 comprises the amino acid sequence GFTFSSYAMN (SEQ ID NO:9); the second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:7); the second VL CDRI comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:7); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO: 8);(v) the second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:7); the second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:7); the second VL CDRI comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:7); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO: 8);(vi) the second VH CDRI comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:7); the second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:7); the second VL CDRI comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:7); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8), wherein the second VL comprises a Y57S conservative substitution,(vii) the second VH CDRI comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:7); the second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:7); the second VL CDRI comprises the amino acid sequence RASQSVSSNYLA (SEQ ID NO: 15); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:7);(viii) the second VH CDRI comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:7); the second VH CDR2 comprises the amino acid sequence SISSSSSSIYYADSVKG (SEQ ID NO: 11); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY- 180 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01(SEQ ID NO:5); the second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NOV); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);(ix) the second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NOV); the second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); the second VH CDR3 comprises the amino acid sequence KSRAGDFDY (SEQ ID NO: 12); the second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NOV); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);(x) the second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NOV); the second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); the second VH CDR3 comprises the amino acid sequence K YSAGDFDY (SEQ ID NO: 13); the second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NOV); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NOV); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NOV);(xi) the second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NOV); the second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); the second VH CDR3 comprises the amino acid sequence KYRYGDFDY (SEQ ID NO: 14); the second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NOV); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NOV); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO: 8);(xii) the second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NOV); the second VH CDR2 comprises the amino acid sequence SISASSSSIYYADSVKG (SEQ ID NO:25); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NOV); the second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NOV); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID- 181 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01NOY); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);(xiii) the second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:7); the second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10), the second VH CDR3 comprises the amino acid sequence KYSAGDFDY (SEQ ID NO: 13); the second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:7); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO: 8);(xiv) the second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:3); the second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); the second VL CDR1 comprises the amino acid sequence RASQSVSSNYLA (SEQ ID NO: 15); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:7);(xv) the second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:7); the second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:7); the second VL CDR1 comprises the amino acid sequence RASQSVSSSNLA (SEQ ID NO: 16); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO: 8);(xvi) the second VH CDR1 comprises the amino acid sequence GFTFSSYSMN (SEQ ID NO:7); the second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); the second ATI CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:7); the second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:7); the second VL CDR2 comprises the amino acid sequence GASSRAT (SEQ ID NO: 17); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO: 8);- 182 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01(xvii) the second VH CDRI comprises the amino acid sequence SYSMN (SEQ ID NO:23); the second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); the second VL CDRI comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8), wherein the second VL comprises a Y57S conservative substitution;(xviii) the second VH CDRI comprises the amino acid sequence SYAMN (SEQ ID NO:24); the second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); the second VL CDRI comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO: 8);(xix) the second VH CDRI comprises the amino acid sequence SYSMN (SEQ ID NO:23), the second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); the second VL CDRI comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO: 8);(xx) the second VH CDRI comprises the amino acid sequence SYSMN (SEQ ID NO:23); the second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); the second VL CDRI comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8), wherein the second VL comprises a Y57S conservative substitution;(xxi) the second VH CDRI comprises the amino acid sequence SYSMN (SEQ ID NO:23); the second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY- 183 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01(SEQ ID NO:5); the second VL CDR1 comprises the amino acid sequence RASQSVSSNYLA (SEQ ID NO: 15); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NOV); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);(xxii) the second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); the second VH CDR2 comprises the amino acid sequence SISSSSSSIYYADSVKG (SEQ ID NO:11); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); the second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NOV); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);(xxiii) the second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); the second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); the second VH CDR3 comprises the amino acid sequence KSRAGDFDY (SEQ ID NO: 12); the second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NOV); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO: 8);(xxiv) the second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); the second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); the second VH CDR3 comprises the amino acid sequence KYSAGDFDY (SEQ ID NO: 13); the second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NOV); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO: 8);(xxv) the second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); the second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); the second VH CDR3 comprises the amino acid sequence KYRYGDFDY (SEQ ID NO: 14), the second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID- 184 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01NOY); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);(xxvi) the second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); the second VH CDR2 comprises the amino acid sequence SISASSSSIYYADSVKG (SEQ ID NO:25), the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); the second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO: 8);(xxvii) the second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); the second VH CDR2 comprises the amino acid sequence SISASSSYIYYADSVKG (SEQ ID NO: 10); the second VH CDR3 comprises the amino acid sequence KYSAGDFDY (SEQ ID NO: 13), the second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8);(xxviii) the second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); the second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); the second VL CDR1 comprises the amino acid sequence RASQSVSSNYLA (SEQ ID NO: 15); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO: 8);(xxix) the second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); the second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:7); the second VL CDR1 comprises the amino acid sequence RASQSVSSSNLA (SEQ ID NO: 16); the second VL CDR2 comprises the amino acid sequence GASNRAT (SEQ ID NO:7); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO: 8); or- 185 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01(xxx) the second VH CDR1 comprises the amino acid sequence SYSMN (SEQ ID NO:23); the second VH CDR2 comprises the amino acid sequence SISSSSSYIYYADSVKG (SEQ ID NO:4); the second VH CDR3 comprises the amino acid sequence KYRAGDFDY (SEQ ID NO:5); the second VL CDR1 comprises the amino acid sequence RASQSVSSSYLA (SEQ ID NO:6); the second VL CDR2 comprises the amino acid sequence GASSRAT (SEQ ID NO: 17); and the second VL CDR3 comprises the amino acid sequence QQQSSSPPT (SEQ ID NO:8).

7. The bispecific antibody of any one of claims 1 to 6, wherein the second VH is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 100-108; and the second VL is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 200-204.

8. The bispecific antibody of claim 1, wherein:the second VH comprises the amino acid sequence of SEQ ID NO: 100 and the second VL comprises the amino acid sequence of SEQ ID NO: 200;the second VH comprises the amino acid sequence of SEQ ID NO: 101 and the second VL comprises the amino acid sequence of SEQ ID NO:200;the second VH comprises the amino acid sequence of SEQ ID NO: 102 and the second VL comprises the amino acid sequence of SEQ ID NO: 200;the second VH comprises the amino acid sequence of SEQ ID NO: 102 and the second VL comprises the amino acid sequence of SEQ ID NO:201;the second VH comprises the amino acid sequence of SEQ ID NO: 102 and the second VL comprises the amino acid sequence of SEQ ID NO:203;the second VH comprises the amino acid sequence of SEQ ID NO: 103 and the second VL comprises the amino acid sequence of SEQ ID NO: 200;the second VH comprises the amino acid sequence of SEQ ID NO: 104 and the second VL comprises the amino acid sequence of SEQ ID NO:200;the second VH comprises the amino acid sequence of SEQ ID NO: 105 and the second VL comprises the amino acid sequence of SEQ ID NO: 200;- 186 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT01the second VH comprises the amino acid sequence of SEQ ID NO: 106 and the second VL comprises the amino acid sequence of SEQ ID NO:200;the second VH comprises the amino acid sequence of SEQ ID NO: 107 and the second VL comprises the amino acid sequence of SEQ ID NO: 200;the second VH comprises the amino acid sequence of SEQ ID NO: 108 and the second VL comprises the amino acid sequence of SEQ ID NO:200;the second VH comprises the amino acid sequence of SEQ ID NO: 100 and the second VL comprises the amino acid sequence of SEQ ID NO:201;the second VH comprises the amino acid sequence of SEQ ID NO: 100 and the second VL comprises the amino acid sequence of SEQ ID NO:202;the second VH comprises the amino acid sequence of SEQ ID NO: 100 and the second VL comprises the amino acid sequence of SEQ ID NO:203; orthe second VH comprises the amino acid sequence of SEQ ID NO: 100 and the second VL comprises the amino acid sequence of SEQ ID NO:204.

9. The bi specific antibody of any one of claims 1 to 8, wherein:(i) the first heavy chain comprises one or more mutations in at least one constant region; (ii) the first light chain comprises one or more mutations in at least one constant region; (iii) the second heavy chain comprises one or more mutations in at least one constant region; and / or(iv) the second light chain comprises one or more mutations in at least one constant region.

10. The bispecific antibody of claim 1, wherein the bispecific antibody comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identity to the amino acid sequence of any one of SEQ ID Nos: 400-407, 412-414, 603-611, 700-702, and 800-802.

11. The bispecific antibody of any one of claims 1 to 10, wherein the bispecific antibody binds to human transferrin receptor and human beta-amyloid.- 187 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT0112. The bispecific antibody of any one of claims 1 to 11, comprising a single chain antibody, an Fab fragment, an F(ab’)2 fragment, an Fab’ fragment, an Fsc fragment, an Fv fragment, an scFv, an sc(Fv)₂, or a diabody.

13. The bispecific antibody of any one of claims 1 to 12, comprising a bivalent antibody, a monovalent antibody, or any combination thereof.

14. A nucleotide sequence or nucleotide sequences encoding the bispecific antibody of any one of claims 1 to 1315. An expression vector or expression vectors comprising the nucleotide sequence or nucleotide sequences of claim 14 operably linked to a promoter.

16. An isolated cell comprising the nucleotide sequence or nucleotide sequences of claim 14 or the expression vector or expression vectors of claim 15.

17. An isolated cell comprising:a first expression vector comprising a first nucleotide sequence encoding a first polypeptide comprising the first VH of the bispecific antibody of any one of claims 1 to 13 operably linked to a promoter;a second expression vector comprising a second nucleotide sequence encoding a second polypeptide comprising the first VL of the bispecific antibody of any one of claims 1 to 13 operably linked to a promoter;a third expression vector comprising a third nucleotide sequence encoding a third polypeptide comprising the second VH of the bispecific antibody of any one of claims 1 to 13 operably linked to a promoter; and / ora fourth expression vector comprising a fourth nucleotide sequence encoding a fourth polypeptide comprising the second VL of the bispecific antibody of any one of claims 1 to 13 operably linked to a promoter.- 188 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT0118. A method of making the bi specific antibody of any one of claims 1 to 13, comprising culturing the cell of claim 16 or 17 and isolating the bispecific antibody.

19. A pharmaceutical composition comprising the bispecific antibody of any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

20. A method of transporting an anti -beta-amyloid antibody across the blood brain barrier via transcytosis, the method comprising administering to a human subject the bispecific antibody of any one of claims 1 to 13 or the pharmaceutical composition of claim 19.

21. A method of delivering an anti-beta-amyloid antibody in vivo, the method comprising administering to a human subject the bispecific antibody of any one of claims 1 to 13 or the pharmaceutical composition of claim 19.

22. A method of treating a neurological and / or neurodegenerative disease in a human subject, the method comprising administering to the human subject the bispecific antibody of any one of claims 1 to 13 or the pharmaceutical composition of claim 19.

23. A method of treating Alzheimer's disease in a human subject, comprising administering to the human subject a therapeutically effective amount of the bispecific antibody of any one of claims 1 to 13 or the pharmaceutical composition of claim 19.

24. A method of treating abnormal accumulation or deposition of Ap in the central nervous system in a human subject, the method comprising administering to the human subject the bispecific antibody of any one of claims 1 to 13 or the pharmaceutical composition of claim 19.

25. A method of treating mild cognitive impairment in a human subject, the method comprising administering to the human subject the bispecific antibody of any one of claims 1 to 13 or the pharmaceutical composition of claim 19.- 189 - 13278272v 1Attorney Docket No. 2011256-2654 / P1939PCT0126. A method of treating Alzheimer's disease in a human subject, the method comprising administering to the human subject a therapeutically effective amount of the bispecific antibody of any one of claims 1 to 13 or the pharmaceutical composition of claim 19, wherein the human subject has p-tau tangles, p-tau threads, and / or p-tau neuritic plaques, optionally wherein the human subject has neocortical p-tau tangles, neocortical p-tau threads, and / or neocortical p-tau neuritic plaques.

27. A method of reducing the amount of tau in a human subject having Alzheimer's disease, the method comprising administering to the human subject an effective amount of the bispecific antibody of any one of claims 1 to 13 or the pharmaceutical composition of claim 19.

28. A method of treating Alzheimer's disease by reducing the amount of tau in a human subject, the method comprising administering to the human subject an effective amount of the bispecific antibody of any one of claims 1 to 13 or the pharmaceutical composition of claim 19.- 190 - 13278272v 1

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