Human PD-1 and CTLA4 neutralizing VHH antibodies and methods of use thereof

Abstract

Products, pharmaceutical compositions, methods of use, and kits are provided which feature single-domain variable heavy-chain (VHH) polypeptides (antibodies) that target, bind, and neutralize PD-1 and / or CTLA4, and that advantageously provide novel therapies targeting PD-1 and CTLA4, for example, in cancer, tumor, or neoplasia treatment.

Description

[0001]Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 HUMAN PD-1 AND CTLA4 NEUTRALIZING VHH ANTIBODIES AND METHODS OF USE THEREOF CROSS REFERENCE TO RELATED APPLICATIONS The present application claims priority to U.S. Provisional Application No. 63 / 692,966 filed September 10, 2024, the entire contents of which are hereby incorporated by reference in its entirety. SEQUENCE LISTING This application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The Sequence Listing XML file, created on September 9, 2025, is named 167774-0138001PCT_SL.xml and is 4,646,476 bytes in size. BACKGROUND Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) are protein receptors that help down-regulate immune responses to cells on which they are expressed. Many cancers over-express these proteins as a means of avoiding immune damage. For this reason, antibodies that inhibit these receptors have been highly successful in treating many cancers. However, currently available antibodies which target PD-1 and CTLA4 have a number of drawbacks. First, combining currently available antibodies targeting PD-1 and CTLA4 increases adverse events in the patient and can precipitate autoimmunity. Second, the currently available antibodies targeting PD-1 and CTLA4 are large antibodies that have relatively poor tumor penetration, consequently requiring higher dosing to achieve efficacy. Third, CTLA4 targeting antibodies are on an IgG1 backbone, which confers an effector function that results in suppression of T regulatory cells (Tregs) and increased toxicity and adverse events in the patient. Therefore, novel therapies targeting PD-1 and CTLA4 are needed. SUMMARY OF THE DISCLOSURE As described below, the present disclosure features compositions including single domain (VHH) polypeptides capable of binding and / or neutralizing human PD-1 and / or human CTLA4, and methods of use thereof. 1 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 In one aspect, the disclosure generally features a multimeric VHH polypeptide which is a pentamer that specifically binds to a human CTLA4 polypeptide, or a fragment thereof, and to a human programmed cell death protein 1 (PD-1) polypeptide, or a fragment thereof, where the pentamer contains CTLA4-binding VHH components, human PD-1-binding VHH components, and an albumin or human albumin-binding VHH component, as follows: (i) [CTLA4-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; (ii) [CTLA4-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; (iii) [albumin or human albumin-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH ] or CDR1-3 thereof -- [CTLA4-binding VHH] or CDR1-3 thereof; (iv) [CTLA4-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; or (v) [PD-1-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; where the VHH binding components are linked or joined by a linker [-]. In embodiments, the CTLA4-binding VHH is selected from a CTLA4 binding VHH polypeptide as set forth in Table 2 and the PD-1-binding VHH polypeptide is selected from a PD-1-binding VHH polypeptide as set forth in Table 1. In other embodiments, the pentamer contains the structure [CTLA4-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; where the VHH binding components are linked or joined by a linker [-]. In embodiments, the pentamer contains the structure [CTLA4-binding XFV-E7 VHH] or CDR1-3 thereof – [CTLA4-binding XJD-A4 VHH] or CDR1-3 thereof – [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; where the VHH binding components are linked or 2 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 joined by a linker [-].In embodiments of this aspect, the pentamer contains the structure [CTLA4-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [PD-1- binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; where the VHH binding components are linked or joined by a linker [-]. In embodiments, the pentamer contains the structure [CTLA4- binding XFV-E7 VHH] or CDR1-3 thereof – [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [CTLA4-binding XJD-A4 VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; where the VHH binding components are linked or joined by a linker [-]. In embodiments, the pentamer contains the structure [albumin or human albumin-binding VHH] or CDR1-3 thereof – [PD-1- binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH ] or CDR1-3 thereof -- [CTLA4-binding VHH] or CDR1-3 thereof; where the VHH binding components are linked or joined by a linker [-]. In embodiments, the pentamer contains the structure [albumin or human albumin-binding VHH] or CDR1-3 thereof – [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [CTLA4-binding XFV-E7 VHH] or CDR1-3 thereof -- [CTLA4-binding XJD-A4 VHH] or CDR1-3 thereof; where the VHH binding components are linked or joined by a linker [-]. In embodiments, the pentamer contains the structure [CTLA4-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [PD-1- binding VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; where the VHH binding components are linked or joined by a linker [-]. In embodiments, the pentamer contains the structure [CTLA4-binding XFV-E7 VHH] or CDR1-3 thereof – [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [CTLA4-binding XJD-A4 VHH] or CDR1-3 thereof – [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; where the VHH binding components are linked or joined by a linker [-]. In embodiments, the pentamer contains the structure [PD-1-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [albumin or human albumin- binding VHH] or CDR1-3 thereof; where the VHH binding components are linked or joined by a linker [-]. In embodiments, the pentamer contains the structure [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [CTLA4-binding XFV- 3 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 E7 VHH] or CDR1-3 thereof – [CTLA4-binding XJD-A4 VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; where the VHH binding components are linked or joined by a linker [-]. In embodiments, the pentamer contains a CTLA4-binding VHH comprising CDR1, CDR2, and CDR3, where CDR1 contains an amino acid sequence GX12X13LDSX14A (SEQ ID NO: 4527); where X12 is F or S; where X13 is S or T; and where X14 is F, V, or Y; CDR2 contains an amino acid sequence GX15X16GX17FTX18 (SEQ ID NO: 4528); where X15 is K or R; where X16 is N or S; where X17 is D, G, or T; and where X18 is M, N, or Q; and CDR3 contains an amino acid sequence X19X20VX21QVFX22LCPX23X24X25X26X27X28X29(SEQ ID NO: 4529); where X19is A or G; where X20is A or T; where X21is L, P, Q, or R; where X22is D, G, or H; where X23is I or L; where X24is S or W; where X25is E or S; where X26is E or P; where X27is N or Y; where X28is R or Y; and where X29is D, E, H, or Y; and / or a CTLA4-binding VHH comprising CDR1, CDR2, and CDR3, where CDR1 contains an amino acid sequence: AASGX40X41SX42PX43X44X45X46X47NX48X49G (SEQ ID NO: 4534); where X40 is S or absent; X41 is I or absent; X42 is S or A; X43 is absent or K; X44 is absent or W; X45 is absent or I; X46 is absent or V; X47 is absent or V; X48 is V, A, or D; and X49 is M or V; CDR2 contains an amino acid sequence: AX50X51TSX52GX53TX54 (SEQ ID NO: 4535); where X50 is I or T; X51 is I or V; X52 is G or S; X53 is T or M; and X54 is K, N, or / R; and CDR3 contains an amino acid sequence: NTKVPTGWNTQQWDEY (SEQ ID NO: 4536); and a human PD-1 binding VHH comprising CDR1, CDR2, and CDR3, where CDR1 contains an amino acid sequence GPSFSRAT (SEQ ID NO: 4521); CDR2 contains an amino acid sequence X1QSGITTY (SEQ ID NO: 4522), where X1 is A or S; and CDR3 contains an amino acid sequence AADIDX2DDFFNPDY (SEQ ID NO: 4523), where X2 is N or S; or where CDR1 contains an amino acid sequence X3X4X5FSX6X7VM (SEQ ID NO: 4524), where X3 is G or R; where X4 is D or R; where X5 is S or T; where X6 is E, P, or T; and where X7 is D, E, or Y; CDR2 contains an amino acid sequence TWX8X9GITY (SEQ ID NO: 4525), where X8 is A, N, or T; and where X9is A or S; and CDR3 contains an amino acid sequence AAAPX10NSDYDFLTGYGX11DS (SEQ ID NO: 4526), where X10is L or Q; and where X11is F or M. In embodiments of this aspect, the pentamer contains: a CTLA4-binding VHH comprising CDR1, CDR2, and CDR3, where CDR1 contains the 4 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 sequence: RASGSTLDSYAIG (SEQ ID NO: 4667) or GSTLDSYA (SEQ ID NO: 4596); CDR2 contains the sequence: CIGKNGDFTQ (SEQ ID NO: 4668) or GKNGDFTQ (SEQ ID NO: 4597); and CDR3 contains the sequence: AAVLQVFHLCPIWSENYH (SEQ ID NO: 4598); and / or a CTLA4-binding VHH comprising CDR1, CDR2, and CDR3, where CDR1 contains the sequence: AASGSISSPNVMG (SEQ ID NO: 4665) or GSISSPNV (SEQ ID NO: 4590); CDR2 contains the sequence: AIITSGGTTK (SEQ ID NO: 4666) or TSGGTTK (SEQ ID NO: 4591); and CDR3 contains the sequence: NTKVPTGWNTQQWDEY (SEQ ID NO : 4592); and a human PD-1 binding VHH comprising CDR1, CDR2, and CDR3, where CDR1 contains where CDR1 contains the sequence: AASGPSFSRATMT (SEQ ID NO: 4669) or GPSFSRAT (SEQ ID NO: 4545); CDR2 contains the sequence: AVISQSGITTY (SEQ ID NO: 4670) or SQSGITTY (SEQ ID NO: 4546); and CDR3 contains the sequence: AADIDSDDFFNPDY (SEQ ID NO: 4547). In embodiments of this aspect, the [albumin or human albumin-binding VHH] component contains CDR1, CDR2, and CDR3, where CDR1 contains amino acid sequence AASGLTSDNYVIG (SEQ ID NO: 4657); CDR2 contains amino acid sequence CISSRDGSTY (SEQ ID NO: 4658); and CDR3 contains amino acid sequence AAQQVWAVCVLQAFEYDY (SEQ ID NO: 4659); where the VHH components are linked or joined by a linker. In another aspect, the disclosure features a multimeric VHH polypeptide comprising CTLA4-binding VHH components, human PD-1-binding VHH components, and an albumin or human albumin-binding VHH component, as follows: (i) [XFV-E7 VHH] – [XJD-A4 VHH] – [XFU-D3 VHH] – [XFU-D3 VHH] – [albumin or human albumin-binding VHH]; (ii) [XF-E7 VHH] – [XFU-D3 VHH] – [XFU-D3 VHH] – [XJD-A4 VHH] – [albumin or human albumin-binding VHH]; (iii) [albumin or human albumin-binding VHH] -- [XFU-D3 VHH] – [XFU-D3 VHH] – [XFV-E7 VHH ] -- [XJD-A4 VHH]; (iv) [XFV-E7 VHH] – [XFU-D3 VHH] – [XJD-A4 VHH] – [XFU-D3 VHH] – [albumin or human albumin-binding VHH]; or (v) [XFU-D3 VHH] – [XFU-D3 VHH] – [XFV-E7 VHH] -- [XJD-A4 VHH] – [albumin or human albumin-binding VHH]; where the VHH components are linked or joined by 5 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 a linker. In embodiments of this aspect, at least one [XFV-E7 VHH] comprising CDR1, CDR2, and CDR3, where CDR1 contains the sequence: AASGSISSPNVMG (SEQ ID NO: 4665) or GSISSPNV (SEQ ID NO: 4590); CDR2 contains the sequence: AIITSGGTTK (SEQ ID NO: 4666) or TSGGTTK (SEQ ID NO: 4591); and CDR3 contains the sequence: NTKVPTGWNTQQWDEY (SEQ ID NO: 4592); at least one [XJD-A4 VHH] comprising CDR1, CDR2, and CDR3, where CDR1 contains the sequence RASGSTLDSYAIG (SEQ ID NO: 4667) or GSTLDSYA (SEQ ID NO: 4596); CDR2 contains the sequence: CIGKNGDFTQ (SEQ ID NO: 4668) or GKNGDFTQ (SEQ ID NO: 4597); and CDR3 contains the sequence: AAVLQVFHLCPIWSENYH (SEQ ID NO: 4598); at least one [XFU-D3 VHH] comprising CDR1, CDR2, and CDR3, where CDR1 CDR1 contains the sequence: AASGPSFSRATMT (SEQ ID NO: 4669) or GPSFSRAT (SEQ ID NO: 4545); CDR2 contains the sequence: AVISQSGITTY (SEQ ID NO: 4670) or SQSGITTY (SEQ ID NO: 4546); and CDR3 contains the sequence: AADIDSDDFFNPDY (SEQ ID NO: 4547); and at least one [albumin or human albumin-binding VHH] comprising CDR1, CDR2, and CDR3, where CDR1 contains the sequence AASGLTSDNYVIG (SEQ ID NO: 4657); CDR2 contains the sequence CISSRDGSTY (SEQ ID NO: 4658); and CDR3 contains the sequence AAQQVWAVCVLQAFEYDY (SEQ ID NO: 4659); where the VHH components are linked or joined by a linker. In embodiments of this aspect, the multimeric VHH polypeptide contains the structure [XFU-D3 VHH] – [XFU-D3 VHH] – [XFV-E7 VHH] -- [XJD-A4 VHH] – [albumin or human albumin-binding VHH]; where the VHH components are linked or joined by a linker. In another aspect, the disclosure features a pentameric, bispecific VHH binding molecule comprising the following structural components: an optional signal peptide; a first human PD-1- binding VHH; a second human PD-1-binding VHH; a first CTLA4-binding VHH; a second CTLA4-binding VHH; an albumin or human albumin-binding VHH; and an optional protease cleavage site and affinity tag. In embodiments of this aspect, the first human PD-1-binding VHH contains XFU-D3 VHH or CDR1-3 thereof; the second human PD-1-binding VHH contains XFU-D3 VHH or CDR1-3 thereof; the first CTLA4-binding VHH contains XFV-E7 VHH or CDR1-3 thereof; and the second CTLA4-binding VHH contains XJD-A4 VHH or CDR1-3 6 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 thereof. In other embodiments, the first and second human PD-1 binding VHHs comprise CDR1, CDR2, and CDR3, where CDR1 contains an amino acid sequence GPSFSRAT (SEQ ID NO: 4521); CDR2 contains an amino acid sequence X1QSGITTY (SEQ ID NO: 4522), where X1is A or S; and CDR3 contains an amino acid sequence AADIDX2DDFFNPDY (SEQ ID NO: 4523), where X2 is N or S; or where CDR1 contains an amino acid sequence X3X4X5FSX6X7VM (SEQ ID NO: 4524), where X3 is G or R; where X4 is D or R; where X5 is S or T; where X6 is E, P, or T; and where X7 is D, E, or Y; CDR2 contains an amino acid sequence TWX8X9GITY (SEQ ID NO: 4525), where X8is A, N, or T; and where X9is A or S; and CDR3 contains an amino acid sequence AAAPX10NSDYDFLTGYGX11DS (SEQ ID NO: 4526), where X10is L or Q; and where X11is F or M; where the first CTLA4-binding VHH contains CDR1, CDR2, and CDR3, where CDR1 contains an amino acid sequence: AASGX40X41SX42PX43X44X45X46X47NX48X49G (SEQ ID NO: 4534); where X40is S or absent; X41is I or absent; X42is S or A; X43is absent or K; X44is absent or W; X45 is absent or I; X46 is absent or V; X47 is absent or V; X48 is V, A, or D; and X49 is M or V; CDR2 contains an amino acid sequence: AX50X51TSX52GX53TX54 (SEQ ID NO: 4535); where X50 is I or T; X51 is I or V; X52 is G or S; X53 is T or M; and X54 is K, N, or / R; and CDR3 contains an amino acid sequence: NTKVPTGWNTQQWDEY (SEQ ID NO: 4536); and where the second CTLA4-binding VHH contains CDR1, CDR2, and CDR3, where CDR1 contains an amino acid sequence GX12X13LDSX14A (SEQ ID NO: 4527); where X12is F or S; where X13is S or T; and where X14is F, V, or Y; CDR2 contains an amino acid sequence GX15X16GX17FTX18(SEQ ID NO: 4528); where X15is K or R; where X16is N or S; where X17is D, G, or T; and where X18 is M, N, or Q; and CDR3 contains an amino acid sequence X19X20VX21QVFX22LCPX23X24X25X26X27X28X29 (SEQ ID NO: 4529); where X19 is A or G; where X20 is A or T; where X21 is L, P, Q, or R; where X22 is D, G, or H; where X23 is I or L; where X24 is S or W; where X25 is E or S; where X26 is E or P; where X27 is N or Y; where X28 is R or Y; and where X29is D, E, H, or Y. In other embodiments, the first and second human PD-1 binding VHHs comprise CDR1, CDR2, and CDR3, where CDR1 contains where CDR1 contains the sequence: AASGPSFSRATMT (SEQ ID NO: 4669) or GPSFSRAT (SEQ ID NO: 4545); CDR2 contains the sequence: AVISQSGITTY (SEQ ID NO: 4670) or SQSGITTY (SEQ ID NO: 4546); and CDR3 contains the sequence: AADIDSDDFFNPDY (SEQ ID NO: 4547); 7 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 where the first CTLA4-binding VHH contains CDR1, CDR2, and CDR3, where CDR1 contains the sequence: AASGSISSPNVMG (SEQ ID NO: 4665) or GSISSPNV (SEQ ID NO: 4590); CDR2 contains the sequence: AIITSGGTTK (SEQ ID NO: 4666) or TSGGTTK (SEQ ID NO: 4591); and CDR3 contains the sequence: NTKVPTGWNTQQWDEY (SEQ ID NO: 4592); and where the second CTLA4-binding VHH contains CDR1, CDR2, and CDR3, where CDR1 contains the sequence: RASGSTLDSYAIG (SEQ ID NO: 4667) or GSTLDSYA (SEQ ID NO: 4596); CDR2 contains the sequence: CIGKNGDFTQ (SEQ ID NO: 4668) or GKNGDFTQ (SEQ ID NO: 4597); and CDR3 contains the sequence: AAVLQVFHLCPIWSENYH (SEQ ID NO: 4598). In other embodiments, the first and second human PD-1 binding VHHs comprise an amino acid sequence having at least 85% identity to amino acid sequence: QVQLVESGGGLVQAGDSLRLSCAASGPSFSRATMTWFRQPPGKEREFVAVISQSGITTY YADSVKGRFTISRDNAKNTVYLRMNSLKPEDTAVYYCAADIDSDDFFNPDYWGQGTQ VTVSS (SEQ ID NO: 4478); where the first CTLA4-binding VHH contains an amino acid sequence having at least 85% identity to amino acid sequence: QVQLVESGGGLVQAGGSLRLSCAASGSISSPNVMGWYRQAPGKQRELVAIITSGGTTKY ADSVKGRFTISRDNAKNTVSLQMNSLKPEDTAVYACNTKVPTGWNTQQWDEYWGQG TQVTVSS (SEQ ID NO: 4493); and where the second CTLA4-binding VHH contains an amino acid sequence having at least 85% identity to amino acid sequence: QVQLVESGGDLVQPGGSLRLSCRASGSTLDSYAIGWFRQAPGKEREGVSCIGKNGDFTQ YVDSVKGRFTISRDNPNNIAYLEMNSLKPEDTAVYYCAAVLQVFHLCPIWSENYHYGQ GTQVTVSS (SEQ ID NO: 4495). In other embodiments, the first and second human PD-1 binding VHHs and the first and second CTLA4 binding VHHs comprise an amino acid sequence having at least 90 or 95% identity to the amino acid sequence of the respective human PD-1 binding VHH and CTLA4 binding VHHs. In other embodiments, the albumin or human albumin-binding VHH contains CDR1, CDR2, and CDR3, where CDR1 contains amino acid sequence AASGLTSDNYVIG (SEQ ID NO: 4657); CDR2 contains amino acid sequence CISSRDGSTY (SEQ ID NO: 4658); and CDR3 contains amino acid sequence 8 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 AAQQVWAVCVLQAFEYDY (SEQ ID NO: 4659). In other embodiments, the albumin or human albumin-binding VHH contains a sequence having at least 85%, 90%, 95%, or 100% identity to amino acid sequence: QVQLVESGGGLVQPGGSLRLSCAASGLTSDNYVIGWFRQAPGKEREGVSCISSRDGSTY YPPSVKGRFTISRDNAKNTVYLEMASLKPEDTAVYYCAAQQVWAVCVLQAFEYDYWG QGTQVTVSS (SEQ ID NO: 4656). In yet another aspect, the disclosure features a multimeric VHH polypeptide that binds to a human CTLA4 polypeptide, or an antigen binding fragment thereof, and to a human programmed cell death protein 1 (PD-1) polypeptide, or an antigen binding fragment thereof, where the multimeric VHH polypeptide contains two or more VHH polypeptides that specifically bind to human CTLA4 polypeptide, two or more VHH polypeptides that specifically bind to human PD-1 polypeptide, and a VHH polypeptide that specifically binds to human albumin polypeptide, where each VHH polypeptide that binds to the human PD-1 polypeptide is a VHH polypeptide which contains complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, where CDR1, CDR2, and CDR3 each have at least 85% amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 1 or where CDR1, CDR2, or CDR2 contains an amino acid sequence which corresponds to CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 1; and where each VHH polypeptide that binds to the human CTLA4 polypeptide is a VHH polypeptide which contains complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, where CDR1, CDR2, and CDR3 each have at least 85% amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 1 or where CDR1, CDR2, or CDR2 contains an amino acid sequence which corresponds to CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 2. In an embodiment of this aspect, each VHH polypeptide that binds to the human PD-1 polypeptide is a VHH polypeptide which contains complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, where CDR1, CDR2, and CDR3 each have at least about 90 % amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 1. In another embodiment of this aspect, each VHH polypeptide that binds to the human PD-1 polypeptide is a VHH polypeptide which contains complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, where CDR1, 9 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 CDR2, and CDR3 each have at least about 95 % amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 1. In an embodiment of this aspect, each VHH polypeptide that binds to the human CTLA4 polypeptide is a VHH polypeptide which contains complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, where CDR1, CDR2, and CDR3 each have at least about 85%, 90 %, 95%, or even 100% amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 2. In another embodiment of this aspect, each VHH polypeptide that binds to the human CTLA4 polypeptide is a VHH polypeptide which contains complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, where CDR1, CDR2, and CDR3 each have at least about 95 % amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 2. In one embodiment of this aspect, in the anti-PD- 1 VHH polypeptide, CDR1 contains an amino acid sequence GPSFSRAT (SEQ ID NO: 4521); CDR2 contains an amino acid sequence X1QSGITTY (SEQ ID NO: 4522), where X1 is A or S; and CDR3 contains an amino acid sequence AADIDX2DDFFNPDY (SEQ ID NO: 4523), where X2 is N or S. In another embodiment of this aspect, in the anti-PD-1 VHH polypeptide, CDR1 contains an amino acid sequence X3X4X5FSX6X7VM (SEQ ID NO: 4524), where X3is G or R; where X4is D or R; where X5is S or T; where X6is E, P, or T; and where X7is D, E, or Y; CDR2 contains an amino acid sequence TWX8X9GITY (SEQ ID NO: 4525), where X8is A, N, or T; and where X9is A or S; and CDR3 contains an amino acid sequence AAAPX10NSDYDFLTGYGX11DS (SEQ ID NO: 4526), where X10 is L or Q; and where X11 is F or M. In another embodiment of this aspect, the anti-PD-1 VHH polypeptide, CDR1 contains an amino acid sequence GPSFSRAT (SEQ ID NO: 4545); CDR2 contains an amino acid sequence SQSGITTY (SEQ ID NO: 4546); and CDR3 contains an amino acid sequence AADIDSDDFFNPDY (SEQ ID NO: 4547). In another embodiment of this aspect, the anti- CTLA4 VHH polypeptide, CDR1 contains an amino acid sequence GX12X13LDSX14A (SEQ ID NO: 4527); where X12is F or S; where X13is S or T; and where X14is F, V, or Y; CDR2 contains an amino acid sequence GX15X16GX17FTX18(SEQ ID NO: 4528); where X15is K or R; where X16is N or S; where X17is D, G, or T; and where X18is M, N, or Q; and CDR3 contains an amino acid sequence X19X20VX21QVFX22LCPX23X24X25X26X27X28X29(SEQ ID NO: 4529); where X19 is A or G; where X20 is A or T; 10 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 where X21is L, P, Q, or R; where X22is D, G, or H; where X23is I or L; where X24is S or W; where X25is E or S; where X26is E or P; where X27is N or Y; where X28is R or Y; and where X29is D, E, H, or Y. In another embodiment of this aspect, in the anti-CTLA4 VHH polypeptide, CDR1 contains an amino acid sequence GRTISGYG (SEQ ID NO: 4530); CDR2 contains an amino acid sequence TWSGGX30X31F (SEQ ID NO: 4531); where X30is N or T; and where X31 is A or T; and CDR3 contains an amino acid sequence ASTVX32X33YWVPVX34RX35X36YYSX37SX38YX39Y (SEQ ID NO: 4532); where X32 is D or G; where X33 is R or V; where X34 is W or Y; where X35 is H or T; where X36 is D or E; where X37 is A or T; where X38 is N or Y; and where X39 is A or V. In another embodiment of this aspect, in the anti-CTLA4 VHH polypeptide, CDR1 contains an amino acid sequence: AASGX40X41SX42PX43X44X45X46X47NX48X49G (SEQ ID NO: 4534); where X40is S or absent; X41is I or absent; X42is S or A; X43is absent or K; X44is absent or W; X45is absent or I; X46is absent or V; X47is absent or V; X48is V, A, or D; and X49is M or V; CDR2 contains an amino acid sequence: AX50X51TSX52GX53TX54(SEQ ID NO: 4535); where X50 is I or T; X51 is I or V; X52 is G or S; X53 is T or M; and X54 is K, N, or / R; and CDR3 contains an amino acid sequence: NTKVPTGWNTQQWDEY (SEQ ID NO: 4536). In another embodiment of this aspect, in the anti- CTLA4 VHH polypeptide, CDR1 contains an amino acid sequence GSISSPNV (SEQ ID NO: 4590); CDR2 contains an amino acid sequence TSGGTTK (SEQ ID NO: 4591); and CDR3 contains an amino acid sequence NTKVPTGWNTQQWDEY (SEQ ID NO: 4592); and / or where CDR1 contains an amino acid sequence GSTLDSYA (SEQ ID NO: 4596); CDR2 contains an amino acid sequence GKNGDFTQ (SEQ ID NO: 4597); and CDR3 contains an amino acid sequence AAVLQVFHLCPIWSENYH (SEQ ID NO: 4598). In another aspect, a multimeric VHH polypeptide that binds to a human CTLA4 polypeptide, or an antigen binding fragment thereof, and to a human programmed cell death protein 1 (PD-1) polypeptide, or an antigen binding fragment thereof, where the multimeric VHH polypeptide contains two or more VHH polypeptides that 11 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 specifically bind to human CTLA4 polypeptide, two or more VHH polypeptides that specifically bind to human PD-1 polypeptide, and a VHH polypeptide that specifically binds to human albumin polypeptide; where at least one VHH polypeptide that binds to the CTLA4 polypeptide contains complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, where: CDR1 contains the sequence: AASGX1X2SX3PX4X5X6X7X8NX9X10G (SEQ ID NO: 4534), where X1 is S or absent; where X2 is I or absent; where X3 is S or A; where X4 is absent or K; where X5is absent or W; where X6is absent or I; where X7is absent or V; where X8is absent or V; where X9is V, A, or D; and where X10is M or V; CDR2 contains the sequence: AX11X12TSX13GX14TX15(SEQ ID NO: 4535), where X11is I or T; where X12is I or V; where X13is G or S; where X14is T or M; and where X15is K, N, or R; and CDR3 contains the sequence: NTKVPTGWNTQQWDEY (SEQ ID NO: 4536); or where at least one VHH polypeptide that binds to the CTLA4 polypeptide contains complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, where: CDR1 contains the sequence: X16A S X17X18X19X20X21S X22A X23G (SEQ ID NO: 4538); where X16is R or A; where X17is G or E; where X18is S, F, or R; where X19is T or S; where X20is L or F; where X21is D or S; where X22is Y, V, or F; and where X23is I or M; CDR2 contains the sequence: X24X25X26X27X28GX29FTX30(SEQ ID NO: 4539); where X24 is C or A; where X25 is I or V; where X26 is G or S; where X27 is R, K, or W; where X28 is S or N; where X29 is G, D, A, or T; and where X30 is Q, N, M or Y; and CDR3 contains the sequence: X31AX32X33QVFX34LCPX35WSEX36YX37 (SEQ ID NO: 4540); where X31 is A or G; where X32 is V or I; where X33 is L, Q, R, or P; where X34 is D or H; where X35is I or L; where X36is N, T, or F; and where X37is Y, E, D, S, or H; and where each VHH polypeptide that binds to the human PD-1 polypeptide contains complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, where: CDR1 contains the sequence: AX38X39GX40X41X42X43X44X45X46X47X48 (SEQ ID NO: 4542); where X38 is A or V; where X39 is S or F; where X40 is P or R; where X41 is S, T, P, or A; where X42 is F or I; where X43 is S or R; where X44 is R or M; where X45 is A or Y; where X46 is T, V, or S; where X47 is M or V; and where X48 is T, A, or G; 12 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 CDR2 contains the sequence: X49X50X51X52X53X54GX55X56TX57(SEQ ID NO: 4543); where X49is A or T; where X50is V, S, or A; where X51is I or V; where X52is A or S; where X53is Q, R, or P; where X54is S or N; where X55is I or D; where X56is T or N; and where X57is Y or D; CDR3 contains the sequence: AADIDX58X59DFFNPDY (SEQ ID NO: 4544); where X58 is N or S; and where X59 is D or N. In an embodiment of this aspect, a multimeric VHH polypeptide that binds to a human CTLA4 polypeptide, or an antigen binding fragment thereof, and to a human programmed cell death protein 1 (PD-1) polypeptide, or an antigen binding fragment thereof, where the multimeric VHH polypeptide contains two or more VHH polypeptides that specifically bind to human CTLA4 polypeptide, two or more VHH polypeptides that specifically bind to human PD-1 polypeptide, and a VHH polypeptide that specifically binds to human albumin polypeptide;where at least one VHH polypeptide that binds to the CTLA4 polypeptide contains complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, where: CDR1 contains the sequence: AASGSISSPNVMG (SEQ ID NO: 4665) or GSISSPNV (SEQ ID NO: 4590); CDR2 contains the sequence: AIITSGGTTK (SEQ ID NO: 4666) or TSGGTTK (SEQ ID NO: 4591); and CDR3 contains the sequence: NTKVPTGWNTQQWDEY (SEQ ID NO: 4592); or where at least one VHH polypeptide that binds to the CTLA4 polypeptide contains complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, where: CDR1 contains the sequence: RASGSTLDSYAIG (SEQ ID NO: 4667) or GSTLDSYA (SEQ ID NO: 4596); CDR2 contains the sequence: CIGKNGDFTQ (SEQ ID NO: 4668) or GKNGDFTQ (SEQ ID NO: 4597); and CDR3 contains the sequence: AAVLQVFHLCPIWSENYH (SEQ ID NO: 4598); and where each VHH polypeptide that binds to the human PD-1 polypeptide contains complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, where: CDR1 contains the sequence: AASGPSFSRATMT (SEQ ID NO: 4669) or GPSFSRAT (SEQ ID NO: 4545); CDR2 contains the sequence: AVISQSGITTY (SEQ ID NO: 4670) or SQSGITTY (SEQ 13 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 ID NO: 4546); and CDR3 contains the sequence: AADIDSDDFFNPDY (SEQ ID NO: 4546). In an embodiment of this aspect, one or more VHH polypeptides that specifically binds to human CTLA4 polypeptide, or a fragment thereof, contains amino acid sequence: (i) QVQLVESGGGLVX1X2GGSLRLSCAASGX3X4SX5PX6X7X8X9X10NX11X12GWYRQ APGKQRX13LX14AX15X16TSX17GX18TX19YX20DSVX21X22RFTISRX23NAX24NTVSLQMX25S LKPEDTAVYX26CNTKVPTGWNTQQWDEYWGQGTQVTVSS (SEQ ID NO: 4533); where X1 is Q or E; where X2 is A or T; where X3 is S or absent; where X4 is I or absent; where X5 is S or A; where X6 is absent or K; where X7 is absent or W; where X8 is absent or I; where X9is absent or V; where X10is absent or V; where X11is V, A, or D; where X12is M or V; where X13is E or G; where X14is V or I; where X15is I or T; where X16is I or V; where X17is G or S; where X18is T or M; where X19is K, N, or R; where X20is A or S; where X21is K or E; where X22 is G or D; where X23 is D or G; where X24 is K or R; where X25 is N, S, or D; and where X26 is A or T; and / or (ii) QVQLVESGGX1X2GGSLRLX3CX4ASX5X6X7X8X9SX10AX11GWX12RQX13PGKEREX 14X15X16X17X18X19X20X21GX22FTX23YX24DSVKGRFTIX25RDX26X27X28NX29X30X31LX32MNX33LX34PX35DTX36X37YX38CX39AX40X41QVFX42LCPX43WSEX44YX45X46GQGTX47VTVSS (SEQ ID NO: 4537); where X1is D or G; where X2is P or A; where X3is S or T; where X4is R or A; where X5is G or E; where X6is S, F, or R; where X7is T or S; where X8is L or F; where X9 is D or S; where X10 is Y, V, or F; where X11 is I or M; where X12 is F or L; where X13 is A or G; where X14 is G or F; where X15 is V, L, or I; where X16 is S or A; where X17 is C or A; where X18 is I or V; where X19 is G or S; where X20 is R, K, or W; where X21 is S or N; where X22 is G, D, A, or T; where X23 is Q, N, M, or Y; where X24 is V, I, S, or A; where X25 is F, L, S, or G; where X26 is N or I; where X27 is P or A; where X28 is K, N, or E; where X29 is T, I, or M; where X30is A or V; where X31is Y or I; where X32is E or Q; where X33is S or N; where X34is K or R; where X35is E or Q; where X36is A or G; where X37is V or I; where X38is Y or F; where X39is A or G; where X40is V or I; where X41is L, Q, R, or P; where X42is D or / H; where X43is I or L; where X44is N, T, or F; where X45is Y, E, D, S, or H; where X46is F, Y, W, or absent; and where X47 is Q or P; and 14 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 where one or more VHH polypeptides that specifically binds to human PD-1 polypeptide, or a fragment thereof, contains amino acid sequence: QVQLVESGGGLVQAGX1SLRLSCAX2X3GX4X5X6X7X8X9X10X11X12WFRQX13PGX14EREFVX15X16X17X18X19X20GX21X22TX23YAX24SVKGRFTISRDNAKNTVX25LX26MNX27LK PEDTAVYYCAADIDX28X29DFFNPDYWGQGTQVTVSS (SEQ ID NO: 4541); where X1 is D or G; where X2 is A or V; where X3 is S or F; where X4 is P or R; where X5 is S, T, P, or A; where X6 is F or I; where X7 is S or R; where X8 is R or M; where X9 is A orY; where X10 is T, V, or S; where X11is M or V; where X12is T, A, or G; where X13is P or A; where X14is K or R; where X15is A or T; where X16is V, S, or A; where X17is I orV; where X18is A or S; where X19is Q, R, or P; where X20is S or N; where X21is I or D; where X22is T or N; where X23is Y or D; where X24is D or N; where X25is Y or F; where X26is R or Q; where X27is S or N; where X28is N or S; and where X29 is D or N. In another embodiment of this aspect, one or more VHH polypeptides that specifically binds to human CTLA4 polypeptide, or a fragment thereof, contains an amino acid sequence having at least 85% identity to an amino acid sequence selected from: (i) QVQLVESGGGLVQAGGSLRLSCAASGSISSPNVMGWYRQAPGKQRELVAIITSG GTTKYADSVKGRFTISRDNAKNTVSLQMNSLKPEDTAVYACNTKVPTGWNTQQWDEY WGQGTQVTVSS (SEQ ID NO: 4493); and / or (ii) QVQLVESGGGLVETGGSLRLSCAASGSAPKWIVVNAVGWYRQAPGKQRGLIAT VTSSGMTNYSDSVEDRFTISRGNARNTVSLQMSSLKPEDTAVYTCNTKVPTGWNTQQW DEYWGQGTQVTVSS (SEQ ID NO: 4495); and where one or more VHH polypeptides that specifically binds to human PD-1 polypeptide, or a fragment thereof, contains an amino acid sequence having at least 85% identity to amino acid sequence: QVQLVESGGGLVQAGDSLRLSCAASGPSFSRATMTWFRQPPGKEREFVAVISQSGITTY YADSVKGRFTISRDNAKNTVYLRMNSLKPEDTAVYYCAADIDSDDFFNPDYWGQGTQ VTVSS (SEQ ID NO: 4478). In another embodiment of this aspect, the one or more VHH polypeptides that specifically binds to human CTLA4 polypeptide, or a fragment thereof, contains an amino acid sequence having 90% or 95% identity to the amino acid sequence of (i) 15 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 or (ii); and where one or more VHH polypeptides that specifically binds to human PD-1 polypeptide, or a fragment thereof, contains an amino acid sequence having 90% or 95% identity to the anti-PD-1 VHH amino acid sequence. In yet another aspect, the disclosure provides a single domain (VHH) polypeptide or an antigen binding fragment thereof that specifically binds to a human programmed cell death protein 1 (PD-1) polypeptide, where the VHH polypeptide contains complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, where the CDR1, CDR2, and CDR3 each have at least 85% amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 1; or where the CDR1, CDR2, and CDR3 comprise an amino acid sequence corresponding to CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 1. In an embodiment of this aspect, CDR1 contains an amino acid sequence GPSFSRAT (SEQ ID NO: 4521), CDR2 contains an amino acid sequence X1QSGITTY (SEQ ID NO: 4522), where X1 is A or S; and CDR3 contains an amino acid sequence AADIDX2DDFFNPDY (SEQ ID NO: 4523), where X2 is N or S. In an embodiment of this aspect, CDR1 contains an amino acid sequence X3X4X5FSX6X7VM (SEQ ID NO: 4524); where X3 is G or R; where X4 is D or R; where X5 is S or T; where X6 is E, P, or T; and where X7 is D, E, or Y; CDR2 contains an amino acid sequence TWX8X9GITY (SEQ ID NO: 4525); where X8is A, N, or T; and where X9is A or S; and CDR3 contains an amino acid sequence AAAPX10NSDYDFLTGYGX11DS (SEQ ID NO: 4526); where X10is L or Q; and where X11is F or M. In another aspect, a single domain (VHH) polypeptide or an antigen binding fragment thereof that specifically binds to a human cytotoxic T-lymphocyte-associated protein 4 (CTLA4) polypeptide, where the VHH polypeptide contains complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, where CDR1, CDR2, and CDR3 each have at least 85% or 90% amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 2; or where the CDR1, CDR2, and CDR3 comprise an amino acid sequence corresponding to CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 2. In an embodiment of this aspect, CDR1 contains an amino acid sequence GX12X13LDSX14A (SEQ ID NO: 4527); where X12is F or S; where X13is S or T; and where X14is F, V, or Y; CDR2 contains an amino acid sequence GX15X16GX17FTX18(SEQ ID NO: 4528); where X15is K or R; where X16is N or S; where X17is D, G, or T; and where X18is M, N, or Q; CDR3 contains an amino acid sequence X19X20VX21QVFX22LCPX23X24X25X26X27X28X29 (SEQ ID NO: 4529); 16 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 where X19is A or G; where X20is A or T; where X21is L, P, Q, or R; where X22is D, G, or H; where X23is I or L; where X24is S or W; where X25is E or S; where X26is E or P; where X27is N or Y; where X28is R or Y; and where X29is D, E, H, or Y. In another embodiment, CDR1 contains an amino acid sequence GRTISGYG (SEQ ID NO: 4530), CDR2 contains an amino acid sequence TWSGGX30X31F (SEQ ID NO: 4531); where X30 is N or T; and where X31 is A or T; and CDR3 contains an amino acid sequence ASTVX32X33YWVPVX34RX35X36YYSX37SX38YX39Y (SEQ ID NO: 4532); where X32 is D or G; where X33is R or V; where X34is W or Y; where X35is H or T; where X36is D or E; where X37is A or T; where X38is N or Y; and where X39is A or V. In yet another aspect, the disclosure provides a multimeric VHH polypeptide or an antigen binding fragment thereof that specifically binds to a human PD-1 polypeptide, where the multimeric VHH polypeptide contains two or more VHH polypeptides that specifically bind to human PD-1 polypeptide, and where each VHH polypeptide is a VHH polypeptide of any previous aspect. In yet another aspect, the disclosure provides a multimeric VHH polypeptide or an antigen binding fragment thereof that specifically binds to a human CTLA4 polypeptide, where the multimeric VHH polypeptide contains two or more VHH polypeptides that specifically bind to human CTLA4 polypeptide, and where each VHH polypeptide is a VHH polypeptide of any previous aspect. In yet another aspect, the disclosure provides a multimeric VHH polypeptide that binds to a human CTLA4 polypeptide, or a fragment thereof, and a human PD-1 polypeptide, or a fragment thereof, where the multimeric VHH polypeptide contains two or more VHH polypeptides that specifically bind to human CTLA4 polypeptide, two or more VHH polypeptides that specifically bind to human PD-1 polypeptide, and a VHH polypeptide that specifically binds to albumin or human albumin polypeptide, where each VHH polypeptide that binds to the human PD-1 polypeptide is a VHH polypeptide of any previous aspect, and 17 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 where each VHH polypeptide that binds to the human CTLA4 polypeptide is a VHH polypeptide of any embodiment described herein. In an embodiment of any of the above aspects or any other aspect of the disclosure delineated herein, the anti-albumin VHH contains a sequence having at least 85%, at least 90%, at least 95%, or 100% identity to amino acid sequence QVQLVESGGGLVQPGGSLRLSCAASGLTSDNYVIGWFRQAPGKEREGVSCISSRDGSTY YPPSVKGRFTISRDNAKNTVYLEMASLKPEDTAVYYCAAQQVWAVCVLQAFEYDYWG QGTQVTVSS (SEQ ID NO: 4656). In an embodiment of any of the above aspects or any other aspect of the disclosure delineated herein, where the anti-albumin VHH contains amino acid sequence QVQLVESGGGLVQPGGSLRLSCAASGLTSDNYVIGWFRQAPGKEREGVSCISSRDGSTY YPPSVKGRFTISRDNAKNTVYLEMASLKPEDTAVYYCAAQQVWAVCVLQAFEYDYWG QGTQVTVSS (SEQ ID NO: 4656). In yet another aspect, the invention provides an isolated polynucleotide encoding the multimeric VHH polypeptide of any previous aspect or any other VHH polypeptide or antigen binding fragment delineated herein. In yet another aspect, the invention provides an isolated polynucleotide encoding the VHH polypeptide of any previous aspect. In yet another aspect, the invention provides an isolated polynucleotide encoding the pentameric bispecific VHH binding molecule of any previous aspect. In an embodiment, the polynucleotide contains or consists essentially of SEQ ID NOs 4660-4664. In yet another aspect, the disclosure provides a vector comprising the isolated polynucleotide of any previous aspect; optionally, where the vector is a viral or a non-viral expression vector. In yet another aspect, the disclosure provides a vector comprising the isolated polynucleotide of a previous aspect; optionally, where the vector is a viral or a non-viral expression vector. In yet another aspect, the disclosure provides a vector comprising the isolated polynucleotide of a previous aspect; optionally, where the vector is a viral or a non-viral 18 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 expression vector. In yet another aspect, the disclosure provides a host cell comprising the vector of a previous aspect. In yet another aspect, the disclosure provides a host cell comprising the vector of a previous aspect. In yet another aspect, the disclosure provides a host cell comprising the vector of a previous aspect. In yet another aspect, the disclosure provides a pharmaceutical composition comprising an effective amount of the multimeric VHH polypeptide of any previous aspect and a pharmaceutically acceptable excipient, carrier, or diluent. In yet another aspect, the disclosure provides a pharmaceutical composition comprising an effective amount of the VHH polypeptide of any previous aspect, and a pharmaceutically acceptable excipient, carrier, or diluent. In yet another aspect, the disclosure provides a pharmaceutical composition comprising an effective amount of the pentameric bispecific VHH binding molecule of any previous aspect, and a pharmaceutically acceptable excipient, carrier, or diluent. In yet another aspect, the disclosure provides a pharmaceutical composition comprising an effective amount of the isolated polynucleotide of any one previous aspect, or the vector of any previous aspect, and a pharmaceutically acceptable excipient, carrier, or diluent. In yet another aspect, the disclosure provides a method of treating a cancer, tumor, or neoplasia in a subject, the method comprising: administering to a subject in need thereof an effective amount of the multimeric VHH polypeptide of any previous aspect, the pentameric bispecific VHH binding molecule of any previous aspect, or the VHH polypeptide of any previous aspect, or a pharmaceutically acceptable composition thereof. In yet another aspect, the disclosure provides a method of treating a cancer, tumor, or neoplasia in a subject, the method comprising: 19 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 administering to a subject in need thereof an effective amount of the isolated polynucleotide of any previous aspect, or a pharmaceutically acceptable composition thereof. In yet another aspect, the disclosure provides a method of treating a cancer, tumor, or neoplasia in a subject, the method comprising: administering to a subject in need thereof an effective amount of the vector of any previous aspect, or a pharmaceutically acceptable composition thereof. In embodiments of the previous aspect, the cancer, tumor, or neoplasia is selected from metastatic cancer, a solid tumor, a hematologic cancer, leukemia, lymphoma, osteosarcoma, rhabdomyosarcoma, neuroblastoma, melanoma, kidney cancer, leukemia, renal transitional cell cancer, Wilm’s cancer, ovarian cancer, pancreatic cancer, breast cancer, triple negative breast cancer, colon cancer, colorectal cancer (CRC), prostate cancer, bone cancer, lung cancer, non-small cell lung cancer (NSCLC), gastric cancer, cervical cancer, ovarian cancer, bladder cancer, synovial sarcoma, head and neck cancer, squamous cell carcinoma, multiple myeloma, renal cancer, retinoblastoma, hepatoblastoma, hepatocellular carcinoma (HCC), melanoma, rhabdoid tumor of the kidney, Ewing’s sarcoma, chondrosarcoma, brain cancer, glioblastoma, meningioma, pituitary adenoma, vestibular schwannoma, a primitive neuroectodermal tumor, medulloblastoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma, choroid plexus papilloma, polycythemia vera, thrombocythemia, idiopathic myelofibrosis, soft tissue sarcoma, thyroid cancer, endometrial cancer, carcinoid, or liver cancer. In embodiments of the previous aspect, the cancer, tumor, or neoplasia is selected from a solid tumor, Non-Small Cell Lung Cancer (NSCLC), triple negative breast cancer, renal cell carcinoma, melanoma, bladder cancer, hepatocellular carcinoma, colon cancer, or colorectal cancer (CRC). In embodiments of the previous aspect, the method has increased safety (e.g., reduced toxicity, reduced inflammation, reduced adverse events, such as immune-related adverse events, less tissue damage, less targeting of healthy tissue, less targeting of T regulatory cells) and / or increased efficacy (e.g., achieves complete tumor regression, sustained remission, and the like) in the subject compared to administration of a reference antibody to the subject or to an untreated control subject. In one embodiment, the subject is a mammal. In another embodiment, the subject is a murine, feline, canine, bovine, or human subject. In embodiments of the previous aspect, the multimeric VHH polypeptide pentamer comprising the structure [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [PD-1-binding 20 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 XFU-D3 VHH] or CDR1-3 thereof – [CTLA4-binding XFV-E7 VHH] or CDR1-3 thereof – [CTLA4-binding XJD-A4 VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3. In embodiments, the multimeric VHH polypeptide pentamer (e.g., Construct #1-5) is administered daily in an effective amount of 0.01mg / kg or 1 mg for 6 weeks. In yet another aspect, the disclosure provides a method of modulating, stimulating, or eliciting an immune response, the method comprising contacting a cell with the multimeric VHH polypeptide of any previous aspect, the pentameric bispecific VHH binding molecule of any previous aspect (e.g., Construct #1-5), or the VHH polypeptide of any previous aspect, or a pharmaceutically acceptable composition thereof. In embodiments of the previous aspect, the pentameric bispecific VHH binding molecule of any previous aspect, the VHH polypeptide of any previous aspect, or the pharmaceutical composition of of any previous aspect for use in therapy. In yet another aspect, the disclosure provides a use of the multimeric VHH polypeptide of any previous aspect, the pentameric bispecific VHH binding molecule of any previous aspect, the VHH polypeptide of any previous aspect, or a pharmaceutically acceptable composition thereof, in a method of treating a cancer, tumor, or neoplasia. In an embodiment, the method is for treating, or the cancer, tumor, or neoplasia is selected from, metastatic cancer, a solid tumor, a hematologic cancer, leukemia, lymphoma, osteosarcoma, rhabdomyosarcoma, neuroblastoma, melanoma, kidney cancer, leukemia, renal transitional cell cancer, Wilm’s cancer, ovarian cancer, pancreatic cancer, breast cancer, triple negative breast cancer, colon cancer, colorectal cancer (CRC), prostate cancer, bone cancer, lung cancer, non-small cell lung cancer (NSCLC), gastric cancer, cervical cancer, ovarian cancer, bladder cancer, synovial sarcoma, head and neck cancer, squamous cell carcinoma, multiple myeloma, renal cancer, retinoblastoma, hepatoblastoma, hepatocellular carcinoma (HCC), melanoma, rhabdoid tumor of the kidney, Ewing’s sarcoma, chondrosarcoma, brain cancer, glioblastoma, meningioma, pituitary adenoma, vestibular schwannoma, a primitive neuroectodermal tumor, medulloblastoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma, choroid plexus papilloma, polycythemia vera, thrombocythemia, idiopathic myelofibrosis, soft tissue sarcoma, thyroid cancer, endometrial cancer, carcinoid, or liver cancer. In another embodiment, the therapy is for treating a cancer, 21 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 tumor, or neoplasia is that is any one or more of a solid tumor, triple negative breast cancer, NSCLC, renal cell carcinoma, melanoma, bladder cancer, hepatocellular carcinoma, colon cancer, or colorectal cancer (CRC). In yet another aspect, the disclosure provides a kit comprising the multimeric VHH polypeptide of any previous aspect, the pentameric bispecific VHH binding molecule of any previous aspect, or the VHH polypeptide of any previous aspect, or a pharmaceutical composition thereof, for treating a tumor, cancer, or neoplasia; and optionally comprising instructions for use. In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, the linker contains a flexible linker or a chemical linker. In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, the linker contains a flexible linker selected from GGn, where n is 3-12. In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, the linker is selected from GGGG, GGGG, or GGGGG (SEQ ID NO: 4654). In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, the pbVHH optionally further contains a signal peptide at the amino terminus of the polypeptide. In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, the pbVHH optionally further contains a signal peptide at the amino terminus of the polypeptide. In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, the pbVHH optionally further contains a signal peptide at the amino terminus of the polypeptide. In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, the pbVHH optionally further contains a signal peptide at the amino terminus of the polypeptide. In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, the multimeric VHH optionally further contains a signal peptide at the amino terminus of the polypeptide. In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, the multimeric VHH optionally further contains a signal peptide at the amino terminus of the polypeptide. In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, the multimeric VHH optionally further contains a signal peptide at the amino terminus of the polypeptide. In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, the multimeric VHH optionally further contains a signal peptide at the amino terminus of the polypeptide. In embodiments of any of the above 22 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 aspects or any other aspect of the disclosure delineated herein, the multimeric VHH polypeptide optionally further comprising an affinity tag at the carboxy terminus of the polypeptide. In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, the multimeric VHH polypeptide optionally further comprising a protease cleavage site linked to the affinity tag at the carboxy terminus of the polypeptide. In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, the multimeric VHH polypeptide contains a cleavage site (e.g., a protease cleavage site, such as a Tev protease site and / or the affinity tag is a His tag comprising 4 to 8 histidine (His) amino acids). In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, the structural components are separated by a linker. In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, the anti-PD-1 VHH polypeptide, CDR1 contains an amino acid sequence GPSFSRAT (SEQ ID NO: 4521); CDR2 contains an amino acid sequence X1QSGITTY (SEQ ID NO: 4522), where X1 is A or S; and CDR3 contains an amino acid sequence AADIDX2DDFFNPDY (SEQ ID NO: 4523), where X2 is N or S. In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, the anti-PD-1 VHH polypeptide, CDR1 contains an amino acid sequence X3X4X5FSX6X7VM (SEQ ID NO: 4524), where X3is G or R; where X4is D or R; where X5is S or T; where X6is E, P, or T; and where X7is D, E, or Y; CDR2 contains an amino acid sequence TWX8X9GITY (SEQ ID NO: 4525), where X8is A, N, or T; and where X9is A or S; and CDR3 contains an amino acid sequence AAAPX10NSDYDFLTGYGX11DS (SEQ ID NO: 4526), where X10 is L or Q; and where X11 is F or M. In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, in the anti-PD-1 VHH polypeptide, CDR1 contains an amino acid sequence GPSFSRAT (SEQ ID NO: 4545); CDR2 contains an amino acid sequence SQSGITTY (SEQ ID NO: 4546); and CDR3 contains an amino acid sequence AADIDSDDFFNPDY (SEQ ID NO: 4547). In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, where, in the anti-CTLA4 VHH polypeptide, CDR1 contains an amino acid sequence GX12X13LDSX14A (SEQ ID NO: 4527); where X12is F or S; where X13is S or T; and where X14is F, V, or Y; CDR2 contains an amino acid sequence GX15X16GX17FTX18(SEQ ID NO: 4528); where X15is K or R; where X16is N or S; where X17is D, G, or T; and where X18is M, N, or Q; and CDR3 contains an amino acid sequence X19X20VX21QVFX22LCPX23X24X25X26X27X28X29 (SEQ 23 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 ID NO: 4529); where X19is A or G; where X20is A or T; where X21is L, P, Q, or R; where X22is D, G, or H; where X23is I or L; where X24is S or W; where X25is E or S; where X26is E or P; where X27is N or Y; where X28is R or Y; and where X29is D, E, H, or Y. In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, where, in the anti-CTLA4 VHH polypeptide, CDR1 contains an amino acid sequence GRTISGYG (SEQ ID NO: 4530); CDR2 contains an amino acid sequence TWSGGX30X31F (SEQ ID NO: 4531); where X30is N or T; and where X31 is A or T; and CDR3 contains an amino acid sequence ASTVX32X33YWVPVX34RX35X36YYSX37SX38YX39Y (SEQ ID NO: 4532); where X32 is D or G; where X33 is R or V; where X34 is W or Y; where X35 is H or T; where X36 is D or E; where X37 is A or T; where X38 is N or Y; and where X39 is A or V. In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, where, in the anti-CTLA4 VHH polypeptide, CDR1 contains an amino acid sequence: AASGX40X41SX42PX43X44X45X46X47NX48X49G (SEQ ID NO: 4534); where X40is S or absent; X41is I or absent; X42is S or A; X43is absent or K; X44is absent or W; X45is absent or I; X46is absent or V; X47is absent or V; X48is V, A, or D; and X49 is M or V; CDR2 contains an amino acid sequence: AX50X51TSX52GX53TX54(SEQ ID NO: 4535); where X50 is I or T; X51 is I or V; X52 is G or S; X53 is T or M; and X54 is K, N, or / R; and CDR3 contains an amino acid sequence: NTKVPTGWNTQQWDEY (SEQ ID NO: 4536). In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, where, in the anti- CTLA4 VHH polypeptide, CDR1 contains an amino acid sequence GSISSPNV (SEQ ID NO: 4590); CDR2 contains an amino acid sequence TSGGTTK (SEQ ID NO: 4591); and CDR3 contains an amino acid sequence NTKVPTGWNTQQWDEY (SEQ ID NO: 4592); and / or where CDR1 contains an amino acid sequence GSTLDSYA (SEQ ID NO: 4596); CDR2 contains an amino acid sequence GKNGDFTQ (SEQ ID NO: 4597); and CDR3 contains an amino acid sequence AAVLQVFHLCPIWSENYH (SEQ ID NO: 4598). In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, 24 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 the multimeric VHH polypeptide is a dimer, trimer, tetramer, pentamer, or hexamer. In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, the multimeric VHH polypeptide contains an albumin or human albumin-binding VHH that contains CDR1, CDR2, and CDR3, where CDR1 contains amino acid sequence AASGLTSDNYVIG (SEQ ID NO: 4657); CDR2 contains amino acid sequence CISSRDGSTY (SEQ ID NO: 4658); and CDR3 contains amino acid sequence AAQQVWAVCVLQAFEYDY (SEQ ID NO: 4659). In embodiments of any of the above aspects or any other aspect of the disclosure delineated herein, the albumin or human albumin-binding VHH contains a sequence having at least 85%, 90%, 95%, or 100% identity to amino acid sequence: QVQLVESGGGLVQPGGSLRLSCAASGLTSDNYVIGWFRQAPGKEREGVSCISSRDGSTY YPPSVKGRFTISRDNAKNTVYLEMASLKPEDTAVYYCAAQQVWAVCVLQAFEYDYWG QGTQVTVSS (SEQ ID NO: 4656). In an aspect, the present disclosure provides a single domain (VHH) polypeptide or an antigen binding fragment thereof that specifically binds to a human programmed cell death protein 1 (PD-1) polypeptide. The VHH polypeptide includes complementarity determining regions (CDRs), CDR1, CDR2, and CDR3. CDR1, CDR2, and CDR3 each have at least about 85% amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 1. In another aspect, the present disclosure provides a VHH polypeptide or an antigen binding fragment thereof that specifically binds to a human programmed cell death protein 1 (PD-1) polypeptide. The VHH polypeptide includes complementarity determining regions (CDRs), CDR1, CDR2, and CDR3. CDR1, CDR2, and CDR3 each comprise or consist essentially of a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 1. In another aspect, the present disclosure provides a VHH polypeptide or an antigen binding fragment thereof that specifically binds to a human cytotoxic T-lymphocyte-associated protein 4 (CTLA4) polypeptide. The VHH polypeptide includes complementarity determining regions (CDRs), CDR1, CDR2, and CDR3. CDR1, CDR2, and CDR3 each have at least about 85% amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 2. In another aspect, the present disclosure provides a VHH polypeptide or an antigen binding fragment thereof that specifically binds to a human cytotoxic T-lymphocyte-associated 25 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 protein 4 (CTLA4) polypeptide. The VHH polypeptide includes complementarity determining regions (CDRs), CDR1, CDR2, and CDR3. CDR1, CDR2, and CDR3 each consist of a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 2. In another aspect, the present disclosure provides a multimeric VHH polypeptide or an antigen binding fragment thereof that specifically binds to a human PD-1 polypeptide. The multimeric VHH polypeptide includes two or more VHH polypeptides that specifically bind to human PD-1 polypeptide. Each VHH polypeptide is a VHH polypeptide of any of the above aspects, or embodiments thereof. In another aspect, the present disclosure provides a multimeric VHH polypeptide or an antigen binding fragment thereof that specifically binds to a human CTLA4 polypeptide. The multimeric VHH polypeptide includes two or more VHH polypeptides that specifically bind to human CTLA4 polypeptide. Each VHH polypeptide is a VHH polypeptide of any of the above aspects, or embodiments thereof. In another aspect, the present disclosure provides a multimeric VHH polypeptide that binds to a human CTLA4 polypeptide, or a fragment thereof, and a human PD-1 polypeptide, or a fragment thereof. The multimeric VHH polypeptide includes two or more VHH polypeptides that specifically bind to human CTLA4 polypeptide, two or more VHH polypeptides that specifically bind to human PD-1 polypeptide, and a VHH polypeptide that specifically binds to human albumin polypeptide. Each VHH polypeptide that binds to the human PD-1 polypeptide is a VHH polypeptide of any of the above aspects, or embodiments thereof, and each VHH polypeptide that binds to the human CTLA4 polypeptide is a VHH polypeptide of any of the above aspects, or embodiments thereof. In another aspect, the present disclosure provides an isolated polynucleotide encoding the polypeptide of any of the above aspects, or embodiments thereof. In another aspect, the present disclosure provides a vector including the isolated polynucleotide of any of the above aspects, or embodiments thereof. Optionally, in some embodiments, the vector is a viral or a non-viral expression vector. In another aspect, the present disclosure provides a host cell including the vector of any of the above aspects, or embodiments thereof. In another aspect, the present disclosure provides a pharmaceutical composition including an effective amount of the VHH polypeptide of any of the above aspects, or 26 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 embodiments thereof, or the multimeric VHH polypeptide of any of the above aspects, or embodiments thereof, and a pharmaceutically acceptable excipient, carrier, or diluent. In another aspect, the present disclosure provides a method of treating a neoplasia in a subject in need thereof. The method involves administering a VHH polypeptide of any of the above aspects, or embodiments thereof, or a multimeric VHH polypeptide of any of the above aspects, or embodiments thereof, to the subject. In another aspect, the present disclosure provides a method of modulating immune response. The method involves contacting a cell with a VHH polypeptide of any of the above aspects, or embodiments thereof, or a multimeric VHH polypeptide of any of the above aspects, or embodiments thereof. In another aspect, the present disclosure provides a kit. The kit includes the VHH polypeptide of any of the above aspects, or embodiments thereof, or a multimeric VHH polypeptide of any of the above aspects, or embodiments thereof, or a pharmaceutical composition thereof, for treating a neoplasia. In some embodiments, the kit optionally includes instructions for use. In any of the above aspects, or embodiments thereof, the VHH polypeptide includes complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, where CDR1, CDR2, and CDR3 each have at least about 90% amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 1. In any of the above aspects, or embodiments thereof, CDR1 includes an amino acid sequence GPSFSRAT (SEQ ID NO: 4521 ), CDR2 includes an amino acid sequence X1QSGITTY (SEQ ID NO: 4522), where X1 is A or S, and CDR3 includes an amino acid sequence AADIDX2DDFFNPDY (SEQ ID NO: 4523), where X2 is N or S. In any of the above aspects, or embodiments thereof, CDR1 includes an amino acid sequence X3X4X5FSX6X7VM (SEQ ID NO: 4524), where X3is G or R; where X4is D or R; where X5is S or T; where X6is E, P, or T; and where X7is D, E, or Y, CDR2 includes an amino acid sequence TWX8X9GITY (SEQ ID NO: 4525), where X8is A, N, or T; and where X9is A or S; and CDR3 includes an amino acid sequence AAAPX10NSDYDFLTGYGX11DS (SEQ ID NO: 4526), where X10 is L or Q; and where X11 is F or M. In any of the above aspects, or embodiments thereof, the VHH polypeptide includes complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, where CDR1, CDR2, 27 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 and CDR3 each have at least about 90% amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 2. In any of the above aspects, or embodiments thereof, CDR1 includes an amino acid sequence GX12X13LDSX14A (SEQ ID NO: 4527), where X12 is F or S; where X13 is S or T; and where X14 is F, V, or Y; CDR2 includes an amino acid sequence GX15X16GX17FTX18 (SEQ IID NO: 4528), where X15 is K or R; where X16 is N or S; where X17 is D, G, or T; and where X18 is M, N, or Q; and CDR3 includes an amino acid sequence X19X20VX21QVFX22LCPX23X24X25X26X27X28X29(SEQ ID NO: 4529), where X19is A or G; where X20is A or T; where X21is L, P, Q, or R; where X22is D, G, or H; where X23is I or L; where X24is S or W; where X25is E or S; where X26is E or P; where X27is N or Y; where X28is R or Y; and where X29is D, E, H, or Y. In any of the above aspects, or embodiments thereof, CDR1 includes an amino acid sequence GRTISGYG (SEQ ID NO: 4530), CDR2 includes an amino acid sequence TWSGGX30X31F (SEQ ID NO: 4531), where X30 is N or T; and where X31 is A or T; and CDR3 includes an amino acid sequence ASTVX32X33YWVPVX34RX35X36YYSX37SX38YX39Y (SEQ ID NO: 4532), where X32is D or G; where X33is R or V; where X34is W or Y; where X35is H or T; where X36is D or E; where X37is A or T; where X38is N or Y; and where X39is A or V. In any of the above aspects, or embodiments thereof, the method has improved safety in the subject as compared to administration of a reference antibody to the subject. Compositions and articles defined by the disclosure were isolated or otherwise manufactured in connection with the examples provided below. Other features and advantages of the disclosure will be apparent from the detailed description, and from the claims. Definitions Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which the described aspects and embodiments belongs. The following references provide one of skill with a general definition of many of the terms used in the aspects and embodiments described herein: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of 28 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 Biology (1991). The following terms have the meanings ascribed to them below, unless specified otherwise. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. As used in the specification and claim(s) herein, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the present disclosure, and vice versa. Furthermore, compositions and products of the present disclosure can be used to achieve methods of the present disclosure. Unless specifically stated or obvious from context, as used herein, the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend, in part, on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 standard deviation or more than 1 standard deviation, e.g., 2 standard deviations of the mean, as typically practiced in the art. Alternatively, and without intending to be limiting, “about” can mean a range of up to 20%, up to 10%, up to 5%, up to 2%, or up to 1% of a given value. Alternatively, and particularly for biological systems or processes, the term can mean within an order of magnitude, e.g., within 5-fold, within 3-fold, within 2.5-fold, or within 2-fold of a value. Where particular values are described in the application and claims, unless otherwise stated, the term “about” means within an acceptable error range for the particular value. Reference herein to “some embodiments,” “an embodiment,” “one embodiment” or “other embodiments” means that a particular feature or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the disclosure. 29 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 By "agent" is meant any small molecule chemical compound, antibody, nucleic acid molecule, or polypeptide (e.g., antibody or VHH antibody), or fragments thereof. By “human albumin” is meant a polypeptide (protein) or fragment thereof having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the amino acid sequence of GenBank Accession Nos. NP_000468.1 or AAA98797.1 and having transport activity in blood. Exemplary human albumin polypeptide sequences are provided below: >NP_000468.1 albumin preproprotein [Homo sapiens] MKWVTFISLLFLFSSAYSRGVFRRDAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHV KLVNEVTEFAKTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQ HKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTEC CQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVS KLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVEND EMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKC CAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLV EVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCF SALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFA AFVEKCCKADDKETCFAEEGKKLVAASQAALGL (SEQ ID NO: 4471) >AAA98797.1 albumin [Homo sapiens] MKWVTFISLLFLFSSAYSRGVFRRDAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHV KLVNEVTEFAKTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQ HKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTEC CQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVS KLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVEND EMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKC CAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLV EVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCF SALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFA AFVEKCCKADDKETCFAEEGKKLVAASQAALGL (SEQ ID NO: 4472) By “ameliorate” is meant decrease, reduce, diminish, suppress, attenuate, arrest, or stabilize the development or progression of a disease or pathology. By "alteration" is meant a change (increase or decrease) in the expression levels or activity of a gene or polypeptide as detected by standard art known methods such as those described herein. As used herein, an alteration includes a 10% change in expression levels, a 25% change, a 40% change, a 50% or a greater change in expression levels. " By "analog" is meant a molecule that is not identical, but has analogous functional or structural features. For example, a polypeptide analog retains the biological activity of a corresponding naturally-occurring polypeptide, while having certain biochemical modifications 30 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 that enhance the analog's function relative to a naturally occurring polypeptide. Such biochemical modifications could increase the analog's protease resistance, membrane permeability, or half-life, without altering, for example, ligand binding. An analog may include an unnatural amino acid. By “antibody” is meant any immunoglobulin polypeptide, or fragment thereof, having immunogen or antigen binding ability. Antibody structure is well known in the art. Briefly, the variable (V) regions or domains of antibody heavy (H) and light (L) chains contain Complementarity-Determining Regions (CDRs), which bind to specific antigens or immunogens (e.g., protein antigens or immunogens). CDRs are situated within framework (FR) sequences of the V regions of the heavy (VH) and light chains (VL) of an antibody. CDRs are the most variable parts of antibodies and are critical components in the diversity of antigen specificities of antibodies produced by B lymphocytes. In general, three CDRs (CDR1, CDR2 and CDR3) are arranged consecutively in a V domain of an antibody. Because a VHH, such as a camelid VHH, is essentially a single chain antibody polypeptide, it contains three CDRs that bind to an antigen or target protein (e.g., PD-1 and / or CTLA4) in the context of four framework (FR) regions, as follows: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. Thus, as would be appreciated by the skilled practitioner in the art, in a VHH polypeptide sequence, FR1 comprises the amino acids positioned to the left of CDR1; FR2 comprises the amino acids positioned between CDR1 and CDR2; FR3 comprises the amino acids positioned between CDR2 and CDR3; and FR4 comprises the amino acids positioned to the right of CDR3. Because most of the sequence variability associated with immunoglobulins and antigen binding is found in the CDRs, these regions are sometimes referred to as hypervariable regions. Typically, CDR1, CDR2 and CDR3 of VHHs contribute to and / or do not interfere with antigen binding. The CDRs and / or FRs of a number of VHHs described herein are shown, for example, in the Figures described and shown herein. A “chimeric antibody” refers to an antibody in which the constant region of an antibody of one species (e.g., rodent, mouse or rat) is replaced with that from a human to achieve a more human-like antibody. Chimeric antibodies may be recombinantly generated by combining the variable light and heavy chain regions obtained from antibody producing cells of one species with the constant light and heavy chain regions from another. In general, chimeric antibodies utilize rodent (or other species, such as rabbit or camelid) variable regions and human constant 31 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 regions in order to produce an antibody with predominantly human constant domains. The production of chimeric antibodies is well known in the art, and may be achieved by standard means, for example, as described in U.S. Patent No.5,624,659, incorporated fully herein by reference. By "binding to" a molecule is meant having a physicochemical affinity for that molecule or a region of the molecule, e.g., an epitope. Binding may be measured by any of the methods practiced in the art, e.g., using an antibody binding assay or an in vitro translation binding assay. “Detect” refers to identifying or determining the presence, absence or amount of an analyte to be detected. By “cytotoxic T-lymphocyte-associated protein 4 (CTLA 4) polypeptide” is meant a polypeptide (protein) or fragment thereof having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the amino acid sequence of GenBank Accession No. AAL07473.1 and having CD80 and / or CD86 binding activity. An exemplary CTLA4 polypeptide sequence is provided below: >AAL07473.1 CTLA4 [Homo sapiens] MACLGFQRHKAQLNLATRTWPCTLLFFLLFIPVFCKAMHVAQPAVVLASSRGIASFVCEYASPG KATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYI CKVELMYPPPYYLGIGNGTQIYVIDPEPCPDSDFLLWILAAVSSGLFFYSFLLTAVSLSKMLKK RSPLTTGVYVKMPPTEPECEKQFQPYFIPIN (SEQ ID NO: 4473) By "detectable label" is meant a compound, substance, or composition that, when linked to a molecule of interest, renders the latter detectable, via spectroscopic, photochemical, biochemical, immunochemical, or chemical means. For example, useful labels include radioactive isotopes, magnetic beads, metallic beads, colloidal particles, fluorescent dyes, electron-dense reagents, enzymes (for example, as commonly used in an ELISA), biotin, digoxigenin, or haptens. By “disease” is meant any condition, disorder, or pathology that damages or interferes with the normal function of a cell, tissue, or organ. Examples of diseases include, without limitation, any cancer or symptom thereof (e.g., tumor growth and / or metastasis). Examples of cancers include metastatic cancer, a solid tumor, a hematologic cancer, leukemia, lymphoma, osteosarcoma, rhabdomyosarcoma, neuroblastoma, kidney cancer, leukemia, renal transitional cell cancer, Wilm’s cancer, ovarian cancer, pancreatic cancer, breast cancer, colon cancer, 32 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 colorectal cancer (CRC), prostate cancer, bone cancer, lung cancer, non-small cell lung cancer (NSCLC), gastric cancer, cervical cancer, synovial sarcoma, head and neck cancer, squamous cell carcinoma, multiple myeloma, renal cell cancer, retinoblastoma, hepatoblastoma, hepatocellular carcinoma, melanoma, rhabdoid tumor of the kidney, Ewing’s sarcoma, chondrosarcoma, brain cancer, glioblastoma, meningioma, pituitary adenoma, vestibular schwannoma, a primitive neuroectodermal tumor, medulloblastoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma, choroid plexus papilloma, polycythemia vera, thrombocythemia, idiopathic myelofibrosis, soft tissue sarcoma, thyroid cancer, endometrial cancer, or carcinoid or liver cancer. In embodiments, the cancer is a lung cancer (e.g., NSCLC), colorectal cancer, renal carcinoma, breast cancer (e.g., triple negative breast cancer), bladder cancer, heptatocellular carcinoma). By "effective amount" is meant the amount of a required to ameliorate, or optimally eliminate, the symptoms of a disease relative to an untreated patient. The effective amount of active compound(s) used to practice the present aspects and embodiments for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an "effective" amount. In some embodiments, the antibody is a single chain antibody comprising a VHH polypeptide or an antigen binding fragment thereof. In some embodiments, an effective amount of Construct #5 is 0.01mg / kg administered daily. In some embodiments, an effective an effective amount of Construct #5 is a flat dose of 1 mg administered daily. In some embodiments, an effective amount of Construct #5 is 0.01mg / kg or 1 mg administered daily (e.g., subcutaneous administration) for 6 weeks. In some embodiments, an effective amount of Construct #1-5 is 0.01mg / kg or 1 mg administered daily for 6 weeks. An “epitope tag” refers to a peptide or amino acid sequence (epitope) that is fused, linked, or coupled to a protein, such as a recombinant protein produced by recombinant techniques, and that can be specifically bound by an antibody, e.g., an anti-tag monoclonal antibody or binding molecule that is directed to or generated against the tag peptide or amino acid sequence. Epitope tags are typically short peptide sequences (e.g., from about 5-30 amino acids, or sometimes up to 40 amino acids, that are selected because high-affinity antibodies can be reliably produced in many different species. Such anti-epitope tag antibodies are optimally 33 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 not cross-reactive with other human peptides or polypeptides and typically do not generate an antibody response, e.g., an anti-tag antibody response, when administered or delivered to a subject. An epitope tag sequence that is fused to a protein provides for the detection and / or purification of the protein using an antibody, e.g., a monoclonal antibody, that specifically binds to the epitope tag. In an embodiment, the protein to which an epitope tag is fused, linked, or coupled is an antibody or VHH protein, e.g., a recombinantly produced antibody or VHH protein. In an embodiment, the VHH is an anti-PD-1 and / or anti-CTLA4 VHH antibody that binds PD-1 and / or CTLA4. In an embodiment, the protein, or a dimeric or multimeric form thereof, may include one or more epitope tags. In an embodiment, an epitope tag is coupled to the amino (NH) terminus of the protein, e.g., a VHH antibody as described herein. In an embodiment, an epitope tag is coupled to the carboxy (COOH) terminus of the protein, e.g., a VHH antibody as described herein. In an embodiment, an epitope tag is coupled to the NH and the COOH termini of the protein, e.g., a VHH antibody as described herein. In an embodiment, a dimeric or multimeric form of the protein includes one or more, e.g., two, three or four, epitope tags linked to one or more of the VHHs comprising the dimeric or multimeric form of the protein. Such epitope tags may be coupled to the VHH components at locations within the dimer or multimer molecule, or at the NH and / or COOH termini of the molecule. In some embodiments, two or more epitope tags may be coupled to a VHH protein in tandem within or at the termini of the VHH protein or dimeric or multimeric form thereof. Examples of epitope tags include, without limitation, FLAG tags (peptide sequence DYKDDDDK (SEQ ID NO: 4474) recognized by an anti-FLAG antibody), polyHistidine (His) tags (5-10 histidine residues (HHHHHH (SEQ ID NO: 4475)) bound by a nickel or cobalt chelate), E-tag, a peptide comprising amino acid sequence GAPVPYPDPLEPR (SEQ ID NO: 4476) recognized by an antibody; and the epitope tag sequences described herein, which are bound by anti-epitope tag antibodies, forming complexes which may facilitate clearance of the protein containing the tags from the body or system. (See, also, B. Brizzard and R. Chubet, 2001, Curr Protoc Neurosci., Chapter 5, Unit 5.8; DOI: 10.1002 / 0471142301.ns0508s00; R. Hernan et al., 2000, Biotechniques, 28(4):789-793; C.E. Fritze et al., 2000, Meths Enzymol., 327:3-16; doi: 10.1016 / s0076-6879(00)27263-7; A. Einhauer et al., 2001, J Biochem Biophys Methods, 49(1- 3):455-65, doi: 10.1016 / s0165-022x(01)00213-5)). 34 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 A "framework (FR) region" or "FR region" includes amino acid residues that are adjacent to the CDRs in VH, and VLregions, and in VHHs. For example, FR region residues may be present in VHHs as described herein, human antibodies, rodent-derived antibodies (e.g., murine and rat antibodies), humanized antibodies, primatized antibodies, chimeric antibodies, antibody fragments (e.g., Fab fragments), VHHs, single-chain antibody fragments (e.g., scFv fragments), antibody domains, and bispecific antibodies, among others. Also by way of example, in a VHH polypeptide sequence, FR1 comprises the amino acids positioned to the left of CDR1; FR2 comprises the amino acids positioned between CDR1 and CDR2; FR3 comprises the amino acids positioned between CDR2 and CDR3; and FR4 comprises the amino acids positioned to the right of CDR3. By "fragment" is meant a portion of a polypeptide or nucleic acid molecule. This portion contains at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% of the entire length of the reference nucleic acid molecule or polypeptide, including percent values between those enumerated. A fragment may contain 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 nucleotides or amino acids. In an embodiment, a fragment or portion possesses or retains activity or function of the polypeptide from which it is derived. In embodiments, a fragment is derived from PD-1 and / or CTLA4. In some embodiments, the fragment is an antigen binding fragment comprising CDRs of a single chain antibody described herein. The term "humanized" antibodies refers to forms of non-human (e.g., murine) antibodies, camelid-derived single domain antibody (sdAb) binding molecules, which are comprised of the heavy chain variable (VH) region of heavy-chain-only antibodies (Abs) or VHHs. Humanized antibodies include chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab')2or other target-binding subdomains of antibodies) which contain minimal sequences derived from non-human immunoglobulin. In general, a humanized antibody or VHH may comprise substantially all of at least one variable domain (or two variable domains in the case of non-VHH antibodies), in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin. All or substantially all of the FR regions of a humanized antibody may also be derived from a human immunoglobulin sequence. In the case of non-VHH antibodies, a humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fc), which may be that of a human immunoglobulin consensus 35 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 sequence. Techniques and protocols for humanizing antibodies (as well as VHHs) are known and practiced in the art, as described, for examples, in Riechmann et al., Nature, 332:323-7, 1988; Kasmiri et al., Methods, 36(1):25-34, 2005; U.S. Patent Nos.5,530,101; 5,585,089; 5,693,761; 5,693,762; and U.S. Patent No.6,180,370 to Queen et al; EP239400; WO 1991 / 09967; U.S. Patent No. 5,225,539; EP592106; and EP519596, the contents of which are incorporated herein by reference. Humanized antibodies or VHHs are molecularly engineered to contain even more human-like immunoglobulin domains, and incorporate only the CDRs of the VHH or animal-derived monoclonal antibody by carefully examining the sequence of the hyper- variable loops of the V regions of the monoclonal antibody or VHH, and fitting them to the structure of the human antibody chains. This process is routinely and commonly carried out by one having skill in the art. See, e.g., U.S. Patent No.6,187,287, the contents of which are incorporated by reference herein. The terms "isolated," "purified," or "biologically pure" refer to material that is free to varying degrees from components which normally accompany it as found in its native state. "Isolate" denotes a degree of separation from original source or surroundings. "Purify" denotes a degree of separation that is higher than isolation. A "purified" or "biologically pure" protein is sufficiently free of other materials such that any impurities do not materially affect the biological properties of the protein or cause other adverse consequences. That is, a nucleic acid or peptide of the aspects and embodiments disclosed and described herein is purified if it is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized. Purity and homogeneity are typically determined using analytical chemistry techniques, for example, polyacrylamide gel electrophoresis or high performance liquid chromatography. The term "purified" can denote that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel. For a protein that can be subjected to modifications, for example, phosphorylation or glycosylation, different modifications may give rise to different isolated proteins, which can be separately purified. As used herein, the terms “polynucleotide,” “DNA molecule” or “nucleic acid molecule” include both sense and anti-sense strands, cDNA, genomic DNA, recombinant DNA, RNA, mRNA, and wholly or partially synthesized nucleic acid molecules. A nucleotide "variant" is a sequence that differs from the recited nucleotide sequence in having one or more nucleotide 36 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 deletions, substitutions or additions. Such modifications are readily introduced using standard mutagenesis techniques, such as oligonucleotide-directed site-specific mutagenesis as described, for example, in Adelman et al., 1983, DNA 2:183. Nucleotide variants are naturally-occurring allelic variants, or non-naturally occurring variants. Variant nucleotide sequences in various embodiments exhibit at least about 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% sequence homology or sequence identity to the recited sequence. Such variant nucleotide sequences hybridize to the recited nucleotide sequence under stringent hybridization conditions. In one embodiment, "stringent conditions" refers to prewashing in a solution of 6 x SSC, 0.2% SDS; hybridizing at 65oCelsius, 6xSSC, 0.2% SDS overnight; followed by two washes of 30 minutes each in 1xSSC, 0.1% SDS at 65oC, and two washes of 30 minutes each in 0.2 x SSC, 0.1% SDS at 65oC. By "isolated polynucleotide" is meant a nucleic acid (e.g., DNA, cDNA, RNA, mRNA) that is free of the genes, which, in the naturally-occurring genome of the organism from which the nucleic acid molecule of the aspects and embodiments described herein is derived, flank the gene. The term therefore includes, for example, a recombinant DNA that is incorporated into a vector; into an autonomously replicating plasmid or virus; or into the genomic DNA of a prokaryote or eukaryote; or that exists as a separate molecule (for example, a cDNA or a genomic or cDNA fragment produced by PCR or restriction endonuclease digestion) independent of other sequences. In addition, the term includes an RNA molecule that is transcribed from a DNA molecule, e.g., mRNA, as well as a recombinant DNA that is part of a hybrid gene encoding additional polypeptide sequence. In an embodiment, a polynucleotide of the disclosure is any polynucleotide encoding a pbVHH polypeptide, variant thereof, or fragment thereof. In embodiments, the polynucleotide encoding Constructs #1-5 correspond to SEQ ID NOs 4660-4664, respectively. The terms "protein", "peptide" and "polypeptide" are used herein to describe any chain of amino acid residues, regardless of length or post-translational modification (for example, glycosylation or phosphorylation). Thus, these terms can be used interchangeably herein to refer to a polymer of amino acid residues. The terms also apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid. Thus, the term "polypeptide" includes full-length proteins, which may be, but need not be, naturally occurring, as well as recombinantly or synthetically produced 37 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 polypeptides that correspond to a full-length protein, or to particular domains or portions of a protein, which may be, but need not be, naturally occurring. The term also encompasses mature proteins which have an added amino-terminal methionine to facilitate expression in prokaryotic cells. The binding molecules of the aspects and embodiments described herein are encoded by polynucleotides and can be chemically synthesized or synthesized by recombinant DNA methods. In embodiments, a polypeptide or fragment thereof of the disclosure is any pbVHH polypeptide or variant thereof, or fragment thereof. By an "isolated polypeptide" is meant a polypeptide of the aspects and embodiments described herein that has been separated from components that naturally accompany it. Typically, the polypeptide is isolated when it is at least 60%, by weight, free from the proteins and naturally-occurring organic molecules with which it is naturally associated. In an embodiment, the preparation is at least 75%, at least 90%, or at least 99%, by weight, a polypeptide of the aspects and embodiments described herein. An isolated polypeptide of the aspects and embodiments described herein may be obtained, for example, by extraction from a natural source, by expression of a recombinant nucleic acid encoding such a polypeptide; or by chemically synthesizing the protein. Purity can be measured by any appropriate method, for example, column chromatography, polyacrylamide gel electrophoresis, or by HPLC analysis. As used herein, “obtaining” as in “obtaining an agent” includes synthesizing, purchasing, deriving, isolating, or otherwise acquiring the agent. By "operably linked" is meant the connection between regulatory elements and one or more polynucleotides (genes) or a coding region. That is, gene expression is typically placed under the control of certain regulatory elements, including constitutive or inducible promoters, tissue-specific regulatory elements, and enhancers. A polynucleotide (gene or genes) or coding region is said to be "operably linked to" or "operatively linked to" or "operably associated with" the regulatory elements, meaning that the polynucleotide (gene or genes) or coding region is controlled or influenced by the regulatory elements. The one or more polynucleotides may be separated by spacers or linkers. By “reduces” is meant a negative or lowering alteration of at least 5%, 10%, 15%, 10%, 25%, 50%, 75%, or 100%. By “programmed cell death protein 1” or “PD-1” is meant a polypeptide (protein) or fragment thereof having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% 38 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 sequence identity to the amino acid sequence of GenBank Accession No UMM61401.1 and having programmed death-ligand 1 (PD-L1) and / or programmed death-ligand 2 (PD-L2) binding activity. An exemplary PD-1 polypeptide sequence is provided below: >UMM61401.1 PD-1 [Homo sapiens] MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFV LNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISL APKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVIC SRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPCVPEQTEYATIVFPSG MGTSSPARRGSADGPRSAQPLRPEDGHCSWPL (SEQ ID NO: 4477) By “reference” is meant a standard or control condition typically used as a comparator in an assay, test, experiment, or trial, as would be understood by one having skill in the pertinent art. In various nonlimiting embodiments, a reference or control is a different polypeptide, such as a conventionally available antibody (e.g., which targets PD-1 and / or CTLA4), or a healthy subject or individual. A "reference sequence" is a defined sequence used as a basis for sequence comparison. A reference sequence may be a subset of or the entirety of a specified sequence; for example, a segment of a full-length cDNA or gene sequence, or the complete cDNA or gene sequence. For polypeptides, the length of the reference polypeptide sequence will generally be at least about 16 amino acids, at least about 20 amino acids, at least about 25 amino acids, about 35 amino acids, about 50 amino acids, or about 100 amino acids. For nucleic acids, the length of the reference nucleic acid sequence will generally be at least about 50 nucleotides, at least about 60 nucleotides, at least about 75 nucleotides, about 100 nucleotides or about 300 nucleotides or any integer thereabout or therebetween. In embodiments, the reference sequence is the sequence of any one of Constructs #1-5. In other embodiments, the reference sequence is the sequence of XFV-E7, XFU-D3, or XJD-A4. In other embodiments, the reference sequence is the sequence of any of XFV-E7, XFU-D3, or XJD-A4 CDR1, CDR2, and / or CDR3. In one embodiment, a reference sequence is the sequence of Construct #5 or an antigen binding fragment thereof. By "specifically binds" is meant a compound, molecule, antibody, or VHH that recognizes and binds a protein, peptide, or polypeptide (e.g., an amino acid sequence of the protein, peptide, or polypeptide), but which does not substantially recognize and bind other 39 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 molecules in a sample, for example, a biological sample, which may contain the protein, peptide, or polypeptide that is specifically bound. "Nucleic acid" (also called polynucleotide herein) refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form. The term encompasses nucleic acids (polynucleotides) containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as a reference nucleic acid, and which are metabolized in a manner similar to the reference nucleic acid. Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral methyl phosphonates, 2-O-methyl ribonucleotides, and peptide-nucleic acids (PNAs). Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (for example, degenerate codon substitutions) and complementary sequences, as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with suitable mixed base and / or deoxyinosine residues (Batzer et al., 1991, Nucleic Acid Res, 19:081; Ohtsuka et al., 1985, J. Biol. Chem., 260:2600-2608; Rossolini et al., 1994, Mol. Cell Probes, 8:91-98). The term nucleic acid can be used interchangeably with gene, cDNA, mRNA, oligonucleotide, and polynucleotide. Nucleic acid molecules or polynucleotides useful in the aspects and embodiments described herein include any nucleic acid molecule or polynucleotide that encodes a polypeptide, e.g., a heteromultimeric binding molecule, of the described aspects and embodiments, or a component or portion thereof. Nucleic acid molecules useful in the methods described herein include any polynucleotide or nucleic acid molecule that encodes a polypeptide e.g., heteromultimeric binding molecule, as described in the aspects and embodiments herein, or a component or portion thereof that has substantial identity to the binding molecule. Such nucleic acid molecules need not be 100% identical with the nucleic acid sequence of the binding molecule, but will typically exhibit substantial identity. Polynucleotides having “substantial identity” to a binding molecule sequence are typically capable of hybridizing with at least one strand of a double- stranded nucleic acid molecule. By "hybridize" is meant pair to form a double-stranded molecule between complementary polynucleotide sequences (e.g., a gene described herein), or 40 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 portions thereof, under various conditions of stringency. (See, e.g., Wahl, G. M. and S. L. Berger, 1987, Methods Enzymol.152:399; Kimmel, A. R., 1987, Methods Enzymol.152:507). For example, stringent salt concentration will ordinarily be less than about 750 mM NaCl and 75 mM trisodium citrate, preferably less than about 500 mM NaCl and 50 mM trisodium citrate, and more preferably less than about 250 mM NaCl and 25 mM trisodium citrate. Low stringency hybridization can be obtained in the absence of organic solvent, e.g., formamide, while high stringency hybridization can be obtained in the presence of at least about 35% formamide, and more preferably at least about 50% formamide. Stringent temperature conditions will ordinarily include temperatures of at least about 30°C, more preferably of at least about 37°C, and most preferably of at least about 42°C. Varying additional parameters, such as hybridization time, the concentration of detergent, e.g., sodium dodecyl sulfate (SDS), and the inclusion or exclusion of carrier DNA, are well known to those skilled in the art. Various levels of stringency are accomplished by combining these various conditions as needed. In an embodiment, hybridization will occur at 30° C in 750 mM NaCl, 75 mM trisodium citrate, and 1% SDS. In an embodiment, hybridization will occur at 37°C in 500 mM NaCl, 50 mM trisodium citrate, 1% SDS, 35% formamide, and 100 g / ml denatured salmon sperm DNA (ssDNA). In an embodiment, hybridization will occur at 42°C in 250 mM NaCl, 25 mM trisodium citrate, 1% SDS, 50% formamide, and 200 g / ml ssDNA. Useful variations on these conditions will be readily apparent to those skilled in the art. For most applications, washing steps that follow hybridization will also vary in stringency. Wash stringency conditions can be defined by salt concentration and by temperature. As above, wash stringency can be increased by decreasing salt concentration or by increasing temperature. For example, stringent salt concentration for the wash steps will preferably be less than about 30 mM NaCl and 3 mM trisodium citrate, and most preferably less than about 15 mM NaCl and 1.5 mM trisodium citrate. Stringent temperature conditions for the wash steps will ordinarily include a temperature of at least about 25°C, more preferably of at least about 42°C, and even more preferably of at least about 68°C. In an embodiment, wash steps will occur at 25°C in 30 mM NaCl, 3 mM trisodium citrate, and 0.1% SDS. In an embodiment, wash steps will occur at 42°C in 15 mM NaCl, 1.5 mM trisodium citrate, and 0.1% SDS. In an embodiment, wash steps will occur at 68° C in 15 mM NaCl, 1.5 mM trisodium citrate, and 0.1% SDS. Additional variations on these conditions will be readily apparent to those skilled in the 41 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 art. Hybridization techniques are well known to those skilled in the art and are described, for example, in Benton and Davis (Science 196:180, 1977); Grunstein and Hogness (Proc. Natl. Acad. Sci., USA 72:3961, 1975); Ausubel et al. (Current Protocols in Molecular Biology, Wiley Interscience, New York, 2001); Berger and Kimmel (Guide to Molecular Cloning Techniques, 1987, Academic Press, New York); and Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, New York. "Percentage of sequence identity" means the value determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide sequence in the comparison window may comprise additions, substitutions, or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions, substitutions, or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity. The term "substantial identity" or "homologous" in their various grammatical forms in the context of polynucleotides means that a polynucleotide comprises a sequence that has a desired identity, for example, at least 60% identity, at least 70% sequence identity, at least 80%, at least 85% identity, at least 90% identity; and at least 95%, compared to a reference sequence using one of the alignment programs described using standard parameters. One of skill will recognize that these values can be appropriately adjusted to determine corresponding identity of proteins encoded by two nucleotide sequences by taking into account codon degeneracy, amino acid similarity, reading frame positioning and the like. Substantial identity of amino acid sequences, for example, the anti-PD-1 and / or anti- CTLA4 polypeptides (PD-1 and / or CTLA4-binding VHH polypeptides) refers to sequence identity between or among amino acid sequences of at least 80%, at least 85%, at least 88%, at least 90%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater, sequence identity, as well as percentages therebetween. In some embodiments, the percent sequence identity refers to the identity between a reference CDR1, CDR2, and / or CDR3 and a variant CDR1, CDR2, and / or CDR3. In embodiments, 100% identity between or among the amino acid sequences of the anti-PD-1 and / or CTLA4 binding VHHs as described herein is 42 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 not required for binding of these polypeptides to the PD-1 and / or CTLA4 or neutralization of PD-1 and / or CTLA4. In a particular embodiment, variations between or among VHH amino acid sequences encompass one or more conservative amino acid substitutions in the sequence. In an embodiment, one or more conservative amino acid substitutions may be in one or more CDR sequences, one or more FR sequences, or a combination thereof. As will be appreciated by the skilled practitioner in the art, some amino acids in a VHH antibody can be modified without significantly altering antigen binding of the VHH antibody. For example, such amino acid sequence modification occurs frequently during in vivo affinity maturation of VHH antibodies, and the best mutations, e.g., for specific and / or high affinity binding to antigen, are positively selected for in the animal during the molecular production of antibodies. It is possible to isolate different VHH intermediates in the affinity maturation process that possess acceptable and specific antigen binding properties and that have significant variations in their CDR sequences. In an embodiment, an anti-PD-1 VHH polypeptide and / or an anti-CTLA4 VHH polypeptide comprises the CDRs of the respective VHH polypeptides set forth in Tables 1 and 2 herein, or depicted in FIG.1 or FIG.2, and / or having at least 85%, at least 88%, at least 90%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater, sequence identity to the sequences of the VHH polypeptides provided in Tables 1 or 2, or depicted in FIG. 1 or FIG.2, as well as percentages therebetween. In other embodiments, an anti-PD-1 VHH polypeptide and / or an anti-CTLA4 VHH polypeptide comprises an amino acid sequence having at least 85%, at least 88%, at least 90%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater, sequence identity (including percentages therebetween), identity to the sequences of the VHH polypeptides depicted in FIG.1 or FIG. 2. Sequence identity is typically measured using sequence analysis software (for example, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis.53705, BLAST, BESTFIT, GAP, or PILEUP / PRETTYBOX programs). Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, deletions, and / or other modifications. Conservative substitutions typically include substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid, asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine. In an exemplary 43 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 approach to determining the degree of identity, a BLAST program may be used, with a probability score between e-3and e-100indicating a closely related sequence. By "subject" is meant a mammal, including, but not limited to, a human or non-human mammal, such as, without limitation, a human or a non-human primate, or a bovine, equine, canine, ovine, or feline mammal. Other mammals include rabbits, goats, llamas, alpacas, mice, rats, guinea pigs, camels, and gerbils. In particular, a “subject” as used herein refers to a human subject, such as a human patient or individual. In some cases, the terms subject, patient and individual are used interchangeably herein. A “VHH binding molecule” or “VHH antibody,” or simply “VHH,” as referred to herein is, in general, a single domain immunoglobulin molecule (antibody) isolated from camelid animals or alpacas, e.g., as described in Maass, D.R., 2007, J. Immunol. Methods, 324(1-2):13- 15) or an antigen binding fragment thereof. As used herein, the terms “treat,” treating,” “treatment,” and the like refer to reducing, diminishing, abating, alleviating, improving, or ameliorating a disorder and / or symptoms associated therewith. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated. The term “multimeric VHH” refers in general to a multi-component protein or polypeptide containing two (e.g., dimeric) or more (e.g., trimeric, tetrameric, pentameric, hexameric, and the like), same or different, VHH binding molecules or antigen binding fragments thereof, which are coupled, joined, or linked, e.g., via linkers or spacer sequences, to each other and / or other components of the molecule. Multimeric VHHs may be dimeric, in that the binding molecule contains two VHH polypeptides that bind to PD-1 and / or CTLA4. The anti-PD-1 and / or CTLA4 VHH polypeptides in a dimeric multimer may be the same or they may be different VHH polypeptides. A dimeric VHH may include two anti-PD-1 VHH polypeptides that are the same or different. A dimeric VHH may include two anti-CTLA4 VHH polypeptides that are the same or different. A dimeric VHH may include one anti-PD-1 VHH polypeptide and one anti-CTLA4 VHH polypeptide. The different anti-PD-1 or anti-CTLA4 VHH polypeptides in a multimeric VHH may bind to different regions, portions, or epitopes (e.g., non-overlapping epitopes) of PD-1 or CTLA4. In an embodiment, the binding of the different anti-PD-1 or anti- CTLA4 VHH polypeptides in a multimeric VHH is not competitive (e.g., each different anti-PD- 44 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 1 or anti-CTLA4 VHH polypeptide in a multimer does not and / or is not expected to reduce the binding efficiency of another anti-PD-1 or anti-CTLA4 VHH polypeptide in a multimer). Alternatively, the multimeric VHHs may be heteromultimeric, in that the multimeric VHH contains more than one or two, e.g., three (trimeric), four (tetrameric), five (pentameric), six (hexameric), etc., same or different, anti-PD-1 and / or anti-CTLA4 VHH polypeptides, and / or other VHH polypeptides (e.g., anti-albumin or anti-human albumin VHHs), such as described herein. In an embodiment, the anti-human albumin binding VHH, JPMB2, QVQLVESGGGLVQPGGSLRLSCAASGLTSDNYVIGWFRQAPGKEREGVSCISSRDGSTY YPPSVKGRFTISRDNAKNTVYLEMASLKPEDTAVYYCAAQQVWAVCVLQAFEYDYWG QGTQVTVSS (SEQ ID NO: 4656). From left to right in the JPMB2 amino acid sequence, CDR1, CDR2, and CDR3, respectively, are underlined. In some embodiments, a heteromultimeric VHH contains two, three, four or more of the same or different anti-PD-1 and / or anti-CTLA4 VHH polypeptides, each of which specifically binds to a PD-1 or CTLA4, e.g., at the same or different or non-overlapping epitopes and / or non- competitively. In some embodiments, a heteromultimeric VHH is a pentamer, including two of the same or different anti-PD-1 VHH polypeptides, two of the same or different anti-CTLA4 polypeptides, and an anti-human albumin polypeptide. Such a heteromultimeric, pentameric VHH polypeptide may be bispecific, as the component VHHs which comprise the VHH polypeptide bind to two different antigens, i.e., PD-1 (human PD-1) and CTLA4 (human CTLA4). As such, a bispecific VHH is able to target two different antigens (e.g., PD-1 and CTLA4) simultaneously. Without being bound by theory, bispecific VHHs are capable of bridging between two different immune cells or molecules, thereby activating, modulating, or enhancing immune responses, In some embodiments, multimeric VHHs of the present disclosure bind more efficiently (e.g., bind more tightly, with more specificity, and / or with a higher binding affinity) and / or have enhanced neutralization potency (e.g., have a percentage of neutralization of PD-1 and / or CTLA4 at a lower concentration) when compared to conventionally available anti-PD-1 and / or anti-CTLA4 antibodies (e.g., nivolumab, pembrolizumab, cemiplimab, ipilimumab, tremelimumab, etc.). In some embodiments, multimeric VHHs of the present disclosure have fewer adverse events when administered to a subject when compared to conventionally available anti-PD-1 and / or anti-CTLA4 antibodies (e.g., nivolumab, pembrolizumab, cemiplimab, ipilimumab, tremelimumab, etc.). In 45 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 embodiments, dimeric multimers and heteromultimeric VHHs comprising two or more anti-PD-1 and / or CTLA4 VHHs bind to and neutralize the activity of the PD-1 and / or the CTLA4 protein. As used herein, the terms “prevent,” “preventing,” “prevention,” “prophylactic treatment,” “protection” and the like refer to reducing the probability of developing a disorder or condition in a subject, who does not have, but who is at risk of, is susceptible to, or disposed to (e.g., genetically disposed to), developing a disease, disorder, pathology, or condition. Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, inclusive of the first and last values. The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. Any compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein. Although various features of the present disclosure can be described in the context of a single embodiment, the features can also be provided in separate embodiments, or in any suitable combination or combination of embodiments. The section headings used herein are for organizational purposes only and are not intended to be limiting to the subject matter described. The features of the present disclosure are set forth with particularity in the appended claims. The features and advantages of the present disclosure will be better understood and obtained by reference to the detailed description infra, which sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and in view of the accompanying drawings as described herein. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 provides a sequence alignment of selected human PD-1 binding VHH families. FIG.1 provides a sequence alignment showing amino acid variations for selected families of human PD-1 binding VHHs. Each VHH family was selected for ability to bind human PD-1. Each VHH family is related based on CDR3 homology (e.g., XFU-D3 and XFU-B3 are in the 46 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 same VHH family). Amino acid variations that did not negate VHH binding to PD-1 within VHH families are underlined. An asterisk indicates a VHH sequence demonstrated to possess hPD-1 neutralizing activity in a cell-based assay. The sequences listed in FIG.1 correspond, in order of occurrence, to SEQ ID NOs: 4478 to 4492, respectively. FIG.2 provides a sequence alignment of selected human CTLA4 binding VHH families. FIG.2 provides a sequence alignment showing amino acid variations for selected families of human CTLA4 binding VHHs. Each VHH family was selected for ability to bind human CTLA4. Each VHH family is related based on CDR3 homology (e.g., XJD-A4, XJD-B6, XJD- C5, XJD-E10, XKV-A12, XKV-F8, XKV-G3 are in the same VHH family). Amino acid variations that did not negate VHH binding to CTLA4 within VHH families are underlined. An asterisk indicates a VHH sequence demonstrated to possess hPD-1 neutralizing activity in a cell- based assay. The sequences listed in FIG. 2 correspond, in order of occurrence, to SEQ ID NOs: 4493 to 4512, respectively. FIG.3 is a graph showing that anti-PD-1 VHH polypeptides exhibit high binding efficiency. FIG.3 provides a graph showing that anti-PD-1 VHH polypeptides (nanobodies) had high binding efficiency / potency to human PD-1. Binding to human PD-1 receptor was measured using A450 absorbance, and was compared to log [M] concentration of each anti-PD-1 VHH polypeptide. FIG.4 is a graph showing that anti-CTLA4 VHH polypeptides exhibit high binding efficiency. FIG.4 provides a graph showing that anti-CTLA4 VHH polypeptides (nanobodies) had high binding efficiency / potency to human CTLA4. Binding to human CTLA4 receptor was measured using A450 absorbance, and was compared to log [M] concentration of each anti- CTLA4 VHH polypeptide. FIG.5 is a graph showing that anti-CTLA4 VHH polypeptide exhibits enhanced neutralization potency, as compared to conventionally available anti-CTLA4 antibodies. FIG. 5 provides a graph showing that a selected anti-CTLA4 VHH polypeptide exhibited significantly enhanced neutralization potency when compared to ipilimumab. Percentage neutralization of CTLA4 was compared to log [M] concentration of a selected anti-CTLA4 VHH polypeptide and ipilimumab. FIG.6 is a graph showing that anti-PD-1 VHH polypeptide exhibits enhanced neutralization potency, as compared to conventionally available anti-PD-1 antibodies. FIG.6 47 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 provides a graph showing that a selected anti-PD-1 VHH polypeptide exhibited significantly enhanced neutralization potency when compared to nivolumab. Percentage neutralization of PD- 1 was compared to log [M] concentration of a selected anti-PD-1 VHH polypeptide and nivolumab. FIG.7 provides the configuration and amino acid sequence of pentavalent VHH construct #1, which comprises a signal peptide (MGWSWILLFLLSVTAGVHS (SEQ ID NO: 4655)), an XFV-E7 VHH which binds to CTLA-4 (amino acid sequence designated by double underlining in the figure), a 5 glycine linker, an XJD-A4 VHH which binds to CTLA-4 (amino acid sequence designated by dotted underlining in the figure), a 5 glycine linker, an XFU-D3 VHH which binds to PD-1 (amino acid sequence designated by dashed underlining in the figure), a 5 glycine linker, a second XFU-D3 VHH which binds to PD-1 (amino acid sequence designated by short dashed underlining in the figure), a 5 glycine linker, a JPMB2 VHH which binds to human and cynomolgus monkey serum albumin (HSA), (amino acid sequence designated by solid underlining in the figure), a Tobacco Etch virus protease (TEV) cut / cleavage sequence, and a 6 histidine tag (His tag). In the construct, the signal peptide sequence is optional. The amino acid sequence of the JPMB2 VHH, underlined in the construct, is as follows: QVQLVESGGGLVQPGGSLRLSCAASGLTSDNYVIGWFRQAPGKEREGVSCISSRDGSTY YPPSVKGRFTISRDNAKNTVYLEMASLKPEDTAVYYCAAQQVWAVCVLQAFEYDYWG QGTQVTVSS (SEQ ID NO: 4656). CDR1, CDR2, and CDR3 (SEQ ID NOs: 4657-4659) of the JPMB2 VHH sequence are underlined in the JPMB2 sequence, from left to right, respectively. FIG.8 provides the configuration and amino acid sequence of pentavalent VHH construct #2, which comprises a signal peptide (MGWSWILLFLLSVTAGVHS (SEQ ID NO: 4655)), an XFV-E7 VHH which binds to CTLA-4 (amino acid sequence designated by double underlining in the figure), a 5 glycine linker, an XFU-D3 VHH which binds to PD-1 (amino acid sequence designated by dashed underlining in the figure), a 5 glycine linker, a second XFU-D3 VHH which binds to PD-1 (amino acid sequence designated by dashed underlining in the figure), a 5 glycine linker, an XJD-A4 VHH which binds to CTLA-4 (amino acid sequence designated by dotted underlining in the figure), a 5 glycine linker, a JPMB2 VHH which binds to human and cynomolgus monkey serum albumin (HSA), (amino acid sequence designated by solid underlining in the figure), a TEV cut / cleavage sequence, and a 6 histidine tag (His tag). In the construct, the signal peptide sequence is optional. The amino acid sequence and CDR1-3 of the 48 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 JPMB2 VHH are as described above for FIG.7. FIG.9 provides the configuration and amino acid sequence of pentavalent VHH construct #3, which comprises a signal peptide (MGWSWILLFLLSVTAGVHS (SEQ ID NO: 4655)), a JPMB2 VHH which binds to human serum albumin (HSA) as well as and cynomolgus monkey serum albumin (amino acid sequence as described above and designated by solid underlining in the figure), a 5 glycine linker, an XFU-D3 VHH which binds to PD-1 (amino acid sequence designated by dashed underlining in the figure), a 5 glycine linker, a second XFU-D3 VHH which binds to PD-1 (amino acid sequence designated by dashed underlining in the figure), a 5 glycine linker, an XFV-E7 VHH which binds to CTLA-4 (amino acid sequence designated by dark underlining in the figure), a 5 glycine linker, an XJD-A4 VHH which binds to CTLA-4 (amino acid sequence designated by dotted underlining in the figure), a TEV cut / cleavage sequence, and a 6 histidine tag (His tag). In the construct, the signal peptide sequence is optional. FIG.10 provides the configuration and amino acid sequence of pentavalent VHH construct #4, which comprises a signal peptide (MGWSWILLFLLSVTAGVHS (SEQ ID NO: 4655)), an XFV-E7 VHH which binds to CTLA-4 (amino acid sequence designated by double underlining in the figure), a 5 glycine linker, an XFU-D3 VHH which binds to PD-1 (amino acid sequence designated by dashed underlining in the figure), a 5 glycine linker, an XJD-A4 VHH which binds to CTLA-4 (amino acid sequence designated by dotted underlining in the figure), a 5 glycine linker, a second XFU-D3 VHH which binds to PD-1 (amino acid sequence designated by dashed underlining in the figure), a 5 glycine linker, a JPMB2 VHH which binds to human and cynomolgus monkey serum albumin (HSA), (sequence as described above and designated by underlining in the figure), a TEV cut / cleavage sequence, and a 6 histidine tag (His tag). In the construct, the signal peptide sequence is optional. FIG.11 provides the configuration and amino acid sequence of pentavalent VHH construct #5, which comprises a signal peptide (MGWSWILLFLLSVTAGVHS (SEQ ID NO: 4655)), an XFU-D3 VHH which binds to PD-1 (amino acid sequence designated by dashed underlining in the figure), a 5 glycine linker, a second XFU-D3 VHH which binds to PD-1 (amino acid sequence designated by dashed underlining in the figure), a 5 glycine linker, an XFV-E7 VHH which binds to CTLA-4 (amino acid sequence designated by solid underlining in the figure), a 5 glycine linker, an XJD-A4 VHH which binds to CTLA-4 (amino acid sequence 49 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 designated by dotted underlining in the figure), a 5 glycine linker, a JPMB2 VHH which binds to human and cynomolgus monkey serum albumin (HSA), (amino acid sequence as described above and underlined in the figure), a TEV cut / cleavage sequence, and a 6 histidine tag (His tag). In the construct, the signal peptide sequence is optional. Pentavalent construct #5 was characterized in the Figures described below. FIG.12 is a schematic showing an exemplary pentavalent VHH comprising a VHH or antigen binding fragment thereof, which binds to human serum albumin (HSA) and is linked to two VHHs or antigen binding fragments thereof, each of which binds to a PD-1 polypeptide, where the VHH’s binding to the PD-1 polypeptide may be the same or different, linked to two VHHs each of which binds to a CTLA-4 polypeptide, where the VHH’s binding to the CTLA-4 polypeptide may be the same or different. FIG.13 is a table showing the binding affinity of a pentavalent VHH Construct #5 with respect to the PD-1 receptor and the CTLA-4 receptor in vitro. As comparisons, the binding affinity of the antibodies Nivolumab, which binds to PD-1, and Ipilimumab, which binds to CTLA-4, are also shown. FIG.14 is a Western blot showing the level of production of the protein corresponding to tin lanes R and N of the blotted gel under reducing and non-reducing conditions. FIG.15 is a plot of the size-exclusion high performance liquid chromatography (SEC- HPLC) results from a pbVHH sample corresponding to Construct #5. FIG.16 is a plot of the percent survival of mice with vehicle, pbVHH corresponding to Construct #5, or combined Pembrolizumab and Ipilimumab treatment over time. FIG.17 shows histological samples indicating the levels of lymphocytic infiltration in various tissues of mice treated with vehicle, pbVHH corresponding to Construct #5 at 4X or 12X the amount of Pembrolizumab dosage, or the combination of Pembrolizumab and Ipilimumab. FIG.18 shows photos of mice indicating the level of paw inflammation in mice treated with vehicle, pbVHH corresponding to Construct #5 at 4X or 12X the amount of Pembrolizumab dosage, or the combination of Pembrolizumab and Ipilimumab. FIGs.19A and 19B show the absolute arthritis score and combined arthritis and colitis scores in mice treated with vehicle, pbVHH corresponding to Construct #5 at 4X or 12X the amount of Pembrolizumab dosage, or the combination of Pembrolizumab and Ipilimumab. FIG. 19A is a bar graph of the absolute arthritis score. FIG.19B is a bar graph of the combined 50 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 clinical summary score, which combines the arthritis and colitis scores of each treatment group. FIGs.20A-20C show the levels of inflammation markers creatine kinase (CK), alanine aminotransferase (ALT), and lactate dehydrogenase in mice treated with vehicle, pbVHH corresponding to Construct #5 at 4X or 12X the amount of Pembrolizumab dosage, or the combination of Pembrolizumab and Ipilimumab. FIG.20A is a bar graph showing the level of creatine kinase (CK). FIG.20B is a bar graph showing the level of alanine aminotransferase (ALT). FIG. 20C is a bar graph showing the level of lactate dehydrogenase (LDH). FIG.21 is a graph showing the effect on mouse tumor volume using MC38 (Colorectal) HuCells with different concentrations of pbVHH corresponding to Construct #5 (5 mg / kg, 1 mg / kg, 0.5 mg / kg, and 0.1 mg / kg), vehicle, or the combination of Pembrolizumab (2 mg / kg) and Ipilimumab (5 mg / kg). FIG.22 is a graph showing the effect on tumor volume in mice re-challenged with MC38 HuCells at day 20 after treatment with Construct #5 curing of the original tumor, relative to vehicle. FIG.23 is a graph showing the serum concentration over time of cynomolgus monkeys after subcutaneous injections of 1 mg / kg Construct #5 administered weekly. FIGs.24A and 24B present schematic illustrations of the CTLA-4 / PD-1 combination neutralization assay, the data for which are shown in FIGs.25 and 26. This represents a reporter base readout. When ligand binds receptor, there is no fluor. When there is neutralization antibody present, the PD1 / PDL1 binding is disrupted. Luc: luciferase. FIG.25 is a graph and summary of the PD-1 / CTLA-4 neutralization concentration of pbVHH corresponding to Construct #5, the AK104 Fc molecule (aka Cadonilimab), the antibody Nivolumab, and the antibody Ipilimumab. FIG.26 is a graph and summary of the PD-1 / CTLA-4 neutralization concentration of all Constructs (#1-#5), the AK104 Fc molecule, the antibody Nivolumab, and the antibody Ipilimumab. FIG.27 is a chart summarizing the Construct #5, AK104 (Cadonilimab), and Volrustomig CTLA-4 and PD-1 binding affinities, reported recommended dosing, and reported recommend administration methods. FIGs.28A-28C show the consensus sequences for the XFV-E7, XFU-D3, and XJD-A4 VHH family members as identified from the phage library. The consensus sequence was 51 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 determined by sequencing each of the individual VHH variants provided in the sequence listing. The sequence of these variants is provided in the attached sequence listing. Each of these VHH variants was selected for specific binding to its cognate immunogen. The consensus sequence is shown on the first line is the amino acid sequence most commonly represented in each clonal family. Above the VHH consensus sequences are shown the amino acid variations that were identified among the sequences in the indicated clonal family. The three CDR sequences for each VHH and their variabilities are also indicated in the Figure. FIG.2A shows the consensus and variability of sequences of the XFV-E7 VHH family, which bind to CTLA-4. FIG. 28B shows the consensus and variability of sequences of the XFU-D3 VHH family, which bind to PD-1. FIG.28C shows the consensus and variability of sequences of the XJD-A4 VHH family, which bind to CTLA-4. The amino acid sequences of XFU-D3 clonal family members are presented in SEQ ID NOs: 1-413. The amino acid sequences of XFV-E7 clonal family members are presented in SEQ ID NOs: 414-501. The amino acid sequences of XJD-A4 clonal family members are presented in SEQ ID NOs: 502-4470. The polynucleotide sequences encoding Constructs #1-5 are provided in the sequence listing. DETAILED DESCRIPTION OF THE INVENTION The disclosure features single-domain variable heavy-chain (VHH) polypeptides and multimeric VHHs (e.g., pentameric), and antigen binding fragments thereof, that specifically bind and / or neutralize PD-1 and / or CTLA4. The disclosure also provides methods for the use of such VHH polypeptides and multimeric VHHs, particularly in the treatment of cancer (e.g., lung cancer, such as NSCLC, colorectal cancer, renal carcinoma, breast cancer, such as triple negative breast cancer, bladder cancer, heptatocellular carcinoma), or symptoms thereof, in a subject in need thereof. The invention is based, at least in part, on the discovery of VHH polypeptides and multimeric (e.g., pentameric) VHHs, and antigen binding fragments of VHH polypeptides, that bind PD-1 and / or CTLA4. Early mouse preclinical studies described herein below of a pentavalent, bispecific PD-1 / CTLA4 VHH antibody fragment (pbVHH) demonstrated superior safety over the current standards of care. Surprisingly, pbVHH fully eradicated tumors by Day 15 in a murine model of colorectal cancer, with sustained efficacy after tumor rechallenge in cured mice without further treatment. Moreover, pharmacokinetic studies in cynomolgus 52 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 monkeys showed that the pbVHH’s described herein were well tolerated. Accordingly, this disclosure provides compositions comprising specific PD-1 / CTLA4 VHH antibody fragments (pbVHH), as well as monovalent, multimeric (e.g., dimeric, trimeric, tetrameric, pentameric, etc.), bispecific, and antigen binding fragments of any of the aforementioned, as well as methods of using such compositions for the treatment of neoplasias, tumors, or cancers, (e.g., lung cancer, such as NSCLC, colorectal cancer, renal carcinoma, breast cancer, such as triple negative breast cancer, bladder cancer, heptatocellular carcinoma) or tumors that are conventionally treated with checkpoint inhibitors (e.g., ipilimumab, pembrolizumab). Multimeric VHHs Multimeric forms of the VHH polypeptides comprise component anti-PD-1 VHHs and anti-CTLA4 VHHs, such as those described herein. The VHH multimeric forms constitute heteromultimeric binding molecules, which may be alternatively known as fusion proteins. The VHH components of the multimeric VHH are consecutively linked, coupled, or joined together, for example, via flexible linkers, either the same or different, in the multimeric binding molecule. In a nonlimiting embodiment, the linker is a polyglycine, such as GGn, wherein n = 3-12. In an embodiment, the polyglycine linker may contain a serine (S) residue therein. In an embodiment, the linker is GGGGG (5 glycines), (SEQ ID NO: 4654). In an embodiment, the linker sequence may be one as shown in Table 3 or in the Figures described herein. In an embodiment, the heteromultimeric VHHs comprise at least one anti-PD-1 VHH and at least one anti-CTLA4 VHH, in different orientations. In an embodiment, the heteromultimeric VHHs comprise at least two anti-PD-1 VHHs and at least two anti-CTLA4 VHHs, in different orientations. In an embodiment, the anti-PD-1 VHH can constitute an amino acid sequence as set forth in Table 1, such as, for example, XFU-D3, a XFU-D3 VHHs; or a XFU-D3 clonal family amino acid sequence as described herein and shown in FIG.28B; or CDRs 1-3 of these VHHs. In an embodiment, the anti-CTLA4 VHH can constitute an amino acid sequence as set forth in Table 2, such as for example, XFV-E7 or XJD-A4; or a XFV-E7 or XJD-A4 clonal family amino acid sequence as described herein and shown in FIG. 28A and FIG. 28C, respectively; or CDRs 1-3 of these VHHs. In a nonlimiting embodiment, the anti-CTLA4 VHHs include XFV-E7 and / or XJD-A4 as described herein. In a nonlimiting embodiment, the anti-PD-1 VHHs include XFU- D3 as described herein. 53 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 In an embodiment, the VHH heteromultimer is a pentameric VHH polypeptide containing five VHH components, namely, one or more than one anti-PD-1 VHH, one or more than one anti-CTLA4 VHH, and a VHH that binds serum albumin, human serum albumin, or non-human primate serum albumin, e.g., cynomolgus (“cyno”) serum albumin. In an embodiment the more than one anti-PD-1 VHH in the multimeric form may be the same or different anti-PD-1 VHH. In an embodiment the more than one anti-CTLA4 VHH in the multimeric form may be the same or different anti-CTLA4 VHH. In embodiments, the pentameric VHH polypeptide contains combinations of anti-CTLA4 VHH and anti-PD-1 VHH polypeptides as described herein and below as different components of the pentameric heteromultimer. In an embodiment, the albumin binding VHH is an anti-human and / or an anti-cyno albumin binding VHH. In an embodiment, the anti-albumin binding VHH is JPMB2 (SEQ ID NO: 4656). In an embodiment, the anti-PD-1 VHH and anti-CTLA4 VHH multimeric polypeptide optionally contains a signal peptide at the amino terminus of the multimer. In an embodiment, the VHH multimeric polypeptide optionally contains a protease cleavage sequence, such as a Tobacco Etch Virus (TEV) protease cleavage consensus sequence and / or an epitope or affinity tag, e.g., a His tag, at the carboxy terminus. The TEV sequence (e.g., ENLYFQG / S), as known in the art, is recognized by TEV protease, which specifically cleaves the TEV sequence (between the Q and G / S amino acid positions) and removes the affinity or epitope tag from the VHH multimer. Examples of pentameric VHH polypeptides and their component VHHs as described herein are shown in FIGs.7-11 and are presented below: Pentameric VHH Polypeptide 1 (Construct #1; FIG.7): [Signal peptide (optional)] – [CTLA4-binding VHH] – [CTLA4-binding VHH] – [PD-1-binding VHH] – [PD-1-binding VHH] – [albumin or human albumin-binding VHH] – [other modifications, e.g., TEV sequence; affinity (His) tag (optional)] Pentameric VHH Polypeptide 2 (Construct #2; FIG.8): [Signal peptide (optional)] – [CTLA4-binding VHH] – [PD-1-binding VHH] – [PD-1-binding VHH] – [CTLA4-binding VHH] –[albumin or human albumin-binding VHH[ – [other modifications, e.g., TEV sequence; affinity (His) tag (optional)] 54 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 Pentameric VHH Polypeptide 3 (Construct #3; FIG.9): [Signal peptide (optional)] – [albumin or human albumin-binding VHH] –[PD-1-binding VHH] – [PD-1-binding VHH] – [CTLA4-binding VHH ]—[CTLA4-binding VHH] – [other modifications, e.g., TEV sequence; affinity (His) tag (optional)] Pentameric VHH Polypeptide 4 (Construct #4; FIG.10): [Signal peptide (optional)] -- [CTLA4-binding VHH] – [PD-1-binding VHH] – [CTLA4-binding VHH] – [PD-1-binding VHH] – [albumin or human albumin-binding VHH] – [other modifications, e.g., TEV sequence; affinity (His) tag (optional)] Pentameric VHH Polypeptide 5 (Construct #5; FIG.11): [Signal peptide (optional)] –-- [PD-1-binding VHH] – [PD-1-binding VHH] – [CTLA4-binding VHH] – [CTLA4-binding VHH] – [albumin or human albumin-binding VHH] – [other modifications, e.g., TEV sequence or affinity (His) tag (optional)] In an embodiment, the pentameric VHH polypeptide contains the following components as described herein, from amino terminus to carboxy terminus: [Signal peptide (optional)] – [XFV-E7 VHH] – [XJD-A4 VHH] – [XFU-D3 VHH] – [XFU-D3 VHH] – [human albumin- binding VHH] – [other modifications, e.g., TEV sequence; affinity (His) tag (optional)]. In another embodiment, the pentameric VHH polypeptide contains the following components as described herein, from amino terminus to carboxy terminus: [Signal peptide (optional)] – [XFV- E7 VHH] – [XFU-D3 VHH] – [XFU-D3 VHH] – [XJD-A4 VHH] –[human albumin-binding VHH[ – [other modifications, e.g., TEV sequence; affinity (His) tag (optional)]. In another embodiment, the pentameric VHH polypeptide contains the following components as described herein, from amino terminus to carboxy terminus: [Signal peptide (optional)] – [human albumin- binding VHH] – [XFU-D3 VHH] – [XFU-D3 VHH] – [XFV-E7 VHH ] -- [XJD-A4 VHH] – [other modifications, e.g., TEV sequence; affinity (His) tag (optional)]. In another embodiment, the pentameric VHH polypeptide contains the following components as described herein, from amino terminus to carboxy terminus: [Signal peptide (optional)] -- [XFV-E7 VHH] – [XFU-D3 VHH] – [XJD-A4 VHH] – [XFU-D3 VHH] – [albumin or human albumin-binding VHH] – [other modifications, e.g., TEV sequence; affinity (His) tag (optional)]. In a particular 55 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 embodiment, the pentameric VHH polypeptide contains the following components as described herein, from amino terminus to carboxy terminus: [Signal peptide (optional)] – [XFU-D3 VHH] -- [XFU-D3 VHH] – [XFV-E7 VHH] – [XJD-A4 VHH] – [albumin or human albumin-binding VHH] – [other modifications, e.g., protease cleavage (e.g., TEV) sequence; affinity tag (e.g., His tag) (optional)]. The components of the pentameric VHH polypeptide are coupled, linked, or joined together by a linker as described herein. In an embodiment, the linker is GGn, wherein n = 3-12. In an embodiment, the linker is GGGGG (SEQ ID NO: 4654). In an embodiment, the linker is a chemical moiety. In particular, and without being bound by theory, multimeric VHHs of the present disclosure may bind PD-1 and / or CTLA4 more efficiently (e.g., bind more tightly, with more specificity, and / or with a higher binding affinity) and / or have enhanced neutralization potency (e.g., have a percentage of neutralization of PD-1 and / or CTLA4 at a lower concentration) when compared to conventionally available anti-PD-1 and / or anti-CTLA4 antibodies (e.g., atezolizumab, avelumab, durvalumab, ipilimumab, tremelimumab, etc.). VHH polypeptides and / or multimeric VHHs of the present disclosure may also have an improved safety profile in a subject (e.g., fewer and / or a lower chance of adverse events, such as immune-related adverse events, less tissue damage, less targeting of healthy tissue, less targeting of T regulatory cells). Described herein are VHH polypeptides and multimeric VHHs developed to target PD-1 and / or CTLA4. Such VHHs are advantageously useful in treating any disease in which PD-1 and / or CTLA4 binding and / or neutralization is useful, for example as anti-cancer agents. The new VHHs and their characterization reported herein can contribute to the development of improved anti-cancer therapeutics having high potencies and broad specificities. Advantageously, the pbVHHs described herein have been found to have fewer adverse side effects (e.g., lower levels of inflammation, swelling, lymphocyte infiltration) than conventional checkpoint inhibitors. The VHH polypeptides and / or multimeric VHHs described herein can also be components of pharmaceutical compositions, including combination therapies, employed as anti-cancer and / or chemotherapy agents. The described VHH polypeptides and / or multimeric VHHs (e.g., pbVHH) provided herein are derived from the heavy-chain- only antibodies produced by camelid animals. The heavy chain variable regions of these antibodies, called VHHs or nanobodies, are small polypeptides of ~14 kDa that are tightly folded, stable, and highly amenable to recombinant 56 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 expression and engineering as multimers or as fusions to other vehicles. VHHs also have a preference for binding to conformational epitopes that often are functional sites on proteins such as enzyme active sites or receptor-binding sites. The anti-PD-1 VHH polypeptides and / or anti-CTLA4 VHH polypeptides and / or multimeric forms thereof (e.g., pbVHH) as described herein are provided as beneficial therapeutic agents (e.g., anti-cancer agents) that bind to and / or neutralize PD-1 and / CTLA4. In some embodiments, anti-PD-1 VHH polypeptides and / or anti-CTLA4 VHH polypeptides and / or multimeric forms thereof as described herein are effective in treating cancers (e.g., lung cancer, such as NSCLC, colorectal cancer, renal carcinoma, breast cancer, such as triple negative breast cancer, bladder cancer, heptatocellular carcinoma) by blocking and / or neutralizing the activities of PD-1 and / or CTLA4 (e.g., by preventing the immunomodulatory and / or immune regulatory functions of PD-1 and / or CTLA4). Based on clinical data from multiple studies, dual blockade of PD-1 and CTLA-4 checkpoint molecules using monoclonal antibodies has clearly shown enhanced clinical responses over monotherapies. However, in such studies, over half of the patients experience severe treatment-related adverse events. To improve upon these outcomes, researchers have investigated bispecific targeting strategies that can restore immune checkpoints focused at the tumor site. In two recent reports, Berezhnoy and Sumrow et al. (2020) and Dovedi et al. (2021) engineered dual PD-1- and CTLA-4-targeting molecules to enhance target binding while limiting toxicity. To achieve this goal, Dovedi et al. generated a bispecific PD-1 and CTLA-4 antibody (immunoglobulin) (MEDI5752, AstraZeneca) using a DuetMab backbone and mutated its IgG1 backbone to avoid antibody fragment crystallizable region (Fc) effector engagement in recipients. Berezhnoy and Sumrow et al. used the DART platform, to construct a tetravalent (2x anti-PD-1, 2x anti-CTLA-4) molecule (MDG019). This molecule was built on an IgG4 backbone, again to reduce Fc-mediated effector functions. In clinical studies, MEDI5752 (1500mg) in combination with chemotherapy (CTx) was compared with pembrolizumab in combination with CTx, as well as a single-arm cohort of MEDI5752 (750 mg) alone. The median duration of response (DoR) was more than double in the MEDI5752 arm compared with the pembrolizumab arm with 20.5 months in the MEDI5752 arm and 9.9 months in the pembrolizumab arm. Median progression-free survival (PFS) was also almost double with 15.1 months in the MEDI5752 arm vs only 8.9 months in the pembrolizumab 57 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 arm, while the median overall survival (OS) was yet not reached in the MEDI5752 arm while OS was 16.5 months in the pembrolizumab arm. These clinical data using molecules having mutated Fc regions clearly demonstrate that avoiding Fc effector function has no effect on the efficacy of such therapies. However, in terms of safety, around 70% of patients in the 1500 mg group discontinued the treatment, with the main reason being immune-related adverse events (iRAEs). Many companies have tried the mutation approach to the IgG 1 backbone to minimize T regulatory (Treg) cell suppressor function; however, most efforts have come up short. The nanobodies (e.g., VHH polypeptides and multimeric VHHs) of the present disclosure have no Fc domain and, therefore, cause no Treg suppression. As described in detail below, murine and primate administration has shown that VHH polypeptides and / or multimeric VHHs (e.g., pbVHH) of the present disclosure have a greatly improved safety profile as compared to conventionally available anti-PD-1 and / or CTLA4 antibodies, while maintaining robust clinical benefits. The amino acid sequences of representative anti-PD-1 VHH polypeptides (antibodies) described herein are set forth, for example, in Table 1, in the figures herein (e.g., FIGs.1, 2, 7- 11, 28, and in the attached Sequence Listing filed herewith). In an embodiment, an anti-PD-1 VHH polypeptide having at least 85%, at least 88%, at least 90%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater, (as well as percentages therebetween) amino acid sequence identity to one or more of the anti-PD-1 VHH polypeptides of Table 1, in the figures (e.g., FIGs. 1, 2, 7-11, 28, and in the attached Sequence Listing is encompassed. In an embodiment, an anti-PD-1 VHH polypeptide having a CDR1, a CDR2, and a CDR3 selected from the CDRs disclosed in the anti-PD-1 VHH polypeptides of Table 1, in the figures (e.g., FIGs.1, 2, 7-11, 28, and in the attached Sequence Listing is encompassed. In an embodiment, the anti-PD-1 VHH polypeptide is XFU-D3, or a polypeptide having at least 85%, at least 88%, at least 90%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater, sequence identity, (as well as percentages therebetween) amino acid sequence identity to the XFU-D3 amino acid sequence. Also encompassed are polynucleotides encoding the anti-PD-1 VHH polypeptides described herein. The amino acid sequences of representative anti-CTLA4 VHH polypeptides (antibodies) described herein are set forth, for example, in Table 2. In an embodiment, an anti-CTLA4 VHH polypeptide having at least 85%, at least 88%, at least 90%, at least 93%, at least 95%, at least 58 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 96%, at least 97%, at least 98%, at least 99% or greater, (as well as percentages therebetween) amino acid sequence identity to one or more of the anti-CTLA4 VHH polypeptides of Table 2 is encompassed. In an embodiment, an anti-CTLA4 VHH polypeptide having a CDR1, a CDR2, and a CDR3 selected from the CDRs disclosed in the anti-CTLA4 VHH polypeptides of Table 2 is encompassed. FIGS.28A, 28B, and 28C indicate the consensus sequences of VHH CDR1, CDR2, and CDR3, as well as exemplary variations that do not interfere with specific binding, and may increase binding affinity. In an embodiment, the anti-CTLA4 VHH polypeptide is XFV-E7 or XJD-A4, or a polypeptide or antigen binding fragment thereof having at least 85%, at least 88%, at least 90%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater, sequence identity, (as well as percentages therebetween) amino acid sequence identity to the XFV-E7 or XJD-A4 amino acid sequence. Also encompassed are polynucleotides encoding the anti-CTLA4 VHH polypeptides described herein. In an embodiment, the disclosure provides a PD-1 / CTLA4 VHH antibody fragments (pbVHH) having the sequence of any one of Constructs 1, 2, 3, 4, or 5; of XFV-E7, XFU-D3, or XJD-A4, or of CDR1, CDR2, and / or CDR3 of any of the aforementioned polypeptides. In one embodiment, a reference sequence is the sequence of Construct #5 or an antigen binding fragment thereof. or antigen binding fragments thereof, having at least 85%, at least 88%, at least 90%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater, sequence identity, (as well as percentages therebetween) amino acid sequence identity to the sequence of Constructs 1, 2, 3, 4, or 5, or antigen binding fragments thereof. In an embodiment, the disclosure provides a pentavalent, bispecific PD-1 / CTLA4 VHH antibody fragments (pbVHH) having the sequence of Construct #5 (FIG.11), where the amino acid sequences of CDR1, CDR2, and CDR3 of the VHH components of the pentavalent construct are presented in Tables 1 and 2 herein. The disclosure also encompasses antigen binding fragments of Construct #5, having at least 85%, at least 88%, at least 90%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater, sequence identity, (as well as percentages therebetween) amino acid sequence identity to the sequence of CDR1, CDR2, and CDR3 of Construct #5. By way of non-limiting example, the binding of CDRs to a target protein may be via conformational binding or interaction, electrostatic binding interaction, hydrogen bonding, Van 59 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 der Waals forces, or hydrophobic bonding, or combinations thereof, as would be appreciated by those having skill in the art. Also provided herein are nucleic acid sequences encoding the pentavalent, bispecific PD- 1 / CTLA4 VHH antibody fragments (pbVHH) of the disclosure. In some embodiments a nucleic acid sequence of the disclosure encodes any one of Constructs # 1, 2, 3, 4, or 5, or constructs having a sequence with at least 85%, at least 88%, at least 90%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% sequence identity thereto. In some embodiments, a nucleic acid sequence of the disclosure comprises any one of SEQ ID NOS: 4660-4664, or a sequence having at least 85%, at least 88%, at least 90%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% sequence identity thereto. The nucleic acids (polynucleotides) of the disclosure may in some embodiments be circular DNA, e.g., a circular DNA plasmid or vector). In some embodiments, a circular DNA sequence of the disclosure comprises one or more promoters or enhancers, protease cleavage sites, posttranscriptional regulatory elements, polyadenylation signals, origin of replication sequence, forward or reverse primers, transcriptional activators, antibiotic resistance genes, and / or antibiotic resistance promoters. In some embodiments, e.g., in the sequences provided in the sequences of SEQ ID NOS: 4660-4664, a circular DNA of the disclosure comprises a CMV enhancer, a CMV promoter, a TEV site, a woodchuck hepatitis virus posttranscriptional regulatory element, a herpes simplex virus thymidine kinase polyadenylation signal, an f1 bacteriophage origin of replication, an SV40 enhancer and early promoter, an SV40 origin of replication, an SV40 polyadenylation signal, an M13 primer, a lac operator, a lac promoter, a CAP binding site, a high-copy-number ColE1 / pMB1 / pBR322 / pUC origin of replication, an ampicillin resistance (AmpR) gene, and / or an AmpR promoter. Each of SEQ ID NOS: 4660- 4664 comprises the sequence of one of Constructs #1-5 as described herein inserted between nucleic acids 742-2766 of the circular DNA sequence. The polynucleotide sequence of Construct #1 is set forth in SEQ ID NO: 4660. The polynucleotide sequence of Construct #2 is set forth in SEQ ID NO: 4661. The polynucleotide sequence of Construct #3 is set forth in SEQ ID NO: 4662. The polynucleotide sequence of Construct #4 is set forth in SEQ ID NO: 4663. The polynucleotide sequence of Construct #5 is set forth in SEQ ID NO: 4664. 60 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 VHH Antibodies A VHH (or VHH antibody or polypeptide) corresponds to the heavy chain of a camelid antibody having a single variable domain (or single variable region), e.g., a camelid-derived single variable H (VH) domain antibody. VHHs are monomeric, small / low molecular weight proteins (e.g., ~14 kDa). VHH technology is based on fully functional antibodies from camelids that lack light chains. These heavy-chain antibody molecules contain a single variable domain (VHH) and, typically, two constant domains (CH2 and CH3). A cloned (recombinantly produced) and isolated VHH domain is a stable polypeptide harboring the antigen-binding capacity of the original heavy-chain antibody. See, e.g., U.S. Patent No. 5,840,526 and U.S. Patent No.6,015,695, each of which is incorporated by reference herein in its entirety. VHHs, called NANOBODIES™, may be produced commercially (Ablynx Inc., Ghent, Belgium). VHHs have a number of advantages, when compared to conventional antibodies and recombinant antibody domains. VHHs are efficiently expressed in E. coli, coupled to detection markers, such as a fluorescent marker, or conjugated with enzymes. The small monomeric nature of VHHs allows VHHs to express and fold efficiently in recombinant hosts, and permits their binding to epitopes (antigenic determinants in antigen proteins), e.g., “hidden epitopes” that are not accessible to whole antibodies of much larger size. Further, VHHs typically bind conformational epitopes, and thus are more likely to neutralize target functions. VHHs are also exhibit stability over time (e.g., are more stable than when compared to conventional antibodies when exposed to extremes of pH and temperature) and have a longer half-life versus non-VHH antibody molecules, which comprise disulfide bonds that are susceptible to chemical reduction or enzymatic cleavage. VHHs are also amenable to designed multimerization, which often leads to higher potencies, and reduces the risk of microbes developing resistance, offering more therapeutic versatility such as multi-specificity. As a therapeutic, a VHH is capable of efficient penetration and rapid clearance. Its single domain nature allows a VHH to be expressed in a cell without a requirement for supramolecular assembly, as is needed for whole antibodies which are typically tetrameric (two heavy chains and two light chains, having a MW of about 150 kDa). Similar to immunoglobulins, VHHs may be modified post-translationally, e.g. to add chemical linkers, detectable moieties, such as fluorescent dyes, enzymes, substrates, chemiluminescent moieties, etc., or specific binding moieties, such as streptavidin, avidin, or biotin, etc., for use in the compositions and methods 61 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 described herein. VHHs have been validated by substantial published research supporting the potential of VHH-based agents as immunotherapeutics for treating enteric diseases. PD-1 PD-1 (PDCD1 and CD279) is a cell surface receptor commonly seen on T cells, B cells and NK cells. Basal level of PD-1 is seen on B cells but not on naïve T cells; its expression is induced upon activation of TCR / BC1. Apart from T cells, natural killer (NK) cells and B cells, PD-1 is also expressed on Tregs, NKT cells, activated monocytes and myeloid dendritic cells (DCs). The ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC) are commonly expressed on macrophages and DCs. PD-L1 is also expressed on T-cells, B-cells, vascular endothelial cells, fibroblastic reticular cells, epithelial cells, pancreatic islet cells, astrocytes, neurons as well as on sites of immune privilege such as trophoblasts in placenta and retinal pigment epithelial cells. Upon binding with their ligands, PD-1 receptors inhibit cell proliferation, cytokine secretion and cytotoxic ability of effector immune cells and thereby blunt the immune response. PD-1 / PD-L1 pathway is found to play a key role in escape of cancer from immunosurveillance, with PD-1 expression seen on effector T-cells and exhausted T-cells in tumor microenvironment (TME) and PD-L1 expression seen on cell surface in several types of cancers including bladder, lung, colon, breast, kidney, ovary, cervix, melanoma, glioblastoma, multiple myeloma and T-cell lymphoma. Three monoclonal anti PD-1 antibodies, pembrolizumab, nivolumab, and cemiplimab are approved by the U.S. Food and Drug Administration (FDA) for the treatment of different types of cancer. CTLA4 CTLA4 (Cytotoxic T-Lymphocyte-Associated Protein 4; cluster of differentiation 152, CD152), is a receptor found on surface of activated T-cells. CTLA4 expression is normally seen upon activation of T-cells, but regulatory T-cells (Tregs), express CTLA4 constitutively due to their high levels of forkhead transcription factor FoxP3, which is known to regulate CTLA4 expression. CTLA4 mainly acts by competing with CD28 receptors for binding to B7 ligands (B7-1 / CD80 and B7-2 / CD86) on antigen presenting cells (APCs). During T-cell activation, CD28 receptors on T-cells bind to B7 ligands on APCs and provide the essential second activation signal for T-cells. However, CTLA4 receptors bind to B7 ligands with higher affinity 62 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 and at a lower surface density and thereby outcompete CD28 receptors for binding with B7 ligands. Lack of second activation signal in presence of CTLA-4 receptors would thus lead to anergy in T-cells. In addition, CTLA-4 receptors are also shown to sequester B7-ligands from the surface of the APCs and result in significant depletion of the ligands on their surface. It has been shown that CTLA-4 engagement with B7-ligands abrogated IL-2 secretion by T-cells and T-cell proliferation that followed TCR activation; that blockade of CTLA-4 using anti-CTLA-4 antibodies resulted in rejection of preestablished tumors. Therapeutic Methods Featured herein are methods for treating or preventing a neoplasia, such as a cancer (e.g., lung cancer, such as NSCLC, colorectal cancer, renal carcinoma, breast cancer, such as triple negative breast cancer, bladder cancer, heptatocellular carcinoma) or tumor, involving the binding of and / or neutralization of PD-1 and / or CTLA4. The methods include administering to a subject in need thereof an effective amount (e.g., a therapeutically effective amount) of an anti- PD-1 and / or an anti-CTLA4 VHH polypeptide or a multimeric (e.g., pentameric) form thereof that is effective to specifically bind to and optimally neutralize the proteins, so as to treat the disease and / or symptoms thereof (e.g., by preventing the immunomodulatory and / or immune regulatory functions of PD-1 and / or CTLA4). In particular embodiments, the methods involve the administration of a pbVHH (e.g., Construct Nos.1, 2, 3, 4, 5) for the treatment of a neoplasia (e.g., cancer), such as colorectal cancer or another cancer typically treated with a checkpoint inhibitor. In an embodiment, the methods involve the administration of a polypeptide comprising XFV-E7, XFU-D3, or XJD-A4, or of CDR1, CDR2, and / or CDR3 of any of the aforementioned polypeptides. In an embodiment, if an anti-PD-1 VHH polypeptide or multimeric form (e.g., pentameric) thereof and / or an anti-CTLA4 VHH polypeptide or multimeric form thereof includes an epitope tag as described further below, an anti-epitope tag antibody may also be administered to the subject (see, e.g., WO 2019 / 094095A1, the contents of which is incorporated by reference herein in its entirety). Methods of treating a subject having a disease (e.g., cancer) as provided herein involve the administration of an effective amount of one or more single-domain variable heavy-chain (VHH) polypeptides (e.g., pbVHH, such as Construct Nos. 1, 2, 3, 4, 5, or of XFV-E7, XFU-D3, or XJD-A4, or of CDR1, CDR2, and / or CDR3 of any of the aforementioned polypeptides.) that 63 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 target and bind to PD-1 and / or CTLA4 to inhibit, block, or neutralize the activity of PD-1 and / or CTLA4. The anti-PD-1 and / or anti-CTLA4 VHH polypeptides may be administered to a subject as monomers or as multimers including two, three, four, five, or more VHH polypeptides, for example. In an embodiment, the method involves administering one or more anti-PD-1 and / or CTLA4 VHH polypeptides to a subject in need, for example, a subject who has a disease in which binding and / or neutralization of PD-1 and / or CTLA4 is beneficial (e.g., cancer). In some embodiments, the anti-PD- 1 and / or anti-CTLA4 VHH polypeptides, and / or multimers thereof described herein may be administered to a subject in need thereof, in combination with one or more other anti-cancer and / or chemotherapy agents known in the art. In an embodiment, the method involves administering an PD-1-binding VHH polypeptide having at least 85%, at least 88%, at least 90%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater, (and percentages therebetween) amino acid sequence identity to one or more of the anti-PD-1 VHH polypeptides described herein, or a polynucleotide encoding the polypeptide, to the subject. In an embodiment, the method involves administering an CTLA4-binding VHH polypeptide, namely, one or more of the anti-CTLA4 VHH polypeptides described herein, or a polynucleotide encoding the polypeptide, to the subject. In an embodiment, the anti-PD-1 and / or anti-CTLA4 VHH polypeptides can be produced in monomeric or multimeric forms (e.g., pentameric) for use in the treatment and therapeutic methods. Multimeric forms of the VHH polypeptides include dimers, trimers, tetramers, pentamers, etc. that are linked, joined, or coupled by flexible linker peptides known in the art (see, e.g., WO 2022 / 006219A2). In embodiments, the linker comprises glycine (e.g., 3, 4, 5, 6, 7, or 8-12 glycines). In an embodiment, the linker comprises five glycine residues (GGGGG (SEQ ID NO: 4654)). In an embodiment, the multimeric VHH polypeptides can contain the same or different VHH polypeptides that bind to PD-1. In an embodiment, the multimeric VHH polypeptides can contain the same or different VHH polypeptides that bind to CTLA4. In an embodiment, the multimeric VHH polypeptides can contain a combination of VHH polypeptides that bind to PD-1 and VHH polypeptides that bind to CTLA4. In an embodiment, the multimeric VHH polypeptides include one or more VHH polypeptides which, without intending to be bound by theory, may be expected to increase the half-life of the multimeric VHH polypeptides in serum (e.g., an anti-serum albumin VHH polypeptide, an anti-cynomolgus albumin VHH polypeptide, 64 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 or an anti-human albumin VHH polypeptide). In some embodiments, the multimeric VHH polypeptides may be pentamers, including two of the same or different anti-PD-1 VHH polypeptides, two of the same or different anti-CTLA4 VHH polypeptides, and an anti-human albumin VHH polypeptide. By way of example, multimeric forms of VHH polypeptides are described, for example, in U.S. Patent No.10,766,950; U.S. Patent No.11,091,563; and U.S. Publication No.2021 / 0221874, the contents of which are incorporated by reference herein. In an embodiment, the multimeric form is a pentameric form of VHH comprising, for example, a human serum albumin binding VHH or antigen binding fragment thereof, two PD-1 VHHs or antigen binding fragments thereof, and two CTLA-4 VIn other embodiments, the monomeric or multimeric (e.g., pentameric) anti-PD-1 and / or anti-CTLA4 VHH polypeptides may be linked to an epitope tag (or E-tag), which can be bound by an anti-E-tag antibody (monoclonal antibody (Mab)), e.g., to aid in purification and / or identification of the VHH polypeptides. Such epitope tags are used in the art and are described, for example, in U.S. Patent Nos. 8,349,326; 8,865,169; 10,766,950; U.S. Publication No.2021 / 0221874; and WO 2022 / 006219A2, the contents of which are incorporated by reference herein. In an embodiment, an anti-PD-1 and / or anti-CTLA4 VHH polypeptide is recombinantly produced and is a recombinant protein. The therapeutic methods include prophylactic as well as therapeutic treatment methods. In an embodiment, the treatment method includes administering a therapeutically effective amount of an anti-PD-1 and / or anti-CTLA4 VHH polypeptide or multimeric (e.g., pentameric) form thereof as described herein, or a pharmaceutical composition comprising these agents, before or during the time that a subject is administered one or more additional drugs or agents (e.g., anti-cancer and / or chemotherapeutic agents), or a treatment involving a course of drugs or agents, to treat the disease in the subject. Exemplary anti-cancer agents include, but are not limited to, chemotherapy agents, radiation therapy agents, immunotherapy agents (e.g., antibodies, CAR-T cells, engineered T cells, etc.), hormone therapy agents, and others known in the art. A subject or patient includes an animal, particularly a mammal, and more particularly, a human. Such an anti-PD-1 and / or CTLA4 VHH polypeptide or multimeric form thereof as described herein, or a pharmaceutical composition comprising these agents, used as therapeutics in treatments will be suitably administered to subjects or patients suffering from, having, susceptible to, or at risk of becoming afflicted with a disease, disorder, or symptom thereof in 65 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 which binding and / or neutralization of PD-1 and / or CTLA4 is beneficial (e.g., cancer). Cancers amenable to treatment using the agents described herein (e.g., Constructs 1, 2, 3, 4, 5) include, but are not limited to lung cancer, such as NSCLC, colorectal cancer, renal carcinoma, breast cancer, such as triple negative breast cancer, bladder cancer, and heptatocellular carcinoma. Determination of patients who are “susceptible” or "at risk" can be made by any objective or subjective determination obtained by the use of a diagnostic test or based upon the opinion of a patient or a health care provider. Identifying a subject in need of the treatments herein can be in the judgment of a subject him / herself, or of a health care / medical professional and can be subjective (e.g., opinion) or objective (e.g., measurable or quantifiable by a test or diagnostic method). Pharmaceutical Compositions An anti-PD-1 and / or anti-CTLA4 VHH polypeptide as described herein or multimeric (e.g., pentameric) form thereof is provided or contained in a pharmaceutical composition, particularly when used in the practice of the above-described treatment methods. In particular embodiments, the pharmaceutical composition comprises a pentavalent, bispecific PD-1 / CTLA4 VHH antibody fragment (pbVHH) (e.g., Constructs #1-5, XFV-E7, XFU-D3, or XJD-A4, or CDR1, CDR2, and / or CDR3 of any of the aforementioned polypeptides). In an embodiment, the pharmaceutical composition comprises a pbVHH having the sequence shown in Construct #5, a variant thereof having at least or at least about 85%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity to Construct #5, or an antigen binding fragment of one of the aforementioned. Typically, a carrier, excipient, or vehicle is included in a composition as described herein, such as a pharmaceutically acceptable carrier, excipient, or vehicle that includes, for example, sterile water, aqueous saline solution, aqueous buffered saline solutions, aqueous sucrose, dextrose, or mannose solutions, aqueous glycerol solutions, ethanol, calcium carbonate, albumin, starch, cellulose, silica gel, polyethylene glycol (PEG), dried skim milk, rice flour, magnesium stearate, and the like, or combinations thereof. The terms "pharmaceutically acceptable carrier" 66 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 and "carrier" refer to any generally acceptable excipient or drug delivery device that is relatively inert and non-toxic. As used herein, the term “pharmaceutically acceptable carrier” includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's The Science and Practice of Pharmacy Ed. by LWW 21stEQ. PA, 2005 (and current versions) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Carriers are selected to prolong dwell time for example following any route of administration, including intraperitoneal (IP), intravenous (IV), subcutaneous (SC), intramuscular (IM), mucosal, sublingual, inhalation or other form of intranasal administration, or other routes of administration, e.g., intradermal, intracranial, intrathecal, intravaginal, rectal, intraorbital, and the like. Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The preparation of such compositions and solutions ensuring sterility, pH, isotonicity, and stability is effected according to protocols established in the art. Generally, a carrier or excipient is selected to minimize allergic and other undesirable effects, and to suit the particular route of administration, e.g., subcutaneous, intramuscular, intranasal, intravenous, oral, and the like. In certain embodiments, the compositions optionally further comprise one or more additional therapeutic agents. 67 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 A therapeutically effective dose refers to that amount of active agent which ameliorates at least one symptom or condition. Therapeutic efficacy and toxicity of active agents can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose that is therapeutically effective in 50% of the population) and LD50 (the dose that is lethal to 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50 / ED50. Pharmaceutical compositions which exhibit large therapeutic indices are especially useful. The data obtained from cell culture assays and from animal studies are used in formulating a range of dosages for human administration. Dosages As described in detail below, murine and primate preclinical studies were carried out. In these studies, a range of doses were evaluated. The range of doses evaluated in the efficacy mouse study described herein informed a human dose schedule and optimization as did the cynomolgus pharmacokinetic study. In embodiments, a human equivalent dose (e.g. of pbVHH Construct #1, 2, 3, 4, or 5) based on the cynomolgus pharmacokinetic study is between about 0.001 and 0.1 mg / kg (e.g., 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1 mg / kg). In embodiments, such dose is administered every 3-7 weeks. In an embodiment, the dose is administered every 5, 6, or 7 weeks. In an embodiment, the human equivalent dose is 0.01 mg / kg (or ~1 mg flat dose), which is provided via subcutaneous administration every 6 weeks. In an embodiment, the human equivalent dose is 0.01 mg / kg (or ~1 mg flat dose) of Construction #5, which is provided via subcutaneous administration every 6 weeks. In other embodiments, a therapeutic dose may be at least about 1 g per kg, at least about 5, 10, 50, 100, 500 g per kg, at least about 1 mg / kg, 5, 10, 50 or 100 mg / kg body weight of a composition or active component thereof per body weight of the subject, although the doses may be more or less depending on age, health status, history of prior infection, and immune status of the subject as would be known by one of skill in the art. Doses may be divided or unitary and may be administered once daily, or repeated at appropriate intervals. Administration of Pharmaceutical Compositions 68 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 After formulation with an appropriate pharmaceutically acceptable carrier, excipient, or vehicle in a desired dosage, a pharmaceutical composition comprising an anti-PD-1 and / or anti- CTLA4 VHH polypeptide or multimeric form thereof can be administered to humans and other mammals by routes known and practiced in the art. The administration of an anti-PD-1 and / or anti-CTLA4 VHH polypeptide or multimeric form thereof as a therapeutic for the treatment or prevention of a disease for which binding and / or neutralization of PD-1 and / or CTLA4 is beneficial (e.g., cancer) may be by any suitable means that results in a concentration of the therapeutic that, combined with other components, if desired, is effective in ameliorating, reducing, eliminating, abating, abrogating, or stabilizing the disease and / or the symptoms thereof in a subject. Cancers suitable for treatment with, for example, Construct #1-5 include lung cancer, such as NSCLC, colorectal cancer, renal carcinoma, breast cancer, such as triple negative breast cancer, bladder cancer, heptatocellular carcinoma. The therapeutic may be administered systemically, for example, formulated in a pharmaceutically-acceptable composition or buffer such as physiological saline. In particular embodiments, the pharmaceutical composition administered comprises a pentavalent, bispecific PD-1 / CTLA4 VHH antibody fragment (pbVHH) (e.g., Constructs #1-5), comprises XFV-E7, XFU-D3, or XJD-A4, or comprises CDR1, CDR2, and / or CDR3 of any of the aforementioned polypeptides. In an embodiment, the pharmaceutical composition administered comprises a pbVHH having the sequence shown in Construct #5, a variant thereof having at least about 85%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity to Construct #5, or an antigen binding fragment of one of the aforementioned. Routes of administration include, for example and without limitation, subcutaneous, intravenous, intraperitoneal, intramuscular, intrathecal, intraperitoneal, or intradermal injections that provide continuous, sustained levels of the therapeutic in the subject. Other routes include, without limitation, intrathecal, intracranial, gastrointestinal, esophageal, oral, rectal, intravaginal, etc. The amount of the therapeutic to be administered varies depending upon the manner of administration, the age and body weight of the subject, and with the clinical symptoms of the disease (e.g., cancer), or associated disease, pathology, and / or symptoms. Generally, amounts will be in the range of those used for other agents used in the treatment of disease for which binding and / or neutralization of PD-1 and / or CTLA4 is beneficial (e.g., cancer), although in certain instances, lower amounts may be suitable because of the increased range of protection and treatment afforded by the described anti-PD-1 and / or anti-CTLA4 VHH polypeptides or 69 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 multimeric forms thereof as therapeutics. A composition is administered at a dosage that ameliorates, decreases, diminishes, abrogates, alleviates, or eliminates the effects of the disease for which binding and / or neutralization of PD-1 and / or CTLA4 is beneficial (e.g., cancer), as determined by a method known to one skilled in the art. In embodiments, a therapeutic or prophylactic treatment agent (e.g., the VHH polypeptides described herein) may be contained in any appropriate amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition. The composition may be provided in a dosage form that is suitable for parenteral (e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal) administration route. The pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York). Pharmaceutical compositions may in some cases be formulated to release the active agent substantially immediately upon administration or at any predetermined time or time period after administration. The latter types of compositions are generally known as controlled release formulations, which include (i) formulations that create a substantially constant concentration of a therapeutic agent or drug within the body over an extended period of time; (ii) formulations that after a predetermined lag time create a substantially constant concentration of a therapeutic agent or drug within the body over an extended period of time; (iii) formulations that sustain action during a predetermined time period by maintaining a relatively, constant, effective level in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the active substance (sawtooth kinetic pattern); (iv) formulations that localize action by, e.g., spatial placement of a controlled release composition adjacent to or in contact with an organ, such as the gut or gastrointestinal system; (v) formulations that allow for convenient dosing, such that doses are administered, for example, once every one or two weeks; and (vi) formulations that target a disease using carriers or chemical derivatives to deliver the therapeutic agent or drug to a particular cell type. For some applications, controlled release formulations obviate the need for frequent dosing during the day to sustain a therapeutic level in plasma, serum, or blood. In an embodiment, one or more anti-PD-1 and / or anti-CTLA4 VHH 70 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 polypeptides or multimeric forms thereof may be formulated with one or more additional components for administration to a subject in need, e.g., patients who suffer from a disease for which binding and / or neutralization of PD-1 and / or CTLA4 is beneficial (e.g., cancer). Any of a number of strategies can be pursued in order to obtain controlled release of a therapeutic agent in which the rate of release outweighs the rate of metabolism of the therapeutic agent or drug in question. In one example, controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings. Thus, the therapeutic agent or drug may be formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the therapeutic agent or drug in a controlled manner. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, molecular complexes, nanoparticles, patches, and liposomes. Compositions for parenteral or oral use may be provided in unit dosage forms (e.g., in single-dose ampules), or in vials containing several doses and in which a suitable preservative may be added (see below). The composition may be in the form of a solution, a suspension, an emulsion, an infusion device, or a delivery device for implantation, or it may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use. Apart from the active agent (i.e., an anti-PD-1 and / or anti-CTLA4 VHH polypeptide or multimeric form thereof), the composition may include suitable parenterally acceptable carriers and / or excipients. The composition may further include suspending, solubilizing, stabilizing, pH-adjusting agents, tonicity adjusting agents, and / or dispersing, agents. In some embodiments, compositions comprising an anti-PD-1 and / or anti-CTLA4 VHH polypeptide or multimeric form thereof are sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like which do not deleteriously react with the active compounds. In some embodiments, an anti-PD-1 and / or anti- CTLA 4 VHH polypeptide or multimeric form thereof are combined, where desired, with other active substances, e.g., enzyme inhibitors, to reduce metabolic degradation. An effective amount of a pharmaceutical composition can vary according to choice or type of an anti-PD-1 and / or anti-CTLA4 VHH polypeptide or multimeric form thereof as described herein, the particular composition formulated, the mode of administration and the age, weight and physical health or 71 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 overall condition of the patient, for example. In an embodiment, an effective amount of an anti- PD-1 and / or anti-CTLA4 VHH polypeptide or multimeric form thereof (and / or anti-epitope tag antibody if one or more of the VHH polypeptides or multimeric form thereof contains an epitope tag) is an amount which is capable of reducing one or more symptoms of a disease for which binding and / or neutralization of PD-1 and / or CTLA4 is beneficial (e.g., cancer). In certain embodiments, a composition includes one or more polynucleotide sequences that encode one or more anti-PD-1 and / or anti-CTLA4 or multimeric forms thereof as described herein. In an embodiment, a polynucleotide sequence encoding an anti-PD-1 and / or anti-CTLA4 VHH polypeptide or multimeric form thereof is in the form of a DNA molecule or multimer. In some embodiments, the composition includes a plurality of nucleotide sequences each encoding an anti-PD-1 and / or anti-CTLA4 VHH polypeptide or multimeric form thereof, or any combination of anti-PD-1 VHH polypeptides or anti-CTLA4 VHH polypeptides or multimeric forms thereof as described herein, such that the anti-PD-1 and / or anti-CTLA4 VHH polypeptides or multimeric forms thereof are expressed and produced in situ. In such compositions, a polynucleotide sequence is administered using any of a variety of delivery systems known to those of ordinary skill in the art, including mammalian, eukaryotic, bacterial, viral vector nucleic acid expression systems. In some embodiments nucleic acid expression systems contain appropriate nucleotide sequences operably linked for expression in a patient (such as suitable promoter and termination signals). In an embodiment, a polynucleotide molecule encoding an anti-PD-1 and / or anti- CTLA4 VHH polypeptide or multimeric form thereof can be introduced using a viral expression system (e.g., vaccinia or other pox virus, retrovirus, lentivirus, or adenovirus associated virus (AAV)), which uses a non-pathogenic (defective), replication competent virus. Techniques for incorporating nucleic acid (DNA) into such expression systems are well known to and practiced by those of ordinary skill in the art. The nucleic acid (DNA) can also be "naked," as described, for example, in Ulmer et al., 1993, Science, 259:1745-1749 and as reviewed by Cohen, 1993, Science 259:1691-1692. Polynucleotides encoding the anti-PD-1 and / or anti-CTLA4 VHHs may be delivered to cells or administered to a subject through the use of nanoparticles, e.g., lipid nanoparticles, comprising DNA or RNA, or coating the DNA or RNA onto biodegradable beads. 72 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 Kits Provided herein are kits for use in connection with the anti-PD-1 and / or anti-CTLA4 VHH polypeptide products, compositions and methods described herein, or polynucleotides encoding such polypeptides. In an aspect, the kits are used in connection with treatments (therapeutic treatments) to treat a disease for which binding and / or neutralization of PD-1 and / or CTLA4 is beneficial (e.g., cancer), in a subject in need thereof. In some embodiments, the kit includes an effective amount of anti-PD-1 and / or anti-CTLA4 VHH polypeptide, or a multimer thereof, as described herein, in unit dosage form. In particular embodiments, the kit comprises a pentavalent, bispecific PD-1 / CTLA4 VHH antibody fragment (pbVHH) (e.g., Constructs #1-5). In an embodiment, the pbVHH comprises any one or more of ; of XFV-E7, XFU-D3, or XJD- A4, or of CDR1, CDR2, and / or CDR3 of any of the aforementioned polypeptides. In an embodiment, the kit comprises a pbVHH having the sequence shown in Construct #5, a variant thereof having at least about 85%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity to Construct #5, or an antigen binding fragment of one of the aforementioned. In other embodiments, the kit includes a therapeutic or prophylactic composition containing an effective amount of an anti-PD-1 and / or anti-CTLA4 VHH polypeptide or multimer thereof in unit dosage form. In still other embodiments, the kit includes a therapeutic or prophylactic composition containing an effective amount of one or more of an anti-PD-1 and / or anti-CTLA4 VHH polypeptide or multimer form thereof, and an anti-epitope tag antibody, in unit dosage form. In some embodiments, the kit comprises a device (e.g., an automated or implantable device for subcutaneous delivery; an implantable drug-eluting device, or a nebulizer or metered-dose inhaler) for dispersal of the composition or a sterile container which contains a pharmaceutical composition. Non-limiting examples of containers include boxes, ampules, bottles, vials, tubes, bags, pouches, blister-packs, or other suitable container forms known in the art. Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding medicaments. If desired, a pharmaceutical composition of the disclosure is provided together with instructions for administering the pharmaceutical composition containing an anti-PD-1 and / or anti-CTLA4 VHH polypeptide to a subject having, or at risk of contracting or developing, disease or pathology, and / or the symptoms thereof, associated with a disease for which binding and / or neutralization of PD-1 and / or CTLA4 is beneficial (e.g., cancer). The instructions will 73 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 generally include information about the use of the composition for the treatment or prevention of the disease for which binding and / or neutralization of PD-1 and / or CTLA4 is beneficial (e.g., cancer). In other embodiments, the instructions include at least one of the following: description of the therapeutic / prophylactic agent; dosage schedule and administration for treatment or prevention of a disease or symptoms thereof for which binding and / or neutralization of PD-1 and / or CTLA4 is beneficial (e.g., cancer); precautions; warnings; indications; counter-indications; over-dosage information; adverse reactions; animal pharmacology; clinical studies; and / or references. The instructions may be printed directly on the container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder supplied in or with the container. EXAMPLES EXAMPLE 1: Discovery and characterization of VHHs targeting PD-1 and CTLA4 To discover new VHHs having binding specificity for PD-1 or CTLA4, alpacas were immunized with human PD-1 or human CTLA4 polypeptides. The animals responded with high serum levels of antibodies to these targets. Techniques were then employed for VHH-display library construction, VHH discovery, expression, purification and characterization. Dozens of VHHs capable of binding each protein target were identified. Next, 9 unique PD-1-binding VHHs (Table 1)(FIG.3) and 15 CTLA4-binding VHHs (Table 2)(FIG.4) were selected for purification and characterization. During the characterization of each VHH, the affinity of the candidate VHHs for their target by dilution ELISAs, their ability to compete for target binding with each other and with a known target-neutralizing mAbs, and their ability to neutralize the target function in cell-based assay were assessed (FIG.5, FIG.6). Dilution ELISA data demonstrated that most of the VHHs have sub-nanomolar binding EC50s, suggestive of high affinity (Tables 3 and 4). 74 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 75 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 *Sequences of CDR1, CDR2, and CDR3 are sequentially underlined in each VHH sequence For each anti-human PD-1 VHH listed in Table 1, the amino acid sequences of CDR1, CDR2, and CDR3 in the VHH sequence are presented sequentially as SEQ ID NOs: 4545-4589, in the order that the VHHs appear in the table. Table 2: VHH Polypeptides Binding to Human CTLA4 76 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 77 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 78 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 *Sequences of CDR1, CDR2, and CDR3 are sequentially underlined in each VHH sequence For each anti-human CTLA4 VHH listed in Table 2, the amino acid sequences of CDR1, CDR2, and CDR3 in the VHH sequence are presented sequentially as SEQ ID NOs: 4590-4652, in the order that the VHHs appear in the table. Human PD-1 and human CTLA-4 neutralization assays were done in cell-based assays. The results (Tables 3 and 4) demonstrated that, while several VHHs to each target may have had some neutralizing potency, one VHH to each target stood out as having the most potency to neutralize their targets. VHH XFU-D3 had the greatest neutralization for PD-1. VHH XFV-E7 had the greatest neutralization for human CTLA4. Table 3: Characteristics of Human PD-1 Binding VHH Polypeptides and Multimers 79 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 ALab code given to each VHHBThe EC50 = VHH concentration that produced estimated 50% of the peak signal on a dilution ELISA, best immobilization methodCCompeted with commercial anti-hCTLA4 mAb for binding to hCTLA4 on ELISADVisual assessment of staining intensity by IFA on transfected cells expressing hCTLA4ECommercial cell-based assay for hCTLA4-neutralizationFBased on competition analysis, target binding competition found within each competition group NS = no significant inhibition detected at 125 nM Trace = significant but minimal neutralization detected at 125 nM ND = not done IC50 = values estimated based on preliminary cell-based assays, replication needed for more robust assessment + / - Showed likely activity ++ Showed moderate activity +++ Showed clear activity ++++ Showed strongest level of activity 80 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 ALab code given to each VHHBThe EC50 = VHH concentration that produced estimated 50% of the peak signal on a dilution ELISA, best immobilization methodCCompeted with commercial anti-hCTLA4 mAb for binding to hCTLA4 on ELISADVisual assessment of staining intensity by IFA on transfected cells expressing hCTLA4ECommercial cell-based assay for hCTLA4-neutralizationFBased on competition analysis , target binding competition found within each competition group NS = no significant inhibition detected at 125 nM ND = not done IC50 = values estimated based on preliminary cell-based assays, replication needed for more robust assessment + / - Showed likely activity ++ Showed moderate activity +++ Showed clear activity ++++ Showed strongest level of activity Linking VHHs into multimers, such as homodimers or heterodimers, often leads to dramatically improved therapeutic properties. Thus, homodimers of XFU-D3 VHH called XFU- D3 / XFU-D3, and homodimers of XFV-E7 VHH called XFV-E7 / XFV-E7 were next produced (Table 5). Various heterodimers in which one component VHH was the lead neutralizing VHH linked to a second VHH which also bound to the same target protein were also produced, but at a 81 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 unique epitope that did not overlap and thus compete for binding with the neutralizing VHH. All of the homodimers and heterodimers were tested in cell-based assays for their potency to neutralize the human PD-1 or human CTLA4 targets. The results (Tables 3 and 4) demonstrated that the neutralizing potencies of the human PD-1 homodimer XFU-D3 / XFU-D3 was clearly superior to each of the heterodimers tested. Interestingly, for human CTLA4, one of the heterodimers containing VHHs XFV-E7 and XJD-A4 (called XFV-E7 / XJD-A4) was more potent than each of the other heterodimers and had approximately equal potency with the XFV- E7 / XFV-E7 homodimer. Thus, both VHH dimers are considered strong CTLA4-neutralizing agents. Importantly, all of these three candidates displayed potencies (IC50s) about 5-fold superior to that of the conventionally available PD-1 and CTLA4-neutralizing mAb therapeutic products. Table 5: VHH Multimers 82 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 83 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 *Spacer sequence separating VHH components is underlined in each VHH multimer sequence. The linker sequence GGGGSGGGGSGGGGS is presented as SEQ ID NO: 4653. Example 2: Detection of VHH clonal families and the amino acid sequences thereof The pool of VHH-displaying phage that were affinity purified through binding to either PD-1 or to CTLA-4 and which led to the discovery of the anti-PD-1 or anti-CTLA-4 VHHs, described herein were used to infect bacteria and cultured overnight. The phagemid DNA was then prepared from each of the pools and was subjected to Illumina sequencing. Using standard bioinformatic analysis of the encoded VHHs in each phagemid pool, all VHHs that were closely related to each of XFV-E7 and XJD-A4 (VHHs which bind CTLA-4) and XFU-D3 (a VHH which binds PD-1) were identified. As a result of their high level of homology, these closely- related VHHs likely evolved from a common B cell progenitor during the affinity maturation process that occurred within the alpacas during the immunization period. These groups of VHHs are called ‘clonal families.’ An alignment of all of the clonal family sequences for VHHs XFU- D3, XFV-E7 and XJD-A4 within each of the three clonal families generated the consensus 84 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 sequences presented in FIG.28. The consensus sequences are the amino acids that are most commonly represented in each clonal family. Above the VHH consensus sequences are shown all of the amino acid variations that were identified among all the VHH sequences in the indicated clonal family. The three CDR sequences are also identified in the figure. Since the VHHs encoding each of these amino acid variations were discovered within the pool of VHH- displaying phage that had been purified by affinity to the PD-1 or CTLA-4 target, each VHH sequence displayed target binding. These data highlight the sequence flexibility of VHHs and identify conserved amino acid positions. Example 3: Discovery and characterization of multivalent PD-1 / CTLA-4 VHH neutralizers with robust pre-clinical safety and efficacy After developing CTLA-4 and PD-1 receptor binding VHH constructs able to neutralize their respective receptors better than the leading antibodies, as shown in FIGs.5 and 6, multispecific VHH constructs neutralizing both PD-1 and CTLA-4 were next developed for immuno-oncology therapies (FIGs.7-11). Current immunotherapy blockages of CTLA-4 and PD-1, combining Ipilimumab and Nivolumab, are more efficacious than either alone, however the combination treatment is associated with significantly increased Grade 3 / 4 toxicity relative to that of the individual antibodies. (Checkmate 067 Trial NCT01844505; Larkin J, et al. NEJM 2015;373:23-34; and Gunturu KS, et al. Support Care Cancer 2022;30:4019-26.) Pentavalent constructs comprising (i) a human serum albumin and cynomolgus monkey serum albumin binding VHH (referred to as HSA), (ii) two PD-1 binding VHHs, and (iii) two CTLA-4 binding VHHs were developed (termed “pbVHH” herein). These pentavalent constructs were engineered to bind non-overlapping epitopes of their targets resulting in improved therapeutic efficacy and safety. The HSA VHH conferred a long serum half life of about 20 days, which enables less frequent dosing, e.g., every 6 weeks. Example configurations of the pentavalent construct sequences may be found in FIGs.7-11, with an example schematic shown in FIG.12. The pentavalent constructs used in the experiments below comprise the XFVE7 domain of the disclosure (binding to CTLA-4), the XJDA4 domain of the disclosure (binding to CTLA-4), two XFUD3 domains (binding to PD-1), as well as a JPMB2 domain (binding to human serum albumin (HSA)). Construct #5 was characterized using a Western blot under reducing and non-reducing conditions (FIG.14). The novel proprietary VHH antibody fragments 85 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 described herein are designed to deliver the efficacy of combination immuno-oncology regimens while addressing the toxicity limitations of current monoclonal antibody therapies. In particular, novel pentavalent, bispecific PD-1 / CTLA4 VHH antibody fragments were developed for the treatment of multiple cancers. One of these was selected for testing in a murine model of cancer. In vitro binding affinity The pbVHH potency in terms of binding affinity to PD-1 and CTLA-4 is shown in FIG. 13, relative to Nivolumab and Ipilimumab antibodies, where the Construct #5 pentavalent construct demonstrates an at least 1000 x higher affinity to each of PD-1 and CTLA-4 relative to the individual standard of care antibodies. Next, the neutralization capability of pbVHH was investigated. To determine CTLA- 4 / PD-1 dual neutralization, a combination bioassay was developed (see Methods). A schematic of the bioassay for CTLA-4 / PD-1 dual neutralization is shown in FIG.24. Each configuration of pbVHH was tested, with Construct #5 demonstrating the best dual neutralization efficacy (FIGs. 26 and 27). Notably, a PD-1 / CTLA-4 bispecific antibody, AK104 (aka Cadonilimab), developed with a modified Fc domain, did not demonstrate the same magnitude of PD-1 / CTLA-4 neutralization as pbVHH 6 (FIGs.26 and 27). Nor did AK104, nor Volrustomig, a bispecific antibody to PD1 and CTLA-4 demonstrate binding affinity to PD-1 and CTLA-4 of the same magnitude as Construct #5 (FIG. 27). Clinical manufacturing The production of the pentavalent Construct #5 protein, as well as the size-exclusion high performance liquid chromatography (SEC-HPLC) of the protein demonstrated high yield and greater than 95% purity, as shown in FIGs.14 and 15. Construct #5 protein production was optimized in Chinese Hamster Ovary (CHO) cells to yield up to 3 g / L which is conducive for downstream clinical manufacturing. Example 4: Pentavalent, bispecific PD-1 / CTLA4 VHH antibody fragment (pbVHH) Cures Cancer in an Animal Model The efficacy of a pentavalent, bispecific PD-1 / CTLA4 VHH antibody fragment (pbVHH) (Fig.12) was assayed in a humanized target tumor bearing murine model of colorectal cancer. The murine model was engrafted with syngeneic tumor cells, and included a double knock-in of 86 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 human PD-1 and CTLA-4. The use of this double knock-in mouse engrafted with a human colorectal cancer cell line MC38 expressing human PD-L1, which recreates a fully humanized ligand-receptor complex that provides for the evaluation of combination therapies. Four treatment groups were used where each group included mice that expressed a double knock-in of human PD-1 / CTLA4 Balb / c mice (n=4 per group). The mice were injected with MC38 HuCells, which is a colorectal tumor cell line that has a high mutational burden, and is sensitive to immune checkpoint immunotherapy. Safety Analysis To assess safety, the following experiment was conducted. A control group of mice received only vehicle, which was phosphate-buffered saline. Another group of mice was treated with conventional therapy: Ipilimumab + pembrolizumab (pembro + ipi), where Ipilimumab was administered at 10 mg / kg and 15 mg / kg pembrolizumab was administered every third day (6 total doses). Ipilimumab is a monoclonal antibody that specifically binds to the CTLA-4 protein. Pembrolizumab is a humanized antibody that specifically binds to the PD-1 protein. There were two experimental groups that received the pentavalent, bispecific PD-1 / CTLA4 VHH (pbVHH) antibody fragment. The sequence of this fragment is shown in FIG. 11. The first experimental group received ten doses (5 mg / kg daily for ten days) (10 total doses). The second experimental group received 10 mg / kg for 16 days pbVHH daily. At the end of the experiment, survival, biomarkers, and histopathology were analyzed (Fig.16, 17, 18). Interestingly, 100% of mice receiving pbVHH survived, while only 50% of mice receiving the conventional therapy, pembro + ipi, survived (FIG.16). This low survival rate was attributable to immune-related adverse events that were observed in the pembro + ipi treated mice. The pembro + ipi therapy resulted in more severe and diffuse lymphocytic infiltration relative to pbVHH (FIG.17). In addition, treatment with pbVHH resulted in far less inflammation than treatment with the conventional therapy (pembro + ipi). The mice were also evaluated for arthritis and colitis (FIG.19A, 19B). Mice receiving pembro + ipi displayed significant arthritis and colitis relative to the untreated control mice or to mice treated with pbVHH. Efficacy Efficacy studies were conducted in a similar fashion, where double knock-in hPD / hCTLA4 C57B / 6 mice were injected with MC38 HuCells and divided into six treatment 87 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 groups. Again, every 3-days each of the six groups of mice (n=5 per group) were treated as follows: a control group received only vehicle (PBS), a second control group that received Nivolumab + ipilimumab (nave + ipi): 2 mg / kg nave + 5 mg / kg ipi; and four dosing groups that received: 0.1, 0.5, 1.0, and 5.0 mg / kg pbVHH. After 15-days, tumor volume was assayed and after tumor rechallenge was carried out. Interestingly, pbVHH exhibited 1000-times higher binding affinity for CTLA-4 relative to Ipi. Full tumor regression was observed in both the 5 mg / kg pbVHH and the ipi + nave group (FIG.21). However, treatment with pbVHH resulted in a cure (FIG.22). The pbVHH treated mice remained in remission after tumor rechallenge with no further dosing (Fig.22). Pharmacokinetics Pharmacokinetic studies were carried out in a 28-day study in 3 cynomolgus monkeys that were treated with 1 mg / kg of pbVHH that was administered subcutaneously once per week. pbVHH serum concentration was evaluated over time (FIG. 22), as were the animals vital signs, and pbVHH tolerability. SQ injections resulted in no abnormal manifestations, such as mental status or behavioral activity that affected the results. The combination of Pembrolizumab and Ipilimumab also resulted in more swelling, inflammation including higher creatine kinase, alanine aminotransferase, and lactate dehydrogenase levels, and lymphocyte infiltration than treatment with pbVHH, as shown in FIGs. 17, 18, 19A-19B, and 20A-20C. Cytokines of animals in each group showed no significant abnormalities during the study (Fig.23). Significantly, FIG. 23 shows no reduction in pbVHH concentration, which indicates that no anti-pbVHH immune response was generated. The multispecific VHH constructs developed herein provide tunable, high affinity binding for multiple targets. In particular, Construct #5 (FIG.11) binds to PD-1 and CTLA-4 with femtomolar affinity as compared to the sub-nanomolar affinity of approved PD-1 and CTLA-4 antibodies. At the same time, the multispecific VHH constructs provided herein exhibit better safety profiles due to their lack of fragment crystallizable (Fc) sequences, demonstrating minimal to no immune related adverse effects or toxicity observed in mouse pre-clinical studies. Notably, complete tumor regression was achieved at moderate doses in mouse models, with sustained remission after tumor rechallenge. The provided multispecific VHH constructs are robust with high stability within a range of pH and temperatures (e.g., including up to 90 ºC). Further, the manufacturing process of the 88 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 multispecific VHH constructs is simplified relative to that of bispecific antibodies. The provided multispecific VHH constructs of the disclosure may be optimized for subcutaneous dosing, and may also be engineered for the desired half-life of the construct. The results described herein above were carried out using the following methods and materials. VHH discovery and identification Standard immunization of 4 alpacas was performed with commercial recombinant proteins containing the extracellular loops of the two targets, expressed by mammalian cells and purified. The VHH-display phage library produced from the immunized alpaca B cells was panned on antibody-captured purified recombinant target proteins. The target-selected phage clones were screened for their ability to recognize their targets by standard ELISAs. The selected VHHs were expressed as soluble recombinant protein, then purified and quantified them, all by standard methods. The purified VHHs were characterized by: standard dilution ELISAs; standard competition studies for binding competition by other VHHs or commercial mAbs to the targets; standard immunofluorescence analysis (IFA) for recognition of mammalian cells engineered to express the target protein; and inhibition of target proteins by standard cell-based neutralizing assays. Characterization of VHH binding and neutralization properties To test the neutralization potency of the VHH polypeptides and multimeric VHHs, two different blockade bioassays were used. For CTLA4, the CTLA-4 Blockade Bioassay (Promega) was used. For PD-1, the PD-1 / PD-L1 Blockade Bioassay was used. Enzyme Linked Immunosorbent Assay (ELISA) Maxisorp ELISA plates (Nunc; Thermo Fisher USA) coated with recombinantly produced hPD-1 and / or hCTLA4 protein (0.5-5 g / ml) overnight at 4°C were used for immuno- binding assays (ELISA). Plates were washed 3 times with 1xPBS + 0.1% Tween, followed by washing 3 times with 1xPBS. Washed plates were blocked (4-5% non-fat dry milk in 1xPBS + 0.1% Tween) for 1 hour at room temperature (RT) with rocking. Serially diluted (1:5) hPD-1 and / or hCTLA4 binding VHHs, diluted in blocking solution, were incubated for 1 hour at RT 89 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 with rocking and washed as above. Equivalent control samples were spiked with a known amount of an irrelevant VHH for use as an internal standard. Binding of the VHHs to recombinant hPD-1 and / or hCTLA4 protein coating the wells was detected at A450 nm using horse radish peroxidase (HRP)-labeled anti-E-tag antibody and an ELISA reader. Bound HRP was detected using 3,3',5,5'-tetramethylbenzidine (TMB substrate, Sigma) and values were plotted as a function of the input VHH concentration. Illustratively, the plates were incubated with goat anti-E-tag-HRP conjugated antibody (Bethyl labs) diluted 1:5000 in blocking solution for 1 hour at RT with rocking and were washed as above before adding TMB microwell peroxidase substrate (KPL) to develop (incubated for 10-40 min). Development was stopped with 1M H2SO4, and the plates were read at 450nm on an ELx808 Ultra Microplate Reader (Bio-Tek instruments), (Mukherjee, J. et al., 2012, PloS ONE 7:e29941). VHH levels in unknown samples were determined by comparison of their signals to those of internal standards as previously described (Mukherjee, J. et al., 2014, PLoS One 9:e106422; Sheoran, AS et al., 2015, Infect Immun, 83:286-291; Moayeri, M. et al., 2016, Clin Vaccine Immunol, doi:10.1128 / cvi.00611-15; Sponseller, JK et al., 2014, J Infect Dis, doi:10.1093 / infdis / jiu605; Tzipori, S. et al., 1995, Infect Immun, 63:3621-3627). EC50values were calculated for the VHH concentration that secreted in a signal equal to 50% of the maximum signal. Computational analysis In general, data were analyzed using GraphPad Prism software version 6. All error bars refer to standard deviations. ELISA data were analyzed using nonlinear regression. Animal experiments Experiments using alpacas (camelids) involving the production of anti- hPD-1 and / or hCTLA4 VHHs as described herein were conducted using animals housed under standard and humane conditions with a standard commercial alpaca diet and tap water provided to the animals ad libitum. All experiments involving animals were performed under protocols approved by Tufts University and National Institute of Allergy and Infectious Diseases (NIAID) Animal Care and Use Committees. Work with alpacas was performed at Tufts under approved protocol Tuskegee University School of Veterinary Medicine (TUSVM) and Institutional Animal Care 90 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 and Use Committee (IACUC) Protocol #G2015-49. CTLA-4 / PD-1 combination neutralization assay The following provides the experimental protocol for the CTLA-4 / PD-1 combined neutralization assay, as shown in FIGs. 24-26. 1. Harvest GS-R2 / PD-L1 cells and gently re-suspend the cells with corresponding complete culture medium to the desired cell density (1.2 E6 cells / mL, 25 μL / well). 2. Add GS-R2 / PD-L1 cell suspension to the 96-well assay plate. 3. Dilute the controls and test samples with assay buffer. 4. Then transfer the diluted controls and test samples to the assay plate. 5. Incubate assay plates in cell incubator (37 °C with 5% CO2) for 0.5 hours. 6. Harvest GS-J4B / CTLA-4 / PD-1 cells and gently re-suspend the cells with assay buffer to the desired cell density (1.2 E6 cells / mL, 25 μL / well). 7. Transfer the GS-J4B / CTLA-4 / PD-1 cell suspension to the assay plate. And then transfer the diluted controls and test samples to the assay plate. 8. Incubate assay plates in cell incubator (37 °C with 5% CO2) for 6 hours. 9. Take out the assay plate from the incubator and add One-Lite Luciferase working solution to the corresponding wells of the assay plate. 10. Record the luminescence signal with PHERAstar CTLA-4 / PD-1 in NFAT luciferase reporter bioassay. Other Embodiments From the foregoing description, it will be apparent that variations and modifications may be made to the invention described herein to adopt it to various usages and conditions. Such embodiments are also within the scope of the following claims. The recitation of a listing of elements in any definition of a variable herein includes definitions of that variable as any single element or combination (or subcombination) of listed elements. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. All patents and publications mentioned in this specification are herein incorporated by reference to the same extent as if each independent patent and publication was specifically and 91 ACTIVE 714443023v3 Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 individually indicated to be incorporated by reference. 92 ACTIVE 714443023v3

Claims

Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 What is claimed is:

1. A multimeric VHH polypeptide which is a pentamer that specifically binds to a human CTLA4 polypeptide, or a fragment thereof, and to a human programmed cell death protein 1 (PD-1) polypeptide, or a fragment thereof, wherein the pentamer comprises CTLA4-binding VHH components, human PD-1-binding VHH components, and an albumin or human albumin- binding VHH component, as follows: (i) [CTLA4-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; (ii) [CTLA4-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; (iii) [albumin or human albumin-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH ] or CDR1-3 thereof -- [CTLA4-binding VHH] or CDR1-3 thereof; (iv) [CTLA4-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; or (v) [PD-1-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; wherein the VHH binding components are linked or joined by a linker [-].

2. The multimeric VHH polypeptide of claim 1, wherein the CTLA4-binding VHH is selected from a CTLA4 binding VHH polypeptide as set forth in Table 2 and the PD-1-binding VHH polypeptide is selected from a PD-1-binding VHH polypeptide as set forth in Table 1.

3. The multimeric VHH polypeptide of claim 1 or 2, wherein the pentamer comprises the structure [CTLA4-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; wherein the VHH binding 93 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 components are linked or joined by a linker [-].

4. The multimeric VHH polypeptide of claim 3, wherein the pentamer comprises the structure [CTLA4-binding XFV-E7 VHH] or CDR1-3 thereof – [CTLA4-binding XJD-A4 VHH] or CDR1-3 thereof – [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; wherein the VHH binding components are linked or joined by a linker [-].

5. The multimeric VHH polypeptide of claim 1 or 2, wherein the pentamer comprises the structure [CTLA4-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; wherein the VHH binding components are linked or joined by a linker [-].

6. The multimeric VHH polypeptide of claim 5, wherein the pentamer comprises the structure [CTLA4-binding XFV-E7 VHH] or CDR1-3 thereof – [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [CTLA4-binding XJD- A4 VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; wherein the VHH binding components are linked or joined by a linker [-].

7. The multimeric VHH polypeptide of claim 1 or 2, wherein the pentamer comprises the structure [albumin or human albumin-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH ] or CDR1-3 thereof -- [CTLA4-binding VHH] or CDR1-3 thereof; wherein the VHH binding components are linked or joined by a linker [-].

8. The multimeric VHH polypeptide of claim 7, wherein the pentamer comprises the structure [albumin or human albumin-binding VHH] or CDR1-3 thereof – [PD-1-binding XFU- D3 VHH] or CDR1-3 thereof – [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [CTLA4- binding XFV-E7 VHH] or CDR1-3 thereof -- [CTLA4-binding XJD-A4 VHH] or CDR1-3 thereof; wherein the VHH binding components are linked or joined by a linker [-].

9. The multimeric VHH polypeptide of claim 1 or 2, wherein the pentamer comprises the structure [CTLA4-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof 94 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 – [CTLA4-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; wherein the VHH binding components are linked or joined by a linker [-].

10. The multimeric VHH polypeptide of claim 9, wherein the pentamer comprises the structure [CTLA4-binding XFV-E7 VHH] or CDR1-3 thereof – [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [CTLA4-binding XJD-A4 VHH] or CDR1-3 thereof – [PD-1-binding XFU- D3 VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; wherein the VHH binding components are linked or joined by a linker [-].

11. The multimeric VHH polypeptide of claim 1 or 2, wherein the pentamer comprises the structure [PD-1-binding VHH] or CDR1-3 thereof – [PD-1-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [CTLA4-binding VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; wherein the VHH binding components are linked or joined by a linker [-].

12. The multimeric VHH polypeptide of claim 11, wherein the pentamer comprises the structure [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [CTLA4-binding XFV-E7 VHH] or CDR1-3 thereof – [CTLA4-binding XJD- A4 VHH] or CDR1-3 thereof – [albumin or human albumin-binding VHH] or CDR1-3 thereof; wherein the VHH binding components are linked or joined by a linker [-].

13. The multimeric VHH polypeptide of any one of claims 1-12, wherein the pentamer comprises: a CTLA4-binding VHH comprising CDR1, CDR2, and CDR3, wherein CDR1 comprises an amino acid sequence GX12X13LDSX14A (SEQ ID NO: 4527); wherein X12 is F or S; wherein X13 is S or T; and wherein X14 is F, V, or Y; CDR2 comprises an amino acid sequence GX15X16GX17FTX18 (SEQ ID NO: 4528); wherein X15 is K or R; wherein X16 is N or S; wherein X17 is D, G, or T; and wherein X18 is M, N, or Q; and CDR3 comprises an amino acid sequence X19X20VX21QVFX22LCPX23X24X25X26X27X28X29 (SEQ ID NO: 4529); wherein X19 is A or G; wherein X20is A or T; wherein X21is L, P, Q, or R; wherein X22is D, G, or H; wherein X23is I or L; wherein X24is S or W; wherein X25is E or S; wherein X26is E or P; wherein X27is N or Y; wherein X28is R or Y; 95 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 and wherein X29is D, E, H, or Y; and / or a CTLA4-binding VHH comprising CDR1, CDR2, and CDR3, wherein CDR1 comprises an amino acid sequence: AASGX40X41SX42PX43X44X45X46X47NX48X49G (SEQ ID NO: 4534); wherein X40 is S or absent; X41 is I or absent; X42 is S or A; X43 is absent or K; X44 is absent or W; X45 is absent or I; X46 is absent or V; X47 is absent or V; X48 is V, A, or D; and X49 is M or V; CDR2 comprises an amino acid sequence: AX50X51TSX52GX53TX54 (SEQ ID NO: 4535); wherein X50 is I or T; X51 is I or V; X52 is G or S; X53 is T or M; and X54 is K, N, or / R; and CDR3 comprises an amino acid sequence: NTKVPTGWNTQQWDEY (SEQ ID NO: 4536); and a human PD-1 binding VHH comprising CDR1, CDR2, and CDR3, wherein CDR1 comprises an amino acid sequence GPSFSRAT (SEQ ID NO: 4521); CDR2 comprises an amino acid sequence X1QSGITTY (SEQ ID NO: 4522), wherein X1 is A or S; and CDR3 comprises an amino acid sequence AADIDX2DDFFNPDY (SEQ ID NO: 4523), wherein X2 is N or S; or wherein CDR1 comprises an amino acid sequence X3X4X5FSX6X7VM (SEQ ID NO: 4524), wherein X3 is G or R; wherein X4 is D or R; wherein X5 is S or T; wherein X6 is E, P, or T; and wherein X7is D, E, or Y; CDR2 comprises an amino acid sequence TWX8X9GITY (SEQ ID NO: 4525), wherein X8is A, N, or T; and wherein X9is A or S; and CDR3 comprises an amino acid sequence AAAPX10NSDYDFLTGYGX11DS (SEQ ID NO: 4526), wherein X10is L or Q; and wherein X11is F or M.

14. The multimeric VHH polypeptide of any one of claims 1-13, wherein the pentamer comprises: a CTLA4-binding VHH comprising CDR1, CDR2, and CDR3, wherein CDR1 comprises the sequence: RASGSTLDSYAIG (SEQ ID NO: 4667) or GSTLDSYA (SEQ ID NO: 4596); CDR2 comprises the sequence: CIGKNGDFTQ (SEQ ID NO: 4668) or GKNGDFTQ (SEQ ID NO: 4597); and CDR3 comprises the sequence: AAVLQVFHLCPIWSENYH (SEQ ID NO: 4598); and / or a CTLA4-binding VHH comprising CDR1, CDR2, and CDR3, wherein CDR1 comprises the sequence: AASGSISSPNVMG (SEQ ID NO: 4665) or GSISSPNV (SEQ ID NO: 4590); CDR2 comprises the sequence: AIITSGGTTK (SEQ ID NO: 4666) or TSGGTTK (SEQ ID NO: 4591); and CDR3 comprises the sequence: NTKVPTGWNTQQWDEY (SEQ ID NO : 4592); and 96 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 a human PD-1 binding VHH comprising CDR1, CDR2, and CDR3, wherein CDR1 comprises wherein CDR1 comprises the sequence: AASGPSFSRATMT (SEQ ID NO: 4669) or GPSFSRAT (SEQ ID NO: 4545); CDR2 comprises the sequence: AVISQSGITTY (SEQ ID NO: 4670) or SQSGITTY (SEQ ID NO: 4546); and CDR3 comprises the sequence: AADIDSDDFFNPDY (SEQ ID NO: 4547).

15. The multimeric VHH polypeptide of any one of claims 1-14, wherein the [albumin or human albumin-binding VHH] component comprises CDR1, CDR2, and CDR3, wherein CDR1 comprises amino acid sequence AASGLTSDNYVIG (SEQ ID NO: 4657); CDR2 comprises amino acid sequence CISSRDGSTY (SEQ ID NO: 4658); and CDR3 comprises amino acid sequence AAQQVWAVCVLQAFEYDY (SEQ ID NO: 4659); wherein the VHH components are linked or joined by a linker.

16. A multimeric VHH polypeptide comprising CTLA4-binding VHH components, human PD-1-binding VHH components, and an albumin or human albumin-binding VHH component, as follows: (i) [XFV-E7 VHH] – [XJD-A4 VHH] – [XFU-D3 VHH] – [XFU-D3 VHH] – [albumin or human albumin-binding VHH]; (ii) [XF-E7 VHH] – [XFU-D3 VHH] – [XFU-D3 VHH] – [XJD-A4 VHH] – [albumin or human albumin-binding VHH]; (iii) [albumin or human albumin-binding VHH] -- [XFU-D3 VHH] – [XFU-D3 VHH] – [XFV-E7 VHH ] -- [XJD-A4 VHH]; (iv) [XFV-E7 VHH] – [XFU-D3 VHH] – [XJD-A4 VHH] – [XFU-D3 VHH] – [albumin or human albumin-binding VHH]; or (v) [XFU-D3 VHH] – [XFU-D3 VHH] – [XFV-E7 VHH] -- [XJD-A4 VHH] – [albumin or human albumin-binding VHH]; wherein the VHH components are linked or joined by a linker.

17. The multimeric VHH polypeptide of claim 16, which comprises: at least one [XFV-E7 VHH] comprising CDR1, CDR2, and CDR3, wherein CDR1 comprises the sequence: AASGSISSPNVMG (SEQ ID NO: 4665) or GSISSPNV (SEQ ID NO: 4590); CDR2 comprises the sequence: AIITSGGTTK (SEQ ID NO: 4666) or TSGGTTK (SEQ 97 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 ID NO: 4591); and CDR3 comprises the sequence: NTKVPTGWNTQQWDEY (SEQ ID NO: 4592); at least one [XJD-A4 VHH] comprising CDR1, CDR2, and CDR3, wherein CDR1 comprises the sequence RASGSTLDSYAIG (SEQ ID NO: 4667) or GSTLDSYA (SEQ ID NO: 4596); CDR2 comprises the sequence: CIGKNGDFTQ (SEQ ID NO: 4668) or GKNGDFTQ (SEQ ID NO: 4597); and CDR3 comprises the sequence: AAVLQVFHLCPIWSENYH (SEQ ID NO: 4598); at least one [XFU-D3 VHH] comprising CDR1, CDR2, and CDR3, wherein CDR1 CDR1 comprises the sequence: AASGPSFSRATMT (SEQ ID NO: 4669) or GPSFSRAT (SEQ ID NO: 4545); CDR2 comprises the sequence: AVISQSGITTY (SEQ ID NO: 4670) or SQSGITTY (SEQ ID NO: 4546); and CDR3 comprises the sequence: AADIDSDDFFNPDY (SEQ ID NO: 4547); and at least one [albumin or human albumin-binding VHH] comprising CDR1, CDR2, and CDR3, wherein CDR1 comprises the sequence AASGLTSDNYVIG (SEQ ID NO: 4657); CDR2 comprises the sequence CISSRDGSTY (SEQ ID NO: 4658); and CDR3 comprises the sequence AAQQVWAVCVLQAFEYDY (SEQ ID NO: 4659); wherein the VHH components are linked or joined by a linker.

18. The multimeric VHH polypeptide of claim 16 or 17, which comprises the structure [XFU-D3 VHH] – [XFU-D3 VHH] – [XFV-E7 VHH] -- [XJD-A4 VHH] – [albumin or human albumin-binding VHH]; wherein the VHH components are linked or joined by a linker.

19. The multimeric VHH polypeptide of any one of claims 1-18, wherein the linker comprises a flexible linker or a chemical linker.

20. The multimeric VHH polypeptide of claim 19, wherein the linker comprises a flexible linker selected from GGn, where n is 3-12.

21. The multimeric VHH polypeptide of claim 19 or 20, wherein the linker is selected from GGGG, GGGG, or GGGGG (SEQ ID NO: 4654).

22. The multimeric VHH polypeptide of any one of claims 1-21, optionally further comprising a signal peptide at the amino terminus of the polypeptide. 98 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 23. The multimeric VHH polypeptide of any one of claims 1-22, optionally further comprising an affinity tag at the carboxy terminus of the polypeptide.

24. The multimeric VHH polypeptide of claim 23, optionally further comprising a protease cleavage site linked to the affinity tag at the carboxy terminus of the polypeptide.

25. The multimeric VHH polypeptide of claim 24, wherein the protease cleavage site is a Tev protease site and / or the affinity tag is a His tag comprising 4 to 8 histidine (His) amino acids.

26. A pentameric, bispecific VHH binding molecule comprising the following structural components: an optional signal peptide; a first human PD-1-binding VHH; a second human PD- 1-binding VHH; a first CTLA4-binding VHH; a second CTLA4-binding VHH; an albumin or human albumin-binding VHH; and an optional protease cleavage site and affinity tag.

27. The pentameric bispecific VHH binding molecule of claim 26, wherein the first human PD-1-binding VHH comprises XFU-D3 VHH or CDR1-3 thereof; the second human PD-1- binding VHH comprises XFU-D3 VHH or CDR1-3 thereof; the first CTLA4-binding VHH comprises XFV-E7 VHH or CDR1-3 thereof; and the second CTLA4-binding VHH comprises XJD-A4 VHH or CDR1-3 thereof.

28. The pentameric bispecific VHH binding molecule of claim 26 or 27, wherein the structural components are separated by a linker.

29. The pentameric bispecific VHH binding molecule of claim 28, wherein the linker comprises a flexible linker selected from GGn, where n is 3-12.

30. The pentameric bispecific VHH binding molecule of claim 28 or 29, wherein the linker is selected from GGGG, GGGG, or GGGGG (SEQ ID NO: 4654).

31. The pentameric bispecific VHH binding molecule of any one of claims 26-30, wherein the first and second human PD-1 binding VHHs comprise CDR1, CDR2, and CDR3, wherein CDR1 comprises an amino acid sequence GPSFSRAT (SEQ ID NO: 4521); CDR2 comprises an amino acid sequence X1QSGITTY (SEQ ID NO: 4522), wherein X1 is A or S; and CDR3 comprises an amino acid sequence AADIDX2DDFFNPDY (SEQ ID NO: 4523), 99 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 wherein X2is N or S; or wherein CDR1 comprises an amino acid sequence X3X4X5FSX6X7VM (SEQ ID NO: 4524), wherein X3is G or R; wherein X4is D or R; wherein X5is S or T; wherein X6is E, P, or T; and wherein X7is D, E, or Y; CDR2 comprises an amino acid sequence TWX8X9GITY (SEQ ID NO: 4525), wherein X8 is A, N, or T; and wherein X9 is A or S; and CDR3 comprises an amino acid sequence AAAPX10NSDYDFLTGYGX11DS (SEQ ID NO: 4526), wherein X10 is L or Q; and wherein X11 is F or M; wherein the first CTLA4-binding VHH comprises CDR1, CDR2, and CDR3, wherein CDR1 comprises an amino acid sequence: AASGX40X41SX42PX43X44X45X46X47NX48X49G (SEQ ID NO: 4534); wherein X40is S or absent; X41is I or absent; X42is S or A; X43is absent or K; X44is absent or W; X45is absent or I; X46is absent or V; X47is absent or V; X48is V, A, or D; and X49is M or V; CDR2 comprises an amino acid sequence: AX50X51TSX52GX53TX54(SEQ ID NO: 4535); wherein X50 is I or T; X51 is I or V; X52 is G or S; X53 is T or M; and X54 is K, N, or / R; and CDR3 comprises an amino acid sequence: NTKVPTGWNTQQWDEY (SEQ ID NO: 4536); and wherein the second CTLA4-binding VHH comprises CDR1, CDR2, and CDR3, wherein CDR1 comprises an amino acid sequence GX12X13LDSX14A (SEQ ID NO: 4527); wherein X12is F or S; wherein X13is S or T; and wherein X14is F, V, or Y; CDR2 comprises an amino acid sequence GX15X16GX17FTX18(SEQ ID NO: 4528); wherein X15is K or R; wherein X16is N or S; wherein X17is D, G, or T; and wherein X18is M, N, or Q; and CDR3 comprises an amino acid sequence X19X20VX21QVFX22LCPX23X24X25X26X27X28X29 (SEQ ID NO: 4529); wherein X19 is A or G; wherein X20 is A or T; wherein X21 is L, P, Q, or R; wherein X22 is D, G, or H; wherein X23 is I or L; wherein X24 is S or W; wherein X25 is E or S; wherein X26 is E or P; wherein X27 is N or Y; wherein X28 is R or Y; and wherein X29is D, E, H, or Y.

32. The pentameric bispecific VHH binding molecule of any one of claims 26-31, wherein the first and second human PD-1 binding VHHs comprise CDR1, CDR2, and CDR3, wherein CDR1 comprises wherein CDR1 comprises the sequence: AASGPSFSRATMT (SEQ ID NO: 4669) or GPSFSRAT (SEQ ID NO: 4545); CDR2 comprises the sequence: AVISQSGITTY (SEQ ID NO: 4670) or SQSGITTY (SEQ ID NO: 4546); and CDR3 comprises the sequence: AADIDSDDFFNPDY (SEQ ID NO: 4547); wherein the first CTLA4-binding VHH comprises CDR1, CDR2, and CDR3, wherein 100 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 CDR1 comprises the sequence: AASGSISSPNVMG (SEQ ID NO: 4665) or GSISSPNV (SEQ ID NO: 4590); CDR2 comprises the sequence: AIITSGGTTK (SEQ ID NO: 4666) or TSGGTTK (SEQ ID NO: 4591); and CDR3 comprises the sequence: NTKVPTGWNTQQWDEY (SEQ ID NO: 4592); and wherein the second CTLA4-binding VHH comprises CDR1, CDR2, and CDR3, wherein CDR1 comprises the sequence: RASGSTLDSYAIG (SEQ ID NO: 4667) or GSTLDSYA (SEQ ID NO: 4596); CDR2 comprises the sequence: CIGKNGDFTQ (SEQ ID NO: 4668) or GKNGDFTQ (SEQ ID NO: 4597); and CDR3 comprises the sequence: AAVLQVFHLCPIWSENYH (SEQ ID NO: 4598).

33. The pentameric bispecific VHH binding molecule of any one of claims 26-32, wherein the first and second human PD-1 binding VHHs comprise an amino acid sequence having at least 85% identity to amino acid sequence: QVQLVESGGGLVQAGDSLRLSCAASGPSFSRATMTWFRQPPGKEREFVAVISQSGITTY YADSVKGRFTISRDNAKNTVYLRMNSLKPEDTAVYYCAADIDSDDFFNPDYWGQGTQ VTVSS (SEQ ID NO: 4478); wherein the first CTLA4-binding VHH comprises an amino acid sequence having at least 85% identity to amino acid sequence: QVQLVESGGGLVQAGGSLRLSCAASGSISSPNVMGWYRQAPGKQRELVAIITSGGTTKY ADSVKGRFTISRDNAKNTVSLQMNSLKPEDTAVYACNTKVPTGWNTQQWDEYWGQG TQVTVSS (SEQ ID NO: 4493); and wherein the second CTLA4-binding VHH comprises an amino acid sequence having at least 85% identity to amino acid sequence: QVQLVESGGDLVQPGGSLRLSCRASGSTLDSYAIGWFRQAPGKEREGVSCIGKNGDFTQ YVDSVKGRFTISRDNPNNIAYLEMNSLKPEDTAVYYCAAVLQVFHLCPIWSENYHYGQ GTQVTVSS (SEQ ID NO: 4495).

34. The pentameric bispecific VHH binding molecule of claim 33, wherein the first and second human PD-1 binding VHHs and the first and second CTLA4 binding VHHs comprise an amino acid sequence having at least 90 or 95% identity to the amino acid sequence of the respective human PD-1 binding VHH and CTLA4 binding VHHs. 101 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 35. The pentameric bispecific VHH binding molecule of any one of claims 26-33, wherein the albumin or human albumin-binding VHH comprises CDR1, CDR2, and CDR3, wherein CDR1 comprises amino acid sequence AASGLTSDNYVIG (SEQ ID NO: 4657); CDR2 comprises amino acid sequence CISSRDGSTY (SEQ ID NO: 4658); and CDR3 comprises amino acid sequence AAQQVWAVCVLQAFEYDY (SEQ ID NO: 4659).

36. The pentameric bispecific VHH binding molecule of any one of claims 27-34, wherein the albumin or human albumin-binding VHH comprises a sequence having at least 85%, 90%, 95%, or 100% identity to amino acid sequence: QVQLVESGGGLVQPGGSLRLSCAASGLTSDNYVIGWFRQAPGKEREGVSCISSRDGSTY YPPSVKGRFTISRDNAKNTVYLEMASLKPEDTAVYYCAAQQVWAVCVLQAFEYDYWG QGTQVTVSS (SEQ ID NO: 4656).

37. A multimeric VHH polypeptide that binds to a human CTLA4 polypeptide, or an antigen binding fragment thereof, and to a human programmed cell death protein 1 (PD-1) polypeptide, or an antigen binding fragment thereof, wherein the multimeric VHH polypeptide comprises two or more VHH polypeptides that specifically bind to human CTLA4 polypeptide, two or more VHH polypeptides that specifically bind to human PD-1 polypeptide, and a VHH polypeptide that specifically binds to human albumin polypeptide, wherein each VHH polypeptide that binds to the human PD-1 polypeptide is a VHH polypeptide which comprises complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, wherein CDR1, CDR2, and CDR3 each have at least 85% amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 1 or wherein CDR1, CDR2, or CDR2 comprises an amino acid sequence which corresponds to CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 1; and wherein each VHH polypeptide that binds to the human CTLA4 polypeptide is a VHH polypeptide which comprises complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, wherein CDR1, CDR2, and CDR3 each have at least 85% amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 1 or wherein CDR1, CDR2, or CDR2 comprises an amino acid sequence which corresponds to CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 2. 102 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 38. The multimeric VHH polypeptide of claim 37, wherein each VHH polypeptide that binds to the human PD-1 polypeptide is a VHH polypeptide which comprises complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, wherein CDR1, CDR2, and CDR3 each have at least about 90 % amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 1.

39. The multimeric VHH polypeptide of claim 37, wherein each VHH polypeptide that binds to the human PD-1 polypeptide is a VHH polypeptide which comprises complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, wherein CDR1, CDR2, and CDR3 each have at least about 95 % amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 1.

40. The multimeric VHH polypeptide of claim 37, wherein each VHH polypeptide that binds to the human CTLA4 polypeptide is a VHH polypeptide which comprises complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, wherein CDR1, CDR2, and CDR3 each have at least about 90 % amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 2.

41. The multimeric VHH polypeptide of claim 37, wherein each VHH polypeptide that binds to the human CTLA4 polypeptide is a VHH polypeptide which comprises complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, wherein CDR1, CDR2, and CDR3 each have at least about 95 % amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 2.

42. The multimeric VHH polypeptide of claim 37, wherein, in the anti-PD-1 VHH polypeptide, CDR1 comprises an amino acid sequence GPSFSRAT (SEQ ID NO: 4521); CDR2 comprises an amino acid sequence X1QSGITTY (SEQ ID NO: 4522), wherein X1 is A or S; and CDR3 comprises an amino acid sequence AADIDX2DDFFNPDY (SEQ ID NO: 4523), wherein X2 is N or S.

43. The multimeric VHH polypeptide of claim 37, wherein, in the anti-PD-1 VHH polypeptide, CDR1 comprises an amino acid sequence X3X4X5FSX6X7VM (SEQ ID NO: 4524), wherein X3 is G or R; wherein X4 is D or R; wherein X5 is S or T; wherein X6 is E, P, or T; and 103 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 wherein X7is D, E, or Y; CDR2 comprises an amino acid sequence TWX8X9GITY (SEQ ID NO: 4525), wherein X8is A, N, or T; and wherein X9is A or S; and CDR3 comprises an amino acid sequence AAAPX10NSDYDFLTGYGX11DS (SEQ ID NO: 4526), wherein X10is L or Q; and wherein X11 is F or M.

44. The multimeric VHH polypeptide of claim 37, wherein, in the anti-PD-1 VHH polypeptide, CDR1 comprises an amino acid sequence GPSFSRAT (SEQ ID NO: 4545); CDR2 comprises an amino acid sequence SQSGITTY (SEQ ID NO: 4546); and CDR3 comprises an amino acid sequence AADIDSDDFFNPDY (SEQ ID NO: 4547).

45. The multimeric VHH polypeptide of any one of claims 37-44, wherein, in the anti- CTLA4 VHH polypeptide, CDR1 comprises an amino acid sequence GX12X13LDSX14A (SEQ ID NO: 4527); wherein X12 is F or S; wherein X13 is S or T; and wherein X14 is F, V, or Y; CDR2 comprises an amino acid sequence GX15X16GX17FTX18(SEQ ID NO: 4528); wherein X15is K or R; wherein X16is N or S; wherein X17is D, G, or T; and wherein X18is M, N, or Q; and CDR3 comprises an amino acid sequence X19X20VX21QVFX22LCPX23X24X25X26X27X28X29 (SEQ ID NO: 4529); wherein X19 is A or G; wherein X20 is A or T; wherein X21 is L, P, Q, or R; wherein X22 is D, G, or H; wherein X23 is I or L; wherein X24 is S or W; wherein X25 is E or S; wherein X26 is E or P; wherein X27 is N or Y; wherein X28 is R or Y; and wherein X29is D, E, H, or Y.

46. The multimeric VHH polypeptide of any one of claims 37-44, wherein, in the anti- CTLA4 VHH polypeptide, CDR1 comprises an amino acid sequence GRTISGYG (SEQ ID NO: 4530); CDR2 comprises an amino acid sequence TWSGGX30X31F (SEQ ID NO: 4531); wherein X30is N or T; and wherein X31is A or T; and CDR3 comprises an amino acid sequence ASTVX32X33YWVPVX34RX35X36YYSX37SX38YX39Y (SEQ ID NO: 4532); wherein X32 is D or G; wherein X33 is R or V; wherein X34 is W or Y; wherein X35 is H or T; wherein X36 is D or E; 104 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 wherein X37is A or T; wherein X38is N or Y; and wherein X39is A or V.

47. The multimeric VHH polypeptide of any one of claims 37-44, wherein, in the anti- CTLA4 VHH polypeptide, CDR1 comprises an amino acid sequence: AASGX40X41SX42PX43X44X45X46X47NX48X49G (SEQ ID NO: 4534); wherein X40is S or absent; X41 is I or absent; X42 is S or A; X43 is absent or K; X44 is absent or W; X45 is absent or I; X46 is absent or V; X47 is absent or V; X48 is V, A, or D; and X49 is M or V; CDR2 comprises an amino acid sequence: AX50X51TSX52GX53TX54 (SEQ ID NO: 4535); wherein X50 is I or T; X51 is I or V; X52 is G or S; X53 is T or M; and X54 is K, N, or / R; and CDR3 comprises an amino acid sequence: NTKVPTGWNTQQWDEY (SEQ ID NO: 4536).

48. The multimeric VHH polypeptide of any one of claims 37-44, wherein, in the anti- CTLA4 VHH polypeptide, CDR1 comprises an amino acid sequence GSISSPNV (SEQ ID NO: 4590); CDR2 comprises an amino acid sequence TSGGTTK (SEQ ID NO: 4591); and CDR3 comprises an amino acid sequence NTKVPTGWNTQQWDEY (SEQ ID NO: 4592); and / or wherein CDR1 comprises an amino acid sequence GSTLDSYA (SEQ ID NO: 4596); CDR2 comprises an amino acid sequence GKNGDFTQ (SEQ ID NO: 4597); and CDR3 comprises an amino acid sequence AAVLQVFHLCPIWSENYH (SEQ ID NO: 4598).

49. A multimeric VHH polypeptide that binds to a human CTLA4 polypeptide, or an antigen binding fragment thereof, and to a human programmed cell death protein 1 (PD-1) polypeptide, or an antigen binding fragment thereof, wherein the multimeric VHH polypeptide comprises two or more VHH polypeptides that specifically bind to human CTLA4 polypeptide, two or more VHH polypeptides that specifically bind to human PD-1 polypeptide, and a VHH polypeptide that specifically binds to human albumin polypeptide; wherein at least one VHH polypeptide that binds to the CTLA4 polypeptide comprises complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, wherein: CDR1 comprises the sequence: AASGX1X2SX3PX4X5X6X7X8NX9X10G (SEQ ID NO: 105 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 4534), wherein X1is S or absent; wherein X2is I or absent; wherein X3is S or A; wherein X4is absent or K; wherein X5is absent or W; wherein X6is absent or I; wherein X7is absent or V; wherein X8is absent or V; wherein X9is V, A, or D; and wherein X10is M or V; CDR2 comprises the sequence: AX11X12TSX13GX14TX15 (SEQ ID NO: 4535), wherein X11 is I or T; wherein X12 is I or V; wherein X13 is G or S; wherein X14 is T or M; and wherein X15 is K, N, or R; and CDR3 comprises the sequence: NTKVPTGWNTQQWDEY (SEQ ID NO: 4536); or wherein at least one VHH polypeptide that binds to the CTLA4 polypeptide comprises complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, wherein: CDR1 comprises the sequence: X16A S X17X18X19X20X21S X22A X23G (SEQ ID NO: 4538); wherein X16is R or A; wherein X17is G or E; wherein X18is S, F, or R; wherein X19is T or S; wherein X20 is L or F; wherein X21 is D or S; wherein X22 is Y, V, or F; and wherein X23 is I or M; CDR2 comprises the sequence: X24X25X26X27X28GX29FTX30 (SEQ ID NO: 4539); wherein X24 is C or A; wherein X25 is I or V; wherein X26 is G or S; wherein X27 is R, K, or W; wherein X28is S or N; wherein X29is G, D, A, or T; and wherein X30is Q, N, M or Y; and CDR3 comprises the sequence: X31AX32X33QVFX34LCPX35WSEX36YX37(SEQ ID NO: 4540); wherein X31is A or G; wherein X32is V or I; wherein X33is L, Q, R, or P; wherein X34is D or H; wherein X35is I or L; wherein X36is N, T, or F; and wherein X37is Y, E, D, S, or H; and wherein each VHH polypeptide that binds to the human PD-1 polypeptide comprises complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, wherein: CDR1 comprises the sequence: AX38X39GX40X41X42X43X44X45X46X47X48 (SEQ ID NO: 4542); wherein X38is A or V; wherein X39is S or F; wherein X40is P or R; wherein X41is S, T, P, or A; wherein X42is F or I; wherein X43is S or R; wherein X44is R or M; wherein X45is A or Y; wherein X46is T, V, or S; wherein X47is M or V; and wherein X48is T, A, or G; CDR2 comprises the sequence: X49X50X51X52X53X54GX55X56TX57(SEQ ID NO: 4543); wherein X49 is A or T; wherein X50 is V, S, or A; wherein X51 is I or V; wherein X52 is A or S; wherein X53 is Q, R, or P; wherein X54 is S or N; wherein X55 is I or D; wherein X56 is T or N; and wherein X57 is Y or D; CDR3 comprises the sequence: AADIDX58X59DFFNPDY (SEQ ID NO: 4544); wherein 106 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 X58is N or S; and wherein X59is D or N.

50. The multimeric VHH polypeptide of claim 49 that binds to a human CTLA4 polypeptide, or an antigen binding fragment thereof, and to a human programmed cell death protein 1 (PD-1) polypeptide, or an antigen binding fragment thereof, wherein the multimeric VHH polypeptide comprises two or more VHH polypeptides that specifically bind to human CTLA4 polypeptide, two or more VHH polypeptides that specifically bind to human PD-1 polypeptide, and a VHH polypeptide that specifically binds to human albumin polypeptide; wherein at least one VHH polypeptide that binds to the CTLA4 polypeptide comprises complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, wherein: CDR1 comprises the sequence: AASGSISSPNVMG (SEQ ID NO: 4665) or GSISSPNV (SEQ ID NO: 4590); CDR2 comprises the sequence: AIITSGGTTK (SEQ ID NO: 4666) or TSGGTTK (SEQ ID NO: 4591); and CDR3 comprises the sequence: NTKVPTGWNTQQWDEY (SEQ ID NO: 4592); or wherein at least one VHH polypeptide that binds to the CTLA4 polypeptide comprises complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, wherein: CDR1 comprises the sequence: RASGSTLDSYAIG (SEQ ID NO: 4667) or GSTLDSYA (SEQ ID NO: 4596); CDR2 comprises the sequence: CIGKNGDFTQ (SEQ ID NO: 4668) or GKNGDFTQ (SEQ ID NO: 4597); and CDR3 comprises the sequence: AAVLQVFHLCPIWSENYH (SEQ ID NO: 4598); and wherein each VHH polypeptide that binds to the human PD-1 polypeptide comprises complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, wherein: CDR1 comprises the sequence: AASGPSFSRATMT (SEQ ID NO: 4669) or GPSFSRAT (SEQ ID NO: 4545); CDR2 comprises the sequence: AVISQSGITTY (SEQ ID NO: 4670) or SQSGITTY (SEQ ID NO: 4546); and CDR3 comprises the sequence: AADIDSDDFFNPDY (SEQ ID NO: 4546).

51. The multimeric VHH polypeptide of claim 49, wherein one or more VHH polypeptides 107 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 that specifically binds to human CTLA4 polypeptide, or a fragment thereof, comprises amino acid sequence: (i) QVQLVESGGGLVX1X2GGSLRLSCAASGX3X4SX5PX6X7X8X9X10NX11X12GWYRQ APGKQRX13LX14AX15X16TSX17GX18TX19YX20DSVX21X22RFTISRX23NAX24NTVSLQMX25S LKPEDTAVYX26CNTKVPTGWNTQQWDEYWGQGTQVTVSS (SEQ ID NO: 4533); wherein X1 is Q or E; wherein X2 is A or T; wherein X3 is S or absent; wherein X4 is I or absent; wherein X5is S or A; wherein X6is absent or K; wherein X7is absent or W; wherein X8is absent or I; wherein X9is absent or V; wherein X10is absent or V; wherein X11is V, A, or D; wherein X12is M or V; wherein X13is E or G; wherein X14is V or I; wherein X15is I or T; wherein X16is I or V; wherein X17is G or S; wherein X18is T or M; wherein X19is K, N, or R; wherein X20is A or S; wherein X21 is K or E; wherein X22 is G or D; wherein X23 is D or G; wherein X24 is K or R; wherein X25 is N, S, or D; and wherein X26 is A or T; and / or (ii) QVQLVESGGX1X2GGSLRLX3CX4ASX5X6X7X8X9SX10AX11GWX12RQX13PGKEREX14X15X16X17X18X19X20X21GX22FTX23YX24DSVKGRFTIX25RDX26X27X28NX29X30X31LX32MNX33LX34PX35DTX36X37YX38CX39AX40X41QVFX42LCPX43WSEX44YX45X46GQGTX47VTVSS (SEQ ID NO: 4537); wherein X1is D or G; wherein X2is P or A; wherein X3is S or T; wherein X4is R or A; wherein X5is G or E; wherein X6is S, F, or R; wherein X7is T or S; wherein X8is L or F; wherein X9 is D or S; wherein X10 is Y, V, or F; wherein X11 is I or M; wherein X12 is F or L; wherein X13 is A or G; wherein X14 is G or F; wherein X15 is V, L, or I; wherein X16 is S or A; wherein X17 is C or A; wherein X18 is I or V; wherein X19 is G or S; wherein X20 is R, K, or W; wherein X21 is S or N; wherein X22 is G, D, A, or T; wherein X23 is Q, N, M, or Y; wherein X24is V, I, S, or A; wherein X25is F, L, S, or G; wherein X26is N or I; wherein X27is P or A; wherein X28is K, N, or E; wherein X29is T, I, or M; wherein X30is A or V; wherein X31is Y or I; wherein X32is E or Q; wherein X33is S or N; wherein X34is K or R; wherein X35is E or Q; wherein X36is A or G; wherein X37is V or I; wherein X38is Y or F; wherein X39is A or G; wherein X40 is V or I; wherein X41 is L, Q, R, or P; wherein X42 is D or / H; wherein X43 is I or L; wherein X44 is N, T, or F; wherein X45 is Y, E, D, S, or H; wherein X46 is F, Y, W, or absent; and wherein X47 is Q or P; and wherein one or more VHH polypeptides that specifically binds to human PD-1 polypeptide, or a 108 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 fragment thereof, comprises amino acid sequence: QVQLVESGGGLVQAGX1SLRLSCAX2X3GX4X5X6X7X8X9X10X11X12WFRQX13PGX14EREFVX15X16X17X18X19X20GX21X22TX23YAX24SVKGRFTISRDNAKNTVX25LX26MNX27LK PEDTAVYYCAADIDX28X29DFFNPDYWGQGTQVTVSS (SEQ ID NO: 4541); wherein X1 is D or G; wherein X2 is A or V; wherein X3 is S or F; wherein X4 is P or R; wherein X5 is S, T, P, or A; wherein X6 is F or I; wherein X7 is S or R; wherein X8 is R or M; wherein X9 is A orY; wherein X10 is T, V, or S; wherein X11 is M or V; wherein X12 is T, A, or G; wherein X13 is P or A; wherein X14is K or R; wherein X15is A or T; wherein X16is V, S, or A; wherein X17is I orV; wherein X18is A or S; wherein X19is Q, R, or P; wherein X20is S or N; wherein X21is I or D; wherein X22is T or N; wherein X23is Y or D; wherein X24is D or N; wherein X25is Y or F; wherein X26is R or Q; wherein X27is S or N; wherein X28is N or S; and wherein X29is D or N.

52. The multimeric VHH polypeptide of claim 49, wherein one or more VHH polypeptides that specifically binds to human CTLA4 polypeptide, or a fragment thereof, comprises an amino acid sequence having at least 85% identity to an amino acid sequence selected from: (i) QVQLVESGGGLVQAGGSLRLSCAASGSISSPNVMGWYRQAPGKQRELVAIITSG GTTKYADSVKGRFTISRDNAKNTVSLQMNSLKPEDTAVYACNTKVPTGWNTQQWDEY WGQGTQVTVSS (SEQ ID NO: 4493); and / or (ii) QVQLVESGGGLVETGGSLRLSCAASGSAPKWIVVNAVGWYRQAPGKQRGLIAT VTSSGMTNYSDSVEDRFTISRGNARNTVSLQMSSLKPEDTAVYTCNTKVPTGWNTQQW DEYWGQGTQVTVSS (SEQ ID NO: 4495); and wherein one or more VHH polypeptides that specifically binds to human PD-1 polypeptide, or a fragment thereof, comprises an amino acid sequence having at least 85% identity to amino acid sequence: QVQLVESGGGLVQAGDSLRLSCAASGPSFSRATMTWFRQPPGKEREFVAVISQSGITTY YADSVKGRFTISRDNAKNTVYLRMNSLKPEDTAVYYCAADIDSDDFFNPDYWGQGTQ VTVSS (SEQ ID NO: 4478).

53. The multimeric VHH polypeptide of claim 52, wherein the one or more VHH polypeptides that specifically binds to human CTLA4 polypeptide, or a fragment thereof, 109 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 comprises an amino acid sequence having 90% or 95% identity to the amino acid sequence of (i) or (ii); and wherein one or more VHH polypeptides that specifically binds to human PD-1 polypeptide, or a fragment thereof, comprises an amino acid sequence having 90% or 95% identity to the anti-PD-1 VHH amino acid sequence.

54. The multimeric VHH polypeptide of any one of claims 1-25 or 37-53, which is a dimer, trimer, tetramer, pentamer, or hexamer.

55. The multimeric VHH polypeptide of any one of claims 1-25 or 37-54, wherein the albumin or human albumin-binding VHH comprises CDR1, CDR2, and CDR3, wherein CDR1 comprises amino acid sequence AASGLTSDNYVIG (SEQ ID NO: 4657); CDR2 comprises amino acid sequence CISSRDGSTY (SEQ ID NO: 4658); and CDR3 comprises amino acid sequence AAQQVWAVCVLQAFEYDY (SEQ ID NO: 4659).

56. The multimeric VHH polypeptide of any one of claims 1-25 or 37-55, wherein the albumin or human albumin-binding VHH comprises a sequence having at least 85%, 90%, 95%, or 100% identity to amino acid sequence: QVQLVESGGGLVQPGGSLRLSCAASGLTSDNYVIGWFRQAPGKEREGVSCISSRDGSTY YPPSVKGRFTISRDNAKNTVYLEMASLKPEDTAVYYCAAQQVWAVCVLQAFEYDYWG QGTQVTVSS (SEQ ID NO: 4656).

57. A single domain (VHH) polypeptide or an antigen binding fragment thereof that specifically binds to a human programmed cell death protein 1 (PD-1) polypeptide, wherein the VHH polypeptide comprises complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, wherein the CDR1, CDR2, and CDR3 each have at least 85% amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 1; or wherein the CDR1, CDR2, and CDR3 comprise an amino acid sequence corresponding to CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 1.

58. The VHH polypeptide or antigen binding fragment thereof of claim 57, wherein CDR1 comprises an amino acid sequence GPSFSRAT (SEQ ID NO: 4521), wherein CDR2 comprises an amino acid sequence X1QSGITTY (SEQ ID NO: 4522), wherein X1 is A or S; and 110 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 wherein CDR3 comprises an amino acid sequence AADIDX2DDFFNPDY (SEQ ID NO: 4523), wherein X2is N or S.

59. The VHH polypeptide or antigen binding fragment thereof of claim 57, wherein CDR1 comprises an amino acid sequence X3X4X5FSX6X7VM (SEQ ID NO: 4524); wherein X3is G or R; wherein X4is D or R; wherein X5is S or T; wherein X6is E, P, or T; and wherein X7 is D, E, or Y; wherein CDR2 comprises an amino acid sequence TWX8X9GITY (SEQ ID NO: 4525); wherein X8 is A, N, or T; and wherein X9 is A or S; and wherein CDR3 comprises an amino acid sequence AAAPX10NSDYDFLTGYGX11DS (SEQ ID NO: 4526); wherein X10 is L or Q; and wherein X11 is F or M.

60. A single domain (VHH) polypeptide or an antigen binding fragment thereof that specifically binds to a human cytotoxic T-lymphocyte-associated protein 4 (CTLA4) polypeptide, wherein the VHH polypeptide comprises complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, wherein CDR1, CDR2, and CDR3 each have at least 85% or 90% amino acid sequence identity to a corresponding CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 2; or wherein the CDR1, CDR2, and CDR3 comprise an amino acid sequence corresponding to CDR1, CDR2, and CDR3 of a VHH polypeptide listed in Table 2.

61. The VHH polypeptide or an antigen binding fragment thereof of claim 60, wherein CDR1 comprises an amino acid sequence GX12X13LDSX14A (SEQ ID NO: 4527); wherein X12 is F or S; wherein X13 is S or T; and wherein X14 is F, V, or Y; wherein CDR2 comprises an amino acid sequence GX15X16GX17FTX18 (SEQ ID NO: 4528); wherein X15 is K or R; wherein X16 is N or S; wherein X17 is D, G, or T; and wherein X18 is M, N, or Q; wherein CDR3 comprises an amino acid sequence X19X20VX21QVFX22LCPX23X24X25X26X27X28X29(SEQ ID NO: 4529); wherein X19is A or G; wherein X20is A or T; wherein X21is L, P, Q, or R; wherein X22is D, G, or H; wherein X23is I or L; wherein X24is S or W; wherein X25is E or S; wherein X26is E or P; wherein X27is N or Y; wherein X28 is R or Y; and wherein X29 is D, E, H, or Y.

62. The VHH polypeptide or an antigen binding fragment thereof of claim 60, 111 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 wherein CDR1 comprises an amino acid sequence GRTISGYG (SEQ ID NO: 4530), wherein CDR2 comprises an amino acid sequence TWSGGX30X31F (SEQ ID NO: 4531); wherein X30is N or T; and wherein X31is A or T; and wherein CDR3 comprises an amino acid sequence ASTVX32X33YWVPVX34RX35X36YYSX37SX38YX39Y (SEQ ID NO: 4532); wherein X32 is D or G; wherein X33 is R or V; wherein X34 is W or Y; wherein X35 is H or T; wherein X36 is D or E; wherein X37 is A or T; wherein X38 is N or Y; and wherein X39 is A or V.

63. A multimeric VHH polypeptide or an antigen binding fragment thereof that specifically binds to a human PD-1 polypeptide, wherein the multimeric VHH polypeptide comprises two or more VHH polypeptides that specifically bind to human PD-1 polypeptide, and wherein each VHH polypeptide is a VHH polypeptide of any of claims 57-59.

64. A multimeric VHH polypeptide or an antigen binding fragment thereof that specifically binds to a human CTLA4 polypeptide, wherein the multimeric VHH polypeptide comprises two or more VHH polypeptides that specifically bind to human CTLA4 polypeptide, and wherein each VHH polypeptide is a VHH polypeptide of any of claims 60-62.

65. A multimeric VHH polypeptide that binds to a human CTLA4 polypeptide, or a fragment thereof, and a human PD-1 polypeptide, or a fragment thereof, wherein the multimeric VHH polypeptide comprises two or more VHH polypeptides that specifically bind to human CTLA4 polypeptide, two or more VHH polypeptides that specifically bind to human PD-1 polypeptide, and a VHH polypeptide that specifically binds to albumin or human albumin polypeptide, wherein each VHH polypeptide that binds to the human PD-1 polypeptide is a VHH polypeptide of any of claims 57-59, and wherein each VHH polypeptide that binds to the human CTLA4 polypeptide is a VHH polypeptide of any of claims 60-62.

66. The multimeric VHH polypeptide of any one of claim 65, wherein the anti-albumin VHH comprises a sequence having at least 85%, at least 90%, at least 95%, or 100% identity to amino 112 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 acid sequence QVQLVESGGGLVQPGGSLRLSCAASGLTSDNYVIGWFRQAPGKEREGVSCISSRDGSTY YPPSVKGRFTISRDNAKNTVYLEMASLKPEDTAVYYCAAQQVWAVCVLQAFEYDYWG QGTQVTVSS (SEQ ID NO: 4656).

67. The multimeric VHH polypeptide of any one of claim 65 or 66, wherein the anti-albumin VHH comprises amino acid sequence QVQLVESGGGLVQPGGSLRLSCAASGLTSDNYVIGWFRQAPGKEREGVSCISSRDGSTY YPPSVKGRFTISRDNAKNTVYLEMASLKPEDTAVYYCAAQQVWAVCVLQAFEYDYWG QGTQVTVSS (SEQ ID NO: 4656).

68. An isolated polynucleotide encoding the multimeric VHH polypeptide of any one of claims 1-25, 37-56, or 63-67.

69. An isolated polynucleotide encoding the VHH polypeptide of any one of claims 57-62.

70. An isolated polynucleotide encoding the pentameric bispecific VHH binding molecule of any one of claims 26-36.

71. A vector comprising the isolated polynucleotide of claim 68; optionally, wherein the vector is a viral or a non-viral expression vector.

72. A vector comprising the isolated polynucleotide of claim 69; optionally, wherein the vector is a viral or a non-viral expression vector.

73. A vector comprising the isolated polynucleotide of claim 70; optionally, wherein the vector is a viral or a non-viral expression vector.

74. A host cell comprising the vector of claim 71.

75. A host cell comprising the vector of claim 72.

76. A host cell comprising the vector of claim 73.

77. A pharmaceutical composition comprising an effective amount of the multimeric VHH polypeptide of any one of claims 1-25, 37-56, or 63-67, and a pharmaceutically acceptable 113 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 excipient, carrier, or diluent.

78. A pharmaceutical composition comprising an effective amount of the VHH polypeptide of any one of claims 57-62, and a pharmaceutically acceptable excipient, carrier, or diluent.

79. A pharmaceutical composition comprising an effective amount of the pentameric bispecific VHH binding molecule of any one of claims 26-36, and a pharmaceutically acceptable excipient, carrier, or diluent.

80. A pharmaceutical composition comprising an effective amount of the isolated polynucleotide of any one of claims 68-70, or the vector of any one of claims 71-73, and a pharmaceutically acceptable excipient, carrier, or diluent.

81. A method of treating a cancer, tumor, or neoplasia in a subject, the method comprising: administering to a subject in need thereof an effective amount of the multimeric VHH polypeptide of any one of claims 1-25, 37-56, or 63-67, the pentameric bispecific VHH binding molecule of any one of claims 26-36, or the VHH polypeptide of any one of claims 57-62, or a pharmaceutically acceptable composition thereof.

82. A method of treating a cancer, tumor, or neoplasia in a subject, the method comprising: administering to a subject in need thereof an effective amount of the isolated polynucleotide of claim 68-70, or a pharmaceutically acceptable composition thereof.

83. A method of treating a cancer, tumor, or neoplasia in a subject, the method comprising: administering to a subject in need thereof an effective amount of the vector of any one of claims 71-73, or a pharmaceutically acceptable composition thereof.

84. The method of any one of claims 81-83, wherein the cancer, tumor, or neoplasia is selected from metastatic cancer, a solid tumor, a hematologic cancer, leukemia, lymphoma, osteosarcoma, rhabdomyosarcoma, neuroblastoma, melanoma, kidney cancer, leukemia, renal transitional cell cancer, Wilm’s cancer, ovarian cancer, pancreatic cancer, breast cancer, triple 114 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 negative breast cancer, colon cancer, colorectal cancer (CRC), prostate cancer, bone cancer, lung cancer, non-small cell lung cancer (NSCLC), gastric cancer, cervical cancer, ovarian cancer, bladder cancer, synovial sarcoma, head and neck cancer, squamous cell carcinoma, multiple myeloma, renal cancer, retinoblastoma, hepatoblastoma, hepatocellular carcinoma (HCC), melanoma, rhabdoid tumor of the kidney, Ewing’s sarcoma, chondrosarcoma, brain cancer, glioblastoma, meningioma, pituitary adenoma, vestibular schwannoma, a primitive neuroectodermal tumor, medulloblastoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma, choroid plexus papilloma, polycythemia vera, thrombocythemia, idiopathic myelofibrosis, soft tissue sarcoma, thyroid cancer, endometrial cancer, carcinoid, or liver cancer.

85. The method of any one of claims 81-84, wherein the cancer, tumor, or neoplasia is selected from a solid tumor, Non-Small Cell Lung Cancer (NSCLC), triple negative breast cancer, renal cell carcinoma, melanoma, bladder cancer, hepatocellular carcinoma, colon cancer, or colorectal cancer (CRC).

86. The method of any one of claims 81-85, wherein the method has improved safety in the subject compared to administration of a reference antibody to the subject.

87. The method of any one of claims 81-85, wherein the multimeric VHH polypeptide pentamer comprising the structure [PD-1-binding XFU-D3 VHH] or CDR1-3 thereof – [PD- 1-binding XFU-D3 VHH] or CDR1-3 thereof – [CTLA4-binding XFV-E7 VHH] or CDR1-3 thereof – [CTLA4-binding XJD-A4 VHH] or CDR1-3 thereof – [albumin or human albumin- binding VHH] or CDR1-3 thereof is administered daily in an effective amount of 0.01mg / kg or 1 mg for 6 weeks.

88. A method of modulating, stimulating, or eliciting an immune response, the method comprising contacting a cell with the multimeric VHH polypeptide of any one of claims 1-25, 37-56, or 63-67, the pentameric bispecific VHH binding molecule of any one of claims 26-36, or the VHH polypeptide of any one of claims 57-62, or a pharmaceutically acceptable composition thereof.

89. The multimeric VHH polypeptide of any one of claims 1-25, 37-56, or 63-67, the 115 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 pentameric bispecific VHH binding molecule of any one of claims 26-36, the VHH polypeptide of any one of claims 57-62, or the pharmaceutical composition of any one of claims 77-80 for use in therapy.

90. Use of the multimeric VHH polypeptide of any one of claims 1-25, 37-56, or 63-67, the pentameric bispecific VHH binding molecule of any one of claims 26-36, the VHH polypeptide of any one of claims 57-62, or a pharmaceutically acceptable composition thereof, in a method of treating a cancer, tumor, or neoplasia.

91. The multimeric VHH polypeptide, the pentameric bispecific VHH binding molecule, or the VHH polypeptide for use in therapy of claim 89, or the use of claim 90, wherein the therapy is for treating, or the cancer, tumor, or neoplasia is selected from, metastatic cancer, a solid tumor, a hematologic cancer, leukemia, lymphoma, osteosarcoma, rhabdomyosarcoma, neuroblastoma, melanoma, kidney cancer, leukemia, renal transitional cell cancer, Wilm’s cancer, ovarian cancer, pancreatic cancer, breast cancer, triple negative breast cancer, colon cancer, colorectal cancer (CRC), prostate cancer, bone cancer, lung cancer, non-small cell lung cancer (NSCLC), gastric cancer, cervical cancer, ovarian cancer, bladder cancer, synovial sarcoma, head and neck cancer, squamous cell carcinoma, multiple myeloma, renal cancer, retinoblastoma, hepatoblastoma, hepatocellular carcinoma (HCC), melanoma, rhabdoid tumor of the kidney, Ewing’s sarcoma, chondrosarcoma, brain cancer, glioblastoma, meningioma, pituitary adenoma, vestibular schwannoma, a primitive neuroectodermal tumor, medulloblastoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma, choroid plexus papilloma, polycythemia vera, thrombocythemia, idiopathic myelofibrosis, soft tissue sarcoma, thyroid cancer, endometrial cancer, carcinoid, or liver cancer.

92. The multimeric VHH polypeptide, the pentameric bispecific VHH binding molecule, or the VHH polypeptide for use in therapy or the use of claim 91, wherein the therapy is for treating, or the cancer, tumor, or neoplasia is selected from a solid tumor, triple negative breast cancer, NSCLC, renal cell carcinoma, melanoma, bladder cancer, hepatocellular carcinoma, colon cancer, or colorectal cancer (CRC).

93. A kit comprising the multimeric VHH polypeptide of any one of claims 1-25, 37-56, or 63-67, the pentameric bispecific VHH binding molecule of any one of claims 26-36, or the VHH 116 ACTIVE 714443023v3Attorney Docket No.: 167774-013801 / PCT Electronic Deposit Date: September 10, 2025 polypeptide of any one of claims 57-62, or a pharmaceutical composition thereof, for treating a tumor, cancer, or neoplasia; and optionally comprising instructions for use. 117 ACTIVE 714443023v3

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