Complex, pharmaceutical composition and related use

Description

COMPLEX, PHARMACEUTICAL COMPOSITION AND RELATED USE Divided from BR 11 2017 023853-5 Cross-referencing to related patent applications.

[001] This application claims priority under 35 U.S.C. § 119(e) for U.S. Provisional Applications Nos. 62 / 157,933, 62 / 273,953, and 62 / 296,032, filed on May 6, 2015, December 31, 2015, and February 16, 2016, respectively, the contents of each of which are incorporated herein by reference in their entirety. FUNDAMENTALS

[002] Throughout and in this disclosure are technical and patent publications, mentioned by an identifying citation or an Arabic numeral. The full bibliographical citation corresponding to the Arabic numeral is found in the descriptive report, preceding the claims. The disclosures of all references cited in this descriptive report are incorporated by reference in the present application to more fully describe the state of the art to which this disclosure belongs.

[003] Several diseases involve improper immune function in the pathogenesis or exacerbation of symptoms. Although several immunotherapies exist, they are frequently associated with off-target effects due to lack of targeting specificity and / or adverse side effects.

[004] Thus, there is a need to find safe and effective therapies for these disorders. This revelation meets that need and also provides related advantages. SUMMARY OF REVELATION

[005] This disclosure relates to a nanomedicine, which, in one aspect, is a complex comprising a nanoparticle core coupled to several disease-relevant antigen-MHC complexes (abbreviated in this descriptive report) Petition 870250027877, dated 07 / 04 / 2025, page 11 / 384 2 / 299 as “pMHCs” or “pMHC complexes”), which are useful for expanding and differentiating T cell populations and treating disease when administered in an effective amount to an individual. The nanoparticle core comprises various compositions or components, as described in more detail in that descriptive report. In some respects, the nanoparticle core has a diameter selected from the group of about 1 nm to about 100 nm; from about 1 nm to about 75 nm; from about 1 nm to about 50 nm; from about 1 nm to about 25 nm; from about 1 nm to about 25 nm; from about 5 nm to about 100 nm; from about 5 nm to about 50 nm; or from about 5 nm to about 25 nm, or from about 15 nm to about 25 nm or about 20 nm.In some embodiments, the core of the nanoparticles has a diameter of about 25 nm to about 60 nm, or about 25 nm to about 50 nm, or about 20 nm to about 40 nm, or about 15 nm to about 50 nm, or about 15 nm to about 40 nm, or about 15 nm to about 35 nm, or about 15 nm to about 30 nm, or about 15 nm to about 25 nm, or alternatively, about 15 nm or about 20 nm or about 25 nm or about 30 nm or about 35 nm or about 40 nm.

[006] In some respects, the number of pMHCs per nanoparticle core (cited in that descriptive report as the “valence” of the nanoparticle complex) may vary from about 1 pMHC complex to 1 nanoparticle core to about 6,000 pMHC complexes to 1 nanoparticle core or, alternatively, from about 10:1 to about 6,000:1 or, alternatively, from about 11:1 to about 6,000:1 or, alternatively, from about 12:1 to about 6,000:1 or, alternatively, at least 2:1 or, alternatively, at least 8:1 or, alternatively, at least 9:1 or, alternatively, at least 10:1 or, alternatively, at least 11:1 or, alternatively, at least 12:1. In some Petition 870250027877, dated 07 / 04 / 2025, p. 12 / 384 3 / 299 aspects, the number of pMHCs per nanoparticle core is from about 10:1 to about 6,000:1, or from about 20:1 to about 5,500:1, or alternatively, from about 10:1 to about 5000:1 or, alternatively, from about 10:1 to about 4000:1 or, alternatively, from about 10:1 to about 3500:1 or, alternatively, from about 10:1 to about 3000:1 or, alternatively, from about 10:1 to about 2500:1 or, alternatively, from about 10:1 to about 2000:1 or, alternatively, from about 10:1 to about 1500:1 or, alternatively, from about 10:1 to 1000:1 or, alternatively, from about 10:1 to about 500:1 or, alternatively, from about 10:1 to about 100:1 or, alternatively, from about 20:1 to about 50:1 or, alternatively, from about 25:1 to about 60:1; alternatively from about 30:1 to about 50:1 or, alternatively, from about 35:1 to about 45:1 or, Alternatively, approximately 40:1.

[007] In some respects, the nanoparticle core has a valence defined by the surface area of ​​the core, also referred to in this descriptive report as density. In these respects, the density of pMHC per nanoparticle is from about 0.025 pMHC / 100 nm2 to about 100 pMHC / 100 nm2 of the surface area of ​​the nanoparticle core or, alternatively, from about 0.406 pMHC / 100 nm2 to about 50 pMHC / 100 nm2; or, alternatively, from about 0.05 pMHC / 100 nm2 to about 25 pMHC / 100 nm2. In certain aspects, the density of pMHC per nanoparticle is from about 0.4 pMHC / 100 nm² to about 25 pMHC / 100 nm², or from about 0.4 pMHC / 100 nm² to about 20 pMHC / 100 nm², or from about 0.4 pMHC / 100 nm² to about 15 pMHC / 100 nm², or from about 0.4 pMHC / 100 nm² to about 14 pMHC / 100 nm², or from about 0.4 pMHC / 100 nm² to about 13 pMHC / 100 nm², or from about 0.4 pMHC / 100 nm² to about 12 pMHC / 100 nm², or from about 0.4 pMHC / 100 nm² to about 11.6 Petition 870250027877, dated 07 / 04 / 2025, p. 13 / 384 4 / 299 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 11.5 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 11 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 10 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 9 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 8 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 7 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 6 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 5 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 4 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 3 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 2.5 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 2 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 1.5 pMHC / 100

[008] nm2.In another aspect, the nanoparticle can have a pMHC density of about 0.22 pMHC / 100 nm2 up to about 10 pMHC / 100 nm2, or from about 0.22 pMHC / 100 nm2 up to about 9 pMHC / 100 nm2, or from about 0.22 pMHC / 100 nm2 up to about 8 pMHC / 100 nm2, or from about 0.22 pMHC / 100 nm2 up to about 7 pMHC / 100 nm2, or from about 0.22 pMHC / 100 nm2 up to about 6 pMHC / 100 nm2, or from about 0.22 pMHC / 100 nm2 up to about 5 pMHC / 100 nm2, or from about 0.22 pMHC / 100 nm2 up to about 4 pMHC / 100 nm2, or from about 0.22 pMHC / 100 nm2 to about 3 pMHC / 100 nm2, or from about 0.22 pMHC / 100 nm2 to about 2 pMHC / 100 nm2, or from about 0.22 pMHC / 100 nm2 to about 1.5 pMHC / 100 nm2. In some aspects, the nanoparticle has a pMHC density of about 0.22 pMHC / 100 nm2 to about 10 pMHC / 100 nm2, or 0.24 pMHC / 100 nm2 to about 9 pMHC / 100 nm2. or from about 0.26 pMHC / 100 nm² to about 8 pMHC / 100 nm², or from about 0.28 pMHC / 100 nm² to about 7 pMHC / 100 nm², or from about 0.24 pMHC / 100 nm² to about 4 pMHC / 100 nm², or from about 0.5 pMHC / 100 nm² to about 3 pMHC / 100 nm², or from about 0.6 pMHC / 100 nm² to about 1.5 pMHC / 100 nm². In a Petition 870250027877, dated 07 / 04 / 2025, p. 14 / 384 5 / 299 additional aspect, the nanoparticle has a pMHC density of about 0.4 pMHC / 100 nm2 to about 1.3 pMHC / 100 nm2 or, alternatively, from about 0.5 pMHC / 100 nm2 to about 0.9 pMHC / 100 nm2 or, alternatively, from about 0.6 pMHC / 100 nm2 to about 0.8 pMHC / 100 nm2.

[009] In some embodiments, the nanoparticle may have a pMHC density of approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4,8, 5,9, 6,0, 6,1, 6,2, 6,3, 6,4, 6,5, 6,6, 6,7, 6,8, 6,9, 7,0, 7,1, 7,2, 7,3, 7,4, 7,5, 7,6, 7,7, 7,8, 7,9, 8,0, 8,1, 8,2, 8,3, 8,4, 8,5, 8,6, 8,7, 8,8, 8,9, 9,0, 9,1, 9,2, 9,3, 9,4, 9,5, 9,6, 9,7, 9,8, 9,9, 10,0, 10,1, 10,2, 10,3, 10,4,10 5, 10, 6, 10, 7, 10, 8, 10, 9, 11, 0, 11, 1, 11, 2, 11, 3, 11, 4, 11, 5, 11, 6, 11, 7 11.9 or 12.0 pMHC / 100 11.8 nm2. In specific embodiments, the nanoparticle may have a pMHC density of about 0.4 pMHC / 100 nm2 to about 1.5 pMHC / 100 nm2 or from about 0.4 pMHC / 100 nm2 to about 6 pMHC / 100 nm2 or from about 0.4 pMHC / 100 nm2 to about 12 pMHC / 100 nm2.

[0010] In yet another aspect, the nanoparticle has a pMHC density as defined in this descriptive report of about 0.4 pMHC / 100 nm2 to about 1.3 pMHC / 100 nm2 or, alternatively, from about 0.5 pMHC / 100 nm2 to about 0.9 pMHC / 100 nm2 or, alternatively, from about 0.6 pMHC / 100 nm2 to about 0.8 pMHC / 100 nm2, and further wherein the nanoparticle core has a diameter of about 25 nm to about 60 nm, or from about 25 nm to about 50 nm, or from about 20 nm to about 40 nm, or from about 15 nm to about 50 nm, or from about 15 nm to about 40 nm, or from about 15 nm to about 35 nm, or from about 15 nm to about 30 nm, or from about 15 nm to about 25 nm, or alternatively, about 15 nm or about 20 nm or about 25 nm or about Petition 870250027877, dated 07 / 04 / 2025, p. 15 / 384 6 / 299 nm or approximately 35 nm or approximately 40 nm.

[0011] In some respects, the nanoparticle core still comprises several co-stimulatory molecules, co-stimulatory antibodies, receptor-blocking inhibitor antibodies and / or several cytokines coupled to the nanoparticle core.

[0012] Thus, certain aspects of the revelation are related to a complex comprising or, alternatively, consisting basically of, or even consisting of nanoparticle cores coupled to various pMHC complexes, wherein the nanoparticle cores optionally further comprise, or further consist of, or alternatively, further consist basically of one or more co-stimulatory molecules and / or one or more cytokines coupled to the nanoparticle core.For these compositions containing multiple complexes, the pMHC complexes in each nanoparticle core are either the same or different from each other; and / or the MHCs of the pMHC complexes in each nanoparticle core are either the same or different from each other; and / or the cytokines in each nanoparticle core are either the same or different from each other; and / or the co-stimulatory molecules in each nanoparticle core are either the same or different from each other; and / or the diameters of the nanoparticle cores are either the same or different from each other; and / or the valences of the pMHC complexes in each nanoparticle core are either the same or different from each other; and / or the densities of the pMHC complexes in each nanoparticle core are either the same or different from each other; and / or the valences of the co-stimulatory molecules in each nanoparticle core are either the same or different from each other; and / or the valences of the cytokines in each nanoparticle core are either the same or different from each other.

[0013] In certain respects, compositions comprising various complexes provided in this descriptive report are provided in this descriptive report. In some Petition 870250027877, dated 07 / 04 / 2025, page 16 / 384 7 / 299 embodiments, the compositions further comprise a carrier, optionally a pharmaceutical carrier. In some embodiments, the compositions provided in this descriptive report may optionally comprise one or more nanoparticle cores coupled to one or more co-stimulatory molecules and / or cytokines. Consequently, in some embodiments, the compositions comprise or, alternatively, consist basically of, or still consist of: 1) several nanoparticle cores coupled to several antigen-MHC complexes, wherein at least a portion of the nanoparticle cores further comprises one or more co-stimulatory molecules and / or one or more cytokines and a second portion of the nanoparticle cores does not yet comprise a co-stimulatory molecule and / or a cytokine, and 2) several nanoparticle cores coupled to one or more co-stimulatory molecules and / or cytokines.

[0014] Additional aspects of the discovery relate to disease-relevant antigens, MHCs, and combinations thereof, optimized for the treatment or prevention of disease in human and animal patients.

[0015] This disclosure also provides compositions and methods of use for any of the above complexes or compositions, each optionally combined with a carrier, for example, a pharmaceutically acceptable carrier.

[0016] This disclosure also provides methods for differentiating or triggering the formation of type 1 regulatory T cells (TR1) in a dose-independent manner. The Applicant found that the pMHC density in the nanoparticle core regulates the ability of pMHC in the nanoparticle core to trigger TR1 cell formation in a dose-independent manner, while the pMHC dose regulates the magnitude of TR1 cell expansion in a pMHC density-independent manner. The Applicant observed that the pMHC density threshold and the dose-independent effects of pMHC density Petition 870250027877, dated 07 / 04 / 2025, page 17 / 384 8 / 299 concerning the formation versus expansion of Tr1 cells are unexpected findings that could not be predicted based on conventional immunological knowledge in the art. These methods require contact (in vitro or in vivo) of cognate T cells with an effective amount of a pMHC-N or a composition disclosed in this descriptive report. In certain aspects, density-dependent methods relate to an activated T cell or a memory T cell being differentiated into an IL-10-producing cognate Tr1 cell that optionally possesses the CD49b and / or Lag3 marker and / or a B cell being differentiated into a regulatory B cell by contact of the activated T cell or memory T cell with an effective amount of the complex or composition disclosed in this descriptive report. In some embodiments, the differentiated Tr1 cell binds to a B cell, thereby differentiating the B cell into a regulatory B cell.In certain aspects of the methods, contact is made in vitro or in vivo. In some embodiments, the pMHC-NP or composition containing several pMHC-NPs has pMHC-NPs that have an average nanoparticle core diameter of about 25 nm to about 60 nm, or about 25 nm to about 50 nm, or about 20 nm to about 40 nm, or about 15 nm to about 50 nm, or about 15 nm to about 40 nm, or about 15 nm to about 35 nm, or about 15 nm to about 30 nm, or about 15 nm to about 25 nm, or alternatively, about 15 nm or about 20 nm or about 25 nm or about 30 nm or about 35 nm or about 40 nm.In some respects, the nanoparticle core still comprises an outer coating or layer, wherein the diameter of the core and outer layer has an average diameter of about 30 nm to about 75 nm, or about 30 nm to about 70 nm, or about 30 nm to about 60 nm, or about 30 nm to about 50 nm or about 40 nm. In some respects, the nanoparticle has an average pMHC density of about 0.4 pMHC / 100 nm² to about 12. Petition 870250027877, dated 07 / 04 / 2025, p. 18 / 384 9 / 299 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 11.6 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 11.5 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 11 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 10 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 9 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 8 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 7 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 6 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 5 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 4 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 3 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 2.5 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 2 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 1.5

[0017] Additional aspects of the disclosure relate to methods for treating or preventing the relevant diseases or conditions as disclosed in this descriptive report by administering an effective amount of a pMHC-NP as disclosed in this descriptive report. Methods for detecting the presence and treatment efficacy with pMHC-NP complexes and compositions as disclosed in this descriptive report are also disclosed. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The following drawings form part of this descriptive report and are included to further demonstrate certain aspects of the present disclosure. The disclosure can be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented in this descriptive report.

[0019] FIGURES 1A-1B show schematic representations of NP complexes. FIGURE 1A is a schematic representation of a single-chain expression construction of Petition 870250027877, dated 07 / 04 / 2025, page 19 / 384 Figure 1A is a schematic representation showing the linkers and two-dimensional structure of NP complexes. As can be seen, an NP can contain the same antigen in complex with the nanoparticle core through various chemical linkers. The image shows a 10 / 299 pMHC-class I (top) and a representative cytometric flow profile of the binding of the corresponding pMHC tetramer (labeled with fluorochrome) to cognate CD8+ T cells.

[0020] FIGURE 2 shows the structure of a typical class II pMHC monomer (top) and a representative FACS profile of cognate CD4+ T cells stained with the corresponding pMHC tetramer or unstained on the left.

[0021] FIGURE 3 shows the chemical structure of Generation 3 Dendri-Graft Poly-L-Lysines (DGLs G3).

[0022] FIGURE 4 shows the synthesis of G3 DendriGraft of Poly-L-Lysines functionalized with PEG-Azido (DGLN).

[0023] FIGURE 5 shows the synthesis of pMHC-DGLN.

[0024] FIGURE 6 shows native and denaturing PAGE analysis of pMHC-DGLN conjugates.

[0025] FIGURE 7 shows AFM analysis of V7CHO-DGLN.

[0026] FIGURES 8A-8B show that V7CHO-DGLN possesses powerful agonistic properties on cognate CD8+ T cells.

[0027] FIGURES 9A-9N show T1D- or EAE-relevant pMHC-NPs expanding Tr1-like cognath disease-suppressing CD4+ T cells in vivo. FIGURES 9A and 9B show tetramer staining profiles (FIGURE 9A) and percentages of tetramer+CD4+ T cells (FIGURE 9B). Data correspond to pre-diabetic NOD females treated for 5 weeks (blood: n = 5, 8, and 6; spleen: n = 5, 18, and 6, respectively). Tet, tetramer. FIGURE 9C shows tetramer staining of splenic CD4+ T cells from treated or untreated Foxp3-eGFP NOD mice. Figure 9D shows tetramer+CD4+ T cells from mice treated with 2.5 mi / IAg7-NP (25 μg pMHC per ml) exhibiting a Tr1 phenotype. Petition 870250027877, dated 07 / 04 / 2025, p. 20 / 384 11 / 299 like. FIGURE 9E shows the incidence of diabetes in NOD scid hosts reconstituted with T cells transfused with CD4+ T cells from different donors ± 2.5mi / IAg7-NPs (25 μg pMHC per ml) (n = 11, 5, 7 and 6 from the top). FIGURE 9F shows percentages of tetramer+CD4+ T cells in NOD scid hosts treated or untreated with 2.5mi / IAg7-NP (25 μg pMHC per ml) (n = 4-5 per group). FIGURE 9G shows the incidence of disease reversal in diabetic mice treated with pMHC-NPs (n = 9, 7, 7, 7 from left to right at the top), or IGRP4-22 peptide (Burton, BR et al. (2014) Nature Commun. 5: 4741-4747) and IGRP4-22-NP peptide (n = 9). FIGURE 9H shows the percentage of tetramer+CD4+ T cells in diabetic mice at emergence, in response to therapy with 2.5mi / IAg7-NP (25 μg pMHC per ml) and age-matched non-diabetic controls (n = 8, 6, 2 and 7 from the left).FIGURE 9I shows insulitis scores (n = 6, 4, 3, and 6 from the left). Representative images are shown below. FIGURES 9J-9M show C57BL / 6 mice that were immunized with pMOG35-55. FIGURE 9J shows EAE scores of mice treated from day 14 (n = 4 each). FIGURE 9K shows EAE scores of mice treated from day 21 (n = 10, 7, and 3 from the top). FIGURE 9L shows the percentage of tetramer+CD4+ T cells in the spleen and blood of mice from FIGURES 9J and 9K (n = 13, 14, and 5 from the top). FIGURE 9M shows representative flow profiles of CD4+ T cells from mice in FIGURES 9J and 9K. FIGURE 9N shows representative microglial IBA1 staining and relative ranking scores in the cerebellum of mice from FIGURE 9K (n = 4-5). P-values ​​were calculated using the Mann-Whitney U test, logrank test (Mantel-Cox), or two-way ANOVA.Error bars, standard error of the mean (SEM).

[0028] FIGURES 10A-10H show that the effects are Petition 870250027877, dated 07 / 04 / 2025, page 21 / 384 12 / 299 disease-specific and dependent on both pMHC and nanoparticles. FIGURES 10A-10F show C57BL / 10.M HLA-DR4-IE transgenic mice immunized with bovine collagen. FIGURE 10A, left, shows changes in joint edema (top) and clinical scores (bottom) in response to uncoated NPs, pMHC-NPs, sc peptide (Burton, BR et al. (2014) Nature Commun. 5: 4741-4747) or iv peptide-coated MPs (Getts, DR et al. (2012) Nature Biotechnol. 30: 1217-1224). Treatment was initiated when joint edema reached 130% of baseline (data normalized to treatment initiation (value out of 100%) (n = 4, 4, 4 and 8 from top). Right, percentage increase in joint edema relative to pre-immunization baseline (value out of 100%).FIGURE 10B shows representative images of knee joint staining with hematoxylin and eosin (first row) and O-safranin / fast green / hematoxylin (second and third rows). The third row shows magnified images of lacunae in the bone and meniscal articular surfaces. 1, pannus formation; 2, meniscal cell infiltration; 3, bone erosion; 4, proteoglycan depletion; 5, chondrocyte loss / lacunae. FIGURE 10C shows mean pathology scores (n = 3-4 per group). FIGURE 10D shows the percentage of tetramer+CD4+ T cells. FIGURE 10E shows representative flow cytometry profiles for TR1 markers in mice treated with mCII259-273 / DR4NP. Figures 10F-10H show C57BL / 6 IAbnull HLA-DR4-IE transgenic mice immunized with hPLP. Figure 10F shows changes in EAE scores (n = 5, 4, 13 (4-9 per group), 5, 19 (4-5 per group, see also Figure 9H), 4 and 5 from the top).FIGURE 10G shows the percentage of tetramer+CD4+ T cells in the spleen of mice from FIGURE 10F (n = 4, 5, 4, 6, 15, 3 and 3 from the left). FIGURE 10H shows representative flow cytometry profiles for markers of... Petition 870250027877, dated 07 / 04 / 2025, page 22 / 384 13 / 299 Tr1. Data were compared using the Mann-Whitney U test or two-way ANOVA. Error bars, SEM.

[0029] FIGURES 11A-11H show that disease reversal involves Tr1 cytokine effects on cognate B cells and local CD11b+ cells, without compromising systemic immunity. FIGURE 11A shows blood glucose levels in diabetic NOD mice treated with 2.5mi / IAg7-NPs (25 μg pMHC per ml) and blocking antibodies (n = 8, 4, 6, 6, 5, and 4 from top right). FIGURE 11B shows IL-10 (eGFP) expression and CD5 and CD1d upregulation by splenic B cells pulsed with 2.5mi eGFP-2.5mi from NOD Il10GFP donors in NOD hosts treated with 2.5mi / IAg7-NP (25 μg pMHC per ml). FIGURE 11C shows weighted results from FIGURE 11B (n = 4, 3, 3 and 7 from the left). FIGURE 11D shows the incidence of diabetes in NOD scid hosts reconstituted with T cells left alone or transfused with CD19+ PLN cells (n = 7, 13 and 7 from the top).FIGURE 11E shows the incidence of diabetes in NOD scid hosts reconstituted with T cells transfused with CD19+ and / or CD4+ cells (n = 7, 6, 3, 7, 8, 11, and 13 from the top). FIGURE 11F shows the cytokine and chemokine profiles of PLN and MLN CD11b+ cells from mice treated with 2.5mi / IAg7-NP (25 μg pMHC per ml) NOD in response to LPS (n = 3-4 each). FIGURE 11G shows the percentage of tetramer CD4+ T cells in the spleens (left) and viral titers in the ovaries (right) of treated NOD mice compared to untreated mice 4 and 14 days after vaccinia virus infection (n = 3 per group). FIGURE 11H shows percentages of tetramer+CD4+ T cells in the spleens (left) and serum titers of anti-dinitrophenyl (DNP) antibody (right) in treated and untreated NOD mice immunized with keyhole limpet hemocyanin (KLH)-DNP (n = 3-5 per group). Data were compared using the Mann-Whitney U test, log-rank test, or ANOVA. Petition 870250027877, dated 07 / 04 / 2025, p. 23 / 384 14 / 299 two-way. Error bars, EPM.

[0030] FIGURES 12A-12G show that CD4+Tr1-like T cells that arise in response to pMHCII-NPs are derived from antigen-experienced precursors. FIGURE 12A, percentage of tetramer+CD4+ T cells in G6pc2- / - hyperglycemic NOD mice compared with NOD mice treated with IGRP4-22 / IAg7 (n = 4 and 7) or 2.5mi / IAg7-NPs (25 μg pMHC per ml) (n = 6 and 9). FIGURE 12B shows blood glucose levels in hyperglycemic NOD G6pc2- / - mice in response to pMHC-NP therapy (n = 4-6 per group). FIGURE 12C shows the upregulation of Tr1 transcripts by eGFP-CD4+ T cells activated with anti-CD3 / anti-CD28 mAb from NOD BDC2.5 Foxp3-eGFP mice in response to different stimuli in vitro (n = 4 mice each). FIGURE 12D shows the changes in relevant Tr1 transcripts in naive or memory BDC2.5 CD4+ T cells in response to 2.5mi / IAg7-NPs (25 μg pMHC per ml) in vivo (n = 6, 6, 5 and 4 from the left). FIGURE 12E shows LAG-3 and CD49b profiles (blue; compared with isotype control in red) of Thy1b+ cells from FIGURE 12D. FIGURE 12F shows the proliferation of CFSE-labeled BDC2.5 CD4+ memory T cells in NOD.Thy1a hosts in response to 2.5 mi / IAg7-NPs (25 μg pMHC per ml).Figure 12G shows the incidence of diabetes in NOD T-cell reconstituted hosts transfused with naive or memory BDC2+ T cells and treated with doses every two weeks of 2.5 mi / IAg7NPs (25 μg pMHC per ml) (n = 4 and 3) or left untreated (n = 4 and 6). P-values ​​were calculated using the Mann-Whitney U test or log-rank (Mantel-Cox) test. Error bars, SEM.

[0031] FIGURES 13A-13I show that T1D-relevant human pMHC-NPs expand cognathic CD4+Tr1-like T cells in NSG hosts grafted with human PBMCs. FIGURE 13A shows the expansion of cognathic CD4+ T cells by GAD555-567(557i) / DR4-NPs Petition 870250027877, dated 07 / 04 / 2025, p. 24 / 384 15 / 299 (top) or PPI76-90 (88s) / DR4-NPs (bottom) in NSG mice grafted with PBMCs from DR4+ T1D patients. FIGURE 13B shows the expression of the CD49b and LAG-3 marker in the sample at the bottom of FIGURE 13A. FIGURE 13C shows the expansion of cognate CD4+ Tr1-like T cells in NSG mice grafted with PBMCs from DR3+ T1D patients in response to IGRP13-25 / DR3-NP therapy. FIGURE 13D shows the percentages (left) and numbers (right) of tetramer+CD4+ T cells in mice grafted with T1D PBMCs in response to treatment (n for spleen and PLN by treatment = 9 / 6, 7 / 6, and 14 / 1 from the left legend). FIGURE 13E shows the IL10 mRNA expression in IGRP13-25 / DR3+CD4+ tetramer T cells from mice treated with IGRP13-25 / DR3—NPS (n = 3 each). FIGURE 13F shows that PLNs from responsive mice contained increased numbers of lymphocytes compared to the other groups (n = 6, 3, 4, 3 from the top legend).Figures 13G and 13H show the correlation between the absolute numbers of IGRP13-25 / DR3+ tetramer cells in PLNs (Figure 13G) or spleen (Figure 13H) and the percentage or absolute number of PLNs or splenic B cells in mice treated with IGRP13-25 / DR3-NP (n = 6 and 7). Figure 13I shows IL-10 secretion by LPS-stimulated CD19+ cells (ex vivo, for 24 h) isolated from the PLNs or spleens of hPBMC-grafted NSG mice treated with IGRP13-25 / DR3-NPS (n = 3 each). P-values ​​were calculated using the Mann-Whitney U test or Pearson's correlation test. Error bars, SEM.

[0032] FIGURES 14A-14N show that sustained expansion of CD4+ Tr1-like cognate T cells by pMHCII-NP therapy restores normal glucose homeostasis in diabetic NOD mice by suppressing antigen presentation and activating non-cognate autoreactive T cells in PLNs and the progression of insulitis. FIGURE 14A, top left, shows the expansion of cognate CD4+ T cells by 2.5 mi / IAg7-NPs (25 μg pMHC per ml) in NOD Foxp3 mice. Petition 870250027877, dated 07 / 04 / 2025, p. 25 / 384 16 / 299 eGFP treated with anti-CD25 mAb. Data correspond to 8-week-old mice treated three times a week with 500 μg of an ip depleting anti-CD25 mAb or control anti-HPRN mAbs, followed by 10 doses of 2.5 mi / IAg7-NPs (25 μg pMHC per ml) starting at 10 weeks of age (two doses per week; n = 4 mice each). Below, tetramer+CD4+ T cells from mice treated with anti-CD25 mAb express TR1 markers. Right, percentage of circulating FOXP3+eGFP+CD4+ cells (top) and CD25+CD4+ cells (bottom). FIGURE 14B shows that tetramer+CD4+ T cells separated from mice treated with 2.5mi / IAg7-NP (25 μg pMHC per ml) proliferate and produce IL-10 and, to a lesser extent, IFNγ in response to stimulation with DCs pulsed with 2.5mi peptides (10 μg ml-1) (n = 3 mice). FIGURE 14C shows representative profiles of CD49b and LAG-3 from the cell surface in tetramer+CD4+ T cells from NOD BDC2 mice.Figure 14D shows the upregulation of CD49b and LAG-3 in BDC2.5 CD4+ T cells activated with anti-CD3 / anti-CD28 mAb from NOD BDC2.5 mice in response to 2.5mi / IAg7-NP (25 μg pMHC per ml) versus 2.5mi peptide (10 μg ml-1) or 2.5mi / IAg7 monomers (25 μg pMHC per ml). Figure 14E shows the upregulation of eGFP (IL-10) in BDC2.5 CD4+ T cells activated with anti-CD3 / anti-CD28 mAb from NOD BDC2 mice. 5 Il10GFP in response to 2.5mi / IAg7-NP (25 μg pMHC per ml) as a function of CD49b and LAG-3 expression. FIGURE 14F shows eGFP (IL-10) expression in CD4+ T cells from NOD Il10GFP mice treated with 2.5mi / IAg7-NP (25 μg pMHC per ml) (2 doses per week for 5 weeks) as a function of CD49b and LAG-3 expression (left, representative profiles; right, eGFP MFI values) (n = 8). FIGURE 14G shows T cell proliferation 8.Transgenic CD8+ 3-TCR tagged with CFSE (IGRP206214 / NRP-V7-specific) in response to pulsed or non-pulsed DCs. Petition 870250027877, dated 07 / 04 / 2025, p. 26 / 384 17 / 299 pulsed with 2.5mi / NRP-V7-peptide in the presence of tetramer- or tetramer+ CD4+ T cells from mice treated with 2.5mi / IAg7NP (25 μg pMHC per ml) and in the presence or absence of cytokine-blocking mAbs, mouse IgG (negative control) or 1-methyl-1-tryptophan (1-MT; an IDO inhibitor). Data correspond to the average number of cells proliferated in 3-7 experiments per condition. FIGURE 14H shows the changes in blood glucose levels of spontaneously hyperglycemic (> 11 mM) NOD female mice treated with 2.5mi / IAg7-NP (25 μg pMHC per ml), IGRP4-22 / IAg7-NP, IGRP128-145 / IAg7-NP or HEL14-22 / IAg7NP (n = 6-9 per group), IGRP4-22 peptide or IGRP4-22-NPs (n = 9, 4-5 each). Mice received two doses per week until irreversibly hyperglycemic or normoglycemic for 4 consecutive weeks, at which point treatment was withdrawn.FIGURE 14I shows the incidence and timing of disease relapse in hyperglycemic NOD female mice made stably normoglycemic by treatment with 2.5mi / IAg7-NP (25 μg pMHC per ml), IGRP4-22 / IAg7-NP, or IGRP128-145 / IAg7-NPs upon treatment withdrawal (after 4 consecutive weeks of normoglycemia). The data correspond to responsive mice in FIGURE 9G. FIGURE 14J shows postprandial serum insulin levels in pMHC-NP-treated mice that reverted to normoglycemia by 50 weeks of age (n = 6) versus newly diabetic (n = 12) and age-matched untreated non-diabetic controls (n = 10). FIGURE 14K shows intraperitoneal glucose tolerance tests (IPGTT) of the mice in FIGURE 14H. FIGURE 14L shows areas under the curve (AUC) in the IPGTTs shown in FIGURE 14K. FIGURE 14M shows serum insulin levels of the IPGTT corresponding to the mice in FIGURE 14K. FIGURE 14N shows T cell proliferation 8.3CD8+ reactive cells to IGRP206-214 labeled with CFSE in PLNs, compared with MLNs from mice treated with 2.5 mi / IAg7-NP (25 μg of pMHC per ml) that reverted to normoglycemia up to 50 weeks of age. Petition 870250027877, dated 07 / 04 / 2025, p. 27 / 384 18 / 299 age, age-matched untreated non-diabetic controls, and newly diabetic mice. The left panels show representative FACS profiles. The right panel compares the percentages of proliferated cells in PLNs after subtracting background proliferation values ​​in non-draining MLNs (n = 6-8 mice per group). P-values ​​were calculated using the Mann-Whitney U test, log-rank test (Mantel-Cox), or two-way ANOVA. Data are means ± SEM.

[0033] FIGURES 15A-15H show that nanoparticles coated with different T1D-relevant pMHCII complexes expand cognate CD4+ Tr1-like T cells in vivo to a similar extent, regardless of epitope dominance or the role of target T cell specificity in the disease process. FIGURE 15A shows the percentage of tetramer+CD4+ T cells in the PLN, MLN, and bone marrow (BM) of mice treated with 2.5mi / IAg7-NP (25 μg pMHC per ml) that reverted to normoglycemia by 50 weeks of age (n = 5-6 mice per lymphoid organ) or relapsed (n = 1-2), compared with newly diabetic mice (n = 5-6) and age-matched untreated non-diabetic controls (n = 4-6).FIGURE 15B shows the percentage of tetramer+CD4+ T cells in splenic CD4+ T cells from mice treated with 2.5mi / IAg7-NP (25 μg pMHC per ml) that reverted to normoglycemia by 50 weeks of age or from untreated non-diabetic mice of compatible age, stained with two T1D-relevant but non-cognate pMHCII tetramers (n = 3-4 per group). FIGURE 15C shows the percentage of tetramer+CD4+ T cells in the blood, spleen, PLN, MLN, and bone marrow of mice treated with IGRP4-22 / IAg7—NP that reverted to normoglycemia by 50 weeks of age (n = 5-6 mice per lymphoid organ), compared with newly diabetic mice (n = 5-8) and age-matched untreated non-diabetic controls (n = 4-6). FIGURE 15D shows the percentage of tetramer+CD4+ T cells in the blood, spleen, PLN, MLN, and bone marrow. Petition 870250027877, dated 07 / 04 / 2025, p. 28 / 384 19 / 299 of mice treated with IGRP128-145 / IAg7-NP that reverted to normoglycemia by 50 weeks of age (n = 5-7 mice per lymphoid organ), compared with newly diabetic mice (n = 4-7) and age-matched untreated non-diabetic controls (n = 5-7). FIGURE 15E shows representative tetramer staining profiles of IGRP4-22 / IAg7, IGRP128-145 / IAg7 and GPI282292 / IAg7 for splenic CD4+ T cells from NOD mice treated with IGRP4-22 / IAg7-NP and IGRP128-145 / IAg7-NP, compared with untreated mice. FIGURE 15F shows the percentages of blood CD4+ T cells from non-diabetic mice cured by IGRP422 / IAg7-NP or by IGRP128-145 / IAg7-NP, treated with HEL14-22 / IAg7-NP and untreated with age-matched staining with non-cognate pMHCII tetramers (n = 3-7 per group).FIGURE 15G shows that tetramer+CD4+ T cells from mice treated with IGRP128145 / IAg7-NP (top) and IGRP4-22 / IAg7-NP (bottom) proliferate and produce IL-10 specifically in response to stimulation with pulsed DCs containing IGRP4-22 or IGRP128-145-peptide, respectively (n = 3 mice each), cpm, counts per minute. FIGURE 15H shows the percentages of IGRP4-22 / IAg7+CD4+ tetramer T cells in the blood, spleen, PLN, MLN, and bone marrow of NOD mice at the onset of hyperglycemia or upon treatment with nanoparticles coated with IGRP4-22 / IAg7-NPs, or IGRP422 peptide, or IGRP4-22 peptide (n = 5-9 mice per organ). P-values ​​were calculated using the Mann-Whitney U test. Data are means ± SEM.

[0034] FIGURES 16A-16F show that relevant EAE pMHCII-NPs expand cognate IL-10-secreting CD4+ Tr1-like T cells and improve established clinical and pathological signs of EAE. FIGURES 16A and 16B show changes in mean weights of C57BL / 6 mice immunized with pMOG35-55 and treated with pMOG38-49 / IAb-NPs or uncoated nanoparticles starting on days 14 (FIGURE 16A) or 21 (FIGURE 16B) after immunization. FIGURE 16C shows the percentage of pMOG38 tetramer T cells. Petition 870250027877, dated 07 / 04 / 2025, page 29 / 384 20 / 299 49 / IAb+CD4+ in peripheral lymph nodes, bone marrow, and central nervous system (CNS) of mice from FIGURES 16A and 16B. FIGURE 16D shows that tetramer+CD4+ T cells from mice treated with pMOG38-49 / IAb-NP proliferate and produce IL-10 and, to a lesser extent, IFNγ in response to stimulation with DCs pulsed with pMOG38-49 peptide. FIGURE 16E, left and center, shows representative Luxol Fast Blue (LFB) / H&E cerebellar staining images of untreated and treated mice from FIGURE 16B exhibiting the presence of inflammatory foci and areas of demyelination (red arrows). Right, average number of inflammatory foci per section. Data correspond to 4 untreated and 5 treated mice. FIGURE 16F shows representative spinal cord sections stained with LFB / H&E from mice in FIGURE 16B. Data were compared using the Mann-Whitney U test. Data are means ± SEM.

[0035] FIGURES 17A-17I show that EAE- or CIA-relevant pMHCII-NPs expand cognate CD4+Tr1-like T cells and improve the clinical and pathological signs of EAE or CIA in transgenic C57BL / 6 IAbnu11 or C57BL / 10.M HLA-DR4-IE mice. FIGURE 17A shows the changes in mean EAE scores of transgenic C57BL / 6 IAbnu11HLA-DR4-IE mice immunized with hPLPi75-i92 or hMOG97-i08 and treated with hPLPi75-i92 / DR4-IE or hMOG97-i08 / DR4-IE—NPs or uncoated nanoparticles starting on the day when the mice reached a score of i.5 (to synchronize the groups regarding disease activity) (n = 3-4 per group). FIGURE 17B shows the percentage of tetramer+CD4+ T cells in the spleen, blood, cervical and inguinal lymph nodes, and CNS of mice from FIGURE 17A. The data correspond to 4 mice treated with pMHC-NP and 6 control mice treated with NP.FIGURE 17C shows the changes in the average weights of C57BL / 6 IAbnu11HLA-DR4-IE transgenic mice from FIGURE 17A, immunized with hPLPi75-i92 or hMOG97-i08 and treated with hPLPi75-i92 / DR4-IE-NPs, hMOG97-i08 / DR4-IE-NPs or non-nanoparticles. Petition 870250027877, dated 07 / 04 / 2025, p. 30 / 384 21 / 299 coated when mice reached a score of 1.5. FIGURE 17D shows LFB / H&E staining of the cerebellum of transgenic C57BL / 6 IAbnu11HLA-DR4-IE mice from FIGURE 17A, showing reductions in inflammation and demyelination in mice treated with hPLP175-192 / DR4-IE or hMOG97-108 / DR4-IENPs, compared with controls. FIGURE 17E shows the percentage of tetramer+CD4+ T cells in lymph nodes and bone marrow of mice in FIGURE 10A (C57BL / 10.M HLA-DR4-IE mice immunized with bovine collagen) at the end of follow-up (10 doses, 5 weeks). FIGURE 17F shows the changes in the mean weights of C57BL / 6 IAbnu11HLA-DR4-IE transgenic mice immunized with hPLP175-192 from FIGURE 10F. FIGURE 17G shows LFB / H&E staining representative of the cerebellum of C57BL / 6 IAbnu11HLA-DR4-IE transgenic mice immunized with hPLP175-192 and treated with hPLP175-192 / DR4-IE-NPs, hMOG97-108 / DR4-IE-NPs, hMOG97-108 peptide iv or subcutaneously.(8 μg per dose), hMOG97-108 / DR4-IE monomer (25 μg per dose), hMOG97-108-NPs peptide (using the molar equivalent of peptide released via pMHC-NPs; 0.68 μg per dose), or hMOG97-108-MPs peptide (15 μg of peptide per dose), compared with mice left untreated or treated with uncoated NPs or MPs (at the same NP / MP number). FIGURE 17H shows the changes in mean EAE scores and body weights of C57BL / 6 IAbnu11HLA-DR4IE-transgenic mice immunized with hPLP175-192 in response to treatment with hMOG97-108 peptide iv or sc (8 μg per dose), hMOG97-108 / DR4-IE monomer (25 μg per dose), hMOG97108-NPs peptide (0.68 μg peptide per dose), hMOG97-108-MPs peptide (15 μg peptide per dose (Getts, DR et al. (2012) Nature Biotechnol. 30: 1217-1224)), or a single dose of hMOG97-108-MPs peptide (15 μg peptide per dose). (Getts, DR et al. (2012) Nature Biotechnol. 30: 1,217-1.224)), compared with mice left untreated or treated with uncoated NPs or MPs (in the same number of NP / MP) (n = 4-5 per group). The cohort of. Petition 870250027877, dated 07 / 04 / 2025, p. 31 / 384 22 / 299 mice treated with one dose had to be discontinued after 2.5 weeks due to rapid disease progression. FIGURE 17I shows the percentages of tetramer+CD4+ T cells in the spleen, blood, cervical and inguinal lymph nodes, and bone marrow of mice from FIGURE 17H (n = 3-9 per group). Data were compared using the Mann-Whitney U test or two-way ANOVA. Data are means ± SEM.

[0036] FIGURES 18A-18Y show that disease reversal by pMHC-NPs is driven by Tr1 cytokines IL-21, IL-10, and TGF-β and involves several downstream cellular targets. FIGURE 18A shows changes in blood glucose levels in diabetic NOD mice (>11 mM) treated with IGRP4-22 / IAg7NPs and blocking mAbs anti-IL-10, anti-IFNy, or anti-TGF-β or anti-HRPN mouse IgG (n = 4-6 per group). Figures 18B and 18C show the percentages of tetramer+CD4+ T cells in the spleens (Figure 18B), and the proliferation of CFSE-labeled 8.3-CD8+ T cells in the PLNs versus MLN of the mice from Figure 11A at the end of the follow-up (Figure 18C). Figure 18D shows the changes in blood glucose in hyperglycemic NOD mice, NOD Il10- / - and NOD Ifng- / - mice (n = 3-6 per group) in response to 2.5 mi / IAg7-NPs (25 μg pMHC per ml). Figures 18E and 18F show the percentages of tetramer+CD4+ T cells in the spleens (Figure 18E), and the proliferation of 8.3-CD8+ T cells.3-CD8+ cells labeled with CFSE in the PLNs versus MLN of mice from FIGURE 18D at the end of follow-up (FIGURE 18F). FIGURE 18G shows the EAE scores of mice treated with pMHC-NPs and mouse IgG or blocking mAbs (n = 4 per group). FIGURE 18H shows LFB / H&E staining of the cerebellum of C57BL / 6 IAbnull HLA-DR4-IE transgenic mice from FIGURE 18G, highlighting differences in inflammation and demyelination in mice treated with hPLP175-192 / DR4-IE-NPs and mouse IgG versus anti-IL-10, anti-TGF-β, or anti-IL-21R blocking mAbs. FIGURE 18I shows the changes in weights. Petition 870250027877, dated 07 / 04 / 2025, p. 32 / 384 23 / 299 mean body weights of transgenic C57BL / 6 IAbnu11HLA-DR4-IE mice from FIGURE 18G. In FIGURE 18J, the percentage of tetramer+CD4+ T cells in the spleen, blood, and inguinal lymph nodes of mice from FIGURE 18G (n = 4 per group). FIGURES 18K and 18L show the changes in mean EAE scores (FIGURE 18K) and body weights (FIGURE 18L) of C57BL / 6 I127r / - mice immunized with pMOG35-55 and treated with pMOG38-49 / IAb-NPs or uncoated nanoparticles starting on the day when the mice reached a score of 1.5 (to synchronize the groups regarding disease activity) (n = 7 and 4, respectively). FIGURE 18M shows IBA1 and LFB / H&E stains representative of the cerebellum and the corresponding relative classification scores of mice from FIGURE 18K (n = 3 and 4, respectively).FIGURE 18N shows the percentage of tetramer+CD4+ T cells in the spleen, blood, inguinal lymph nodes, and bone marrow of mice from FIGURE 18K (left), and representative CD49b and LAG-3 staining profiles of tetramer+ versus tetramer- cells (right). FIGURE 18O shows the percentage of B220+ cells in PLNs or MLNs from mice treated with 2.5mi / IAg7-NP- (25 μg pMHC per ml) or HEL14-22 / IAg7NP (n = 4 per group). FIGURE 18P shows the correlation between the percentages of PLN and B220+ splenic cells and tetramer+CD4+ T cells from 2.5mi / IAg7 in additional mouse cohorts treated with 2.5mi / IAg7-NPs (25 μg pMHC per ml), across a range of total pMHC doses (0.75-25 μg total pMHC) (n = 24-28). FIGURE 18Q, on the left, shows the in vitro proliferation of BDC2 T cells.5 CD4+ cells labeled with CFSE against B cells pulsed with 2.5mi peptide (10 μg ml-1) or GPI282-292 purified from PLNs or MLNs of NOD mice, untreated mice or mice treated with 2.5mi / IAg7-NPs (25 μg pMHC per ml) (n = 5-6 per group). On the right, representative CFSE dilution profiles. In summary, the profiles show the extent of CFSE dilution in BDC2 T cells. 5 CD4+ cells labeled with CFSE. Petition 870250027877, dated 07 / 04 / 2025, p. 33 / 384 24 / 299 cultured in the presence of B cells pulsed with 2.5mi peptide (10 μg ml-1) or GPI282-292 purified from PLNs or MLNs of untreated or 2.5mi / IAg7-NP-treated NOD mice (25 μg pMHC per ml). FIGURE 18R, PLN-derived B cells (105) from 2.5mi / IAg7-NP-treated mice (25 μg pMHC per ml) secrete IL-10 ex vivo in response to LPS (1 μg ml-1). The data correspond to 6 pMHC-treated and 5 untreated NOD mice. Figures 18S and 18T show changes in the percentages of B cells pulsed with 2.5mi (10 μg ml-1) (PKH26 labeled) compared with GPI282-292 peptide-pulsed (CFSE labeled) (Figure 18S) or DCs (Figure 18T) 7 days after transfer (in a 1:1 ratio) in untreated or 2.5mi / IAg7-NP-treated NOD mice (25 μg pMHC per ml). Histograms show weighted proportions for each cell type and condition (n = 3-4 mice per cell type and condition).FIGURE 18U shows the percentages of CD5+CD1dhieGFP+B220+ cells in mice treated as in FIGURE 11B plus blocking Abs (n = 4 each). FIGURE 18V shows that LPS-stimulated PLN B cells from NOD mice treated with 10 doses of 2.5mi / IAg7NPs (25 μg pMHC per ml) suppress the proliferation of CFSE-labeled BDC2 T cells pulsed with peptides 2.5mi (10 μg ml-1) in vitro, as compared with LPS-stimulated PLN B cells from untreated controls. FIGURE 18X shows the percentage of CD19+CD3- cells in the blood before and after 3 doses of 250 μg of anti-CD20 mAb (n = 4). In FIGURE 18Y, the upregulation induced by 2.5 mi / IAg7-NP (25 μg pMHC per ml) of IL-21 and IL-10 mRNA in BDC2.5 eGFP-CD4+ memory T cells from NOD Foxp3-eGFP BDC2.5-TCR donors in NOD Thy1a hosts (n = 5). P-values ​​were calculated by Pearson correlation, Mann-Whitney U test, or two-way ANOVA. Data are means ± SEM.

[0037] FIGURE 19 shows the effects of cytokine blockade or genetic deficiency on the cytokine profile of Petition 870250027877, dated 07 / 04 / 2025, p. 34 / 384 25 / 299 CD4+ cognath T cells expanded by 2.5 mi / IAg7-NPs (25 μg pMHC per ml). n = 3 mice each. Data are means ± SEM.

[0038] FIGURES 20A and 20B show that human T1D relevant pMHCII-NPs, but not peptide-free or peptide-coated nanoparticles or microparticles, expand cognathous CD4+Tr1-like T cells in NSG hosts grafted with human PBMCs. FIGURE 20A shows the FACS (cognate tetramer versus control staining in hCD4+ T cells) profiles of mouse samples identified as responsive in Table 2. Numerical data on tetramer+ T cells are presented in Table 2. FIGURE 20B shows representative FACS (cognate tetramer versus control staining in hCD4+ splenic T cells) profiles of healthy human NSG hosts grafted with control PBMCs treated with IGRP13-25 / DR3-NPs (left), or human NSG T1D hosts grafted with PBMCs treated with IGRP13-25 peptide, IGRP13-25 peptide-coated nanoparticles, IGRP13-25 peptide-coated microparticles, or left untreated (right).See the legend for FIGURES 13A-13I for details.

[0039] FIGURE 21 shows a schematic representation of the proposed mode of operation of pMHCII-based nanomedicines. pMHCII-coated NPs (pMHC-NP, without co-stimulatory molecules) promote the differentiation of disease-sensitized (antigen-experienced) IFNγ-producing CD4+ Th1 cells into CD4+Tr1-like memory T cells, followed by systemic expansion. The differentiation process (but not the subsequent expansion) requires both IFNγ and IL-10, while IL-27 is dispensable. pMHC-NP-expanded CD4+Tr1-like autoreactive T cells (monospecific) then suppress other autoreactive T cell responses by secreting IL-21, IL-10, and TGF-β, which act on local APCs (B cells, CD11c+ and CD11b+ cells) that capture the cognate autoantigen and thus present cognate pMHCII complexes to Tr1-like cells. Petition 870250027877, dated 07 / 04 / 2025, page 35 / 384 26 / 299 expanded. This interaction inhibits the pro-inflammatory function of the targeted APCs and blocks their ability to present other class I and class II pMHC complexes to the specificities of non-pMHC-NP-cognate autoreactive T cells (note that local APCs take up both cognate and non-cognate autoantigens shed into the medium simultaneously). Suppression of antigen presentation requires IL-10 and TGF-β, but not IFNγ or IL-21. Furthermore, cognate interactions between pMHC-NP-expanded CD4+ Tr1 T cells and cognate autoantigen-specific autoreactive B cells (capable of displaying cognate pMHCII complex on the surface) promote their differentiation into Breg cells in an IL-21-dependent manner, which contributes to promoting local immunosuppression, likely through IL-10 secretion.The suppression of antigen presentation selectively targets APCs that display the cognate pMHC, but to the extent that local APCs that capture the cognate autoantigen also capture other autoantigens simultaneously, the pMHC-NP-enhanced autoregulatory CD4+ T cells block the presentation of other autoantigenic pMHC complexes to a wide range of autoreactive T cells. This suppression is disease-specific and self-limiting.

[0040] FIGURES 22A-22C show the expansion properties of autoregulatory T cells of PF-M NPs coated with class I and class II pMHC in vivo as a function of pMHC density and dose. (FIGURE 22A) Percentages of 2.5mi / IAg7 tetramer+ cells (25 μg pMHC per ml) in splenic CD4+ T cells from 10-week-old NOD mice treated with 10 doses (given over 5 weeks) of 2.5mi / IAg7-PF-M preparations exhibiting different pMHC valences. The x-axis values ​​correspond to the amounts of pMHC (in μg) given at each dose. The data correspond to the net values ​​of tetramer+ cells after subtraction of staining with a negative control tetramer (HEL14-22 / IAg7). (FIGURE 22B) Treg Tr1 CD4+ expansion power of Petition 870250027877, dated 07 / 04 / 2025, p. 36 / 384 27 / 299 doses of 2.5mi / IAg7-PF-M vs. 2.5mi / IAg7-SFP-Z NPs given over 5 weeks. Data correspond to preparations carrying 22-45 pMHCs / NP. (FIGURE 22C) Percentage increase in mean fluorescence intensity of the TR1 cell marker CD49b in tetramer-positive 2.5mi / IAg7 (25 μg pMHC per ml) cells expanded in vivo by different 2.5mi / IAg7-NP preparations as a function of pMHC density. This relationship did not exist when CD49b upregulation levels were tabulated as a function of pMHC dose. BRIEF DESCRIPTION OF THE TABLES

[0041] Table 1. Functionalized PEG linkers.

[0042] Table 2. Codons.

[0043] Tables 3A and 3B. Transcriptional profile of pMHC-NP-expanded CD4+ T cells. (A) QRT-PCR for a panel of 384 immunological markers in 2.5mi / IAg7 tetramer+ CD4+ T cells detached from 10-15 weeks-old NOD mice treated with 10 doses of 2.5mi / IAg7-NPs (25 μg pMHC per ml) (n = 3 and 4 samples, respectively). Cells were stimulated in vitro with anti-CD3 / anti-CD28 mAb-coated Dynabeads before RNA collection. The panel summarizes the most significant differences. (B) QRT-PCR for 8 TR1-relevant markers, including markers not represented in the primer set used in (A). The data correspond to four additional samples of 2.5 mi / IAg7 tetramer CD4+ T cells (25 μg pMHC per ml) and seven 2.5 mi / IAg7 tetramers (25 μg pMHC per ml).

[0044] Table 4A, 4B and 4C. Human T1D donors and final outcome of pMHC-NP therapy in PBMC-grafted NSG hosts.

[0045] Table 5 is an exemplary list of cancer-relevant antigens for use in this disclosure.

[0046] Table 6 is an exemplary list of diabetes-relevant antigens for use in this disclosure. Petition 870250027877, dated 07 / 04 / 2025, page 37 / 384 28 / 299

[0047] Table 7 is an exemplary list of antigens relevant to multiple sclerosis for use in this disclosure.

[0048] Table 8 is an exemplary list of antigens relevant to celiac disease for use in this disclosure.

[0049] Table 9 is an exemplary list of antigens relevant to primary biliary cirrhosis for use in this disclosure.

[0050] Table 10 is an exemplary list of antigens relevant to pemphigus foliaceus and antigens relevant to pemphigus vulgaris for use in this disclosure.

[0051] Table 11 is an exemplary list of antigens relevant to a neuromyelitis optica spectrum disorder for use in this disclosure.

[0052] Table 12 is an exemplary list of antigens relevant to allergic asthma for use in this disclosure.

[0053] Table 13 is an exemplary list of antigens relevant to inflammatory bowel disease for use in this disclosure.

[0054] Table 14 is an exemplary list of antigens relevant to systemic lupus erythematosus for use in this disclosure.

[0055] Table 15 is an exemplary list of antigens relevant to atherosclerosis for use in this disclosure.

[0056] Table 16 is an exemplary list of antigens relevant to chronic obstructive pulmonary disease and antigens relevant to emphysema for use in this disclosure.

[0057] Table 17 is an exemplary list of antigens relevant to psoriasis for use in this disclosure.

[0058] Table 18 is an exemplary list of antigens relevant to autoimmune hepatitis for use in this disclosure.

[0059] Table 19 is an exemplary list of antigens relevant to uveitis for use in this disclosure.

[0060] Table 20 is an exemplary list of antigens Petition 870250027877, dated 07 / 04 / 2025, pages 38 / 384 29 / 299 relevant to Sjogren's syndrome for use in this disclosure.

[0061] Table 21 is an exemplary list of antigens relevant to scleroderma for use in this disclosure.

[0062] Table 22 is an exemplary list of antigens relevant to antiphospholipid syndrome for use in this disclosure.

[0063] Table 23 is an exemplary list of antigens relevant to ANCA-associated vasculitis for use in this disclosure.

[0064] Table 24 is an exemplary list of antigens relevant to stiff-person syndrome for use in this disclosure. DETAILED DESCRIPTION

[0065] It should be understood that this disclosure is not limited to the particular embodiments described, insofar as these obviously vary. It should also be understood that the terminology used in this descriptive report is solely for the purpose of describing particular embodiments and is not intended to be limiting, insofar as the scope of this disclosure will be limited only by the appended claims.

[0066] It should be noted that, as used in this descriptive report and in the attached claims, the singular forms a, an, or include plural referents, unless the context clearly dictates otherwise. Thus, for example, reference to an excipient includes several excipients. The term at least one means one or more.

[0067] Throughout this descriptive report, the term approximately is used to indicate that a value includes the standard deviation of the error for the device or method being used to determine the value. The term approximately, when used before a numerical designation, for example, temperature, time, quantity, and concentration, including a range, indicates approximations that may vary by (+) or (-) 10%. Petition 870250027877, dated 07 / 04 / 2025, pp. 39 / 384 30 / 299 5%, or 1%. DEFINITIONS

[0068] Unless otherwise defined, all technical and scientific terms used in this descriptive report have the same meaning commonly understood by those skilled in the art to which this disclosure pertains. As used in this descriptive report, the following terms have the following meanings.

[0069] As used in this descriptive report, the term “comprising” or “comprises” is intended to mean that the compositions and methods include the cited elements, but do not exclude others. The term “consisting basically of,” when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting basically of the elements as defined in this descriptive report would exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed disclosure, for example, compositions for the treatment or prevention of multiple sclerosis. The term “consisting of” shall mean excluding more than residual elements of other substantial ingredients and steps of the method. Embodiments defined by each of these transitional terms are within the scope of this disclosure.

[0070] The terms “inhibition,” “reduction,” or “prevention,” or any variation of these terms, when used in the claims and / or descriptive report, include any measurable decrease or complete inhibition to achieve a desired result.

[0071] The term “biocompatible” means that the components of the delivery system will not cause injury to tissue or damage to the human biological system. To convey biocompatibility, polymers and excipients that had a Petition 870250027877, dated 07 / 04 / 2025, page 40 / 384 31 / 299 history of safe use in humans or with GRAS (Generally Accepted as Safe) status will be used preferentially. The term "biocompatibility" means that the ingredients and excipients used in the composition will ultimately be bioabsorbed or cleared by the body without adverse effects on the body. For a composition to be biocompatible, and considered non-toxic, it cannot cause toxicity to cells. Similarly, the term "bioabsorbable" refers to nanoparticles made of materials that undergo bioabsorption in vivo over a period of time so that long-term accumulation of the material in the patient is avoided. In certain embodiments, the biocompatible nanoparticle is bioabsorbed over a period of less than 2 years, preferably less than 1 year, and even more preferably less than 6 months.The rate of bioabsorption is related to particle size, the material used, and other factors well recognized by those skilled in the art. A mixture of biocompatible, bioabsorbable materials can be used to form the nanoparticles used in this discovery. In one embodiment, iron oxide and a bioabsorbable, biocompatible polymer can be combined. For example, iron oxide and PGLA can be combined to form a nanoparticle.

[0072] The term “dendrimer”, as used in this descriptive report, refers to a repeatedly branched molecule, also called an arborol or a cascade molecule. With regard to nanoparticle synthesis, the term “dendrimer core” refers to the use of the dendrimer as the central component of a nanoparticle, such that it forms the basis of the nanoparticle structure. In some embodiments, the nanoparticle core disclosed in this descriptive report comprises a dendrimer.

[0073] The term “polymeric micelle”, as used in this Petition 870250027877, dated 07 / 04 / 2025, page 41 / 384 32 / 299 descriptive report refers to an amphilic structure comprising a hydrophobic core and a hydrophilic shell that can be prepared from block copolymers. With respect to nanoparticle synthesis, the term “polymer micelle core” refers to the use of the polymer micelle as the central component of a nanoparticle, such that it forms the basis of the nanoparticle structure. In some embodiments, the nanoparticle core disclosed in this descriptive report comprises a polymer micelle.

[0074] An antigen-MHC-nanoparticle complex (“NP complex” or “complex” or “pMHC-NP” or “nanoparticle complex”) refers to the presentation of a peptide, carbohydrate, lipid, or other segment, fragment, or epitope of an antigenic molecule or antigenic protein (i.e., autopeptide or autoantigen) on a surface, for example, a nanoparticle core.

[0075] The “nanoparticle core” is the nanoparticle substrate that may or may not include layers or coatings. The nanoparticle complex comprises the core with at least the antigen-MHC complex coupled to the core.

[0076] The term “density,” when referring to pMHCs per nanoparticle, is calculated as the surface area of ​​the nanoparticle core with or without outer layers, which may also include linkers. The surface area is the total available surface area of ​​the construct used. In one aspect, when a PEG linker is used, this can increase the total diameter of the nanoparticle core by about 20 nm² of the nanoparticle, which consequently increases the surface area of ​​the total available surface area of ​​the nanoparticle. In other words, it is the final surface area of ​​the nanoparticle without the addition of one or more of the pMHCs, co-stimulatory molecules, and / or cytokines.

[0077] The term “antigen, as used in this report Petition 870250027877, dated 07 / 04 / 2025, page 42 / 384 33 / 299 descriptive, refers to any part, fragment or segment of a molecule that can induce an immune response in an individual or to an expansion of an immune cell, preferably a T or B cell.

[0078] The term alkyl refers to saturated aliphatic monovalent hydrocarbyl groups having from 1 to 10 carbon atoms (i.e., C1-C10 alkyl) or 1 to 6 carbon atoms (i.e., C1-C6 alkyl) or 1 to 4 carbon atoms. This term includes, by way of example only, linear and branched hydrocarbyl groups such as, for example, methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2), isobutyl ((CH3UCHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-) and neopentyl ((CH3)3CCH2-).

[0079] The term alkoxy refers to -O-alkyl.

[0080] A mimetic is an analog of a certain ligand or peptide, wherein the analog is substantially similar to the ligand. Substantially similar means that the analog has a binding profile similar to the ligand, except that the mimetic has one or more functional groups or modifications that collectively account for less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, or less than about 5% of the molecular weight of the ligand.

[0081] The term immune cells includes, for example, white blood cells (leukocytes) that are derived from hematopoietic stem cells (HSCs) produced in the bone marrow, lymphocytes (T cells, B cells, natural killer (NK) cells), and myeloid-derived cells (neutrophils, eosinophils, basophils, monocytes, macrophages, dendritic cells). As used in this descriptive report, the term B cell refers to a type of lymphocyte in the humoral immunity of the adaptive immune system. B cells function primarily to produce antibodies and serve as antigen-presenting cells. Petition 870250027877, dated 07 / 04 / 2025, page 43 / 384 34 / 299 release cytokines and develop memory B cells after activation by interaction with antigen. B cells are distinguished from other lymphocytes, for example, T cells, by the presence of a B cell receptor on the cell surface. As used in this descriptive report, the term “T cell” refers to a type of lymphocyte that matures in the thymus. T cells play an important role in cell-mediated immunity and are distinguished from other lymphocytes, for example, B cells, by the presence of a T cell receptor on the cell surface. T cells can be isolated or obtained from a commercially available source. The term “T cell” includes all types of immune cells that express CD3, including T helper cells (CD4+ cells), cytotoxic T cells (CD8+ cells), natural killer T cells, regulatory T cells (Treg), and gamma-delta T cells.A “cytotoxic cell” includes CD8+ T cells, natural killer (NK) cells, and neutrophils, all of which are capable of mediating cytotoxic responses.

[0082] The term “effector T cells,” as used in this descriptive report, refers to T cells that can specifically bind to an antigen and mediate an immune response (effector function) without the need for further differentiation. Examples of effector T cells include CTLs, Th1 cells, Th2 cells, memory effector cells, and T-helper cells. In contrast to effector T cells, naive T cells have not encountered their specific antigen / MHC complex, nor have they responded to it by proliferating and differentiating into an effector T cell. Effector T cells can be at rest (in the G0 phase of the cell cycle) or activated (proliferating).

[0083] The term “antipathogenic autoreactive T cell” refers to a T cell with antipathogenic properties (i.e., T cells that fight back against an autoimmune disease such as, for example, MS, an MS-related disease or disorder, or prediabetes). These T cells may include anti- Petition 870250027877, dated 07 / 04 / 2025, page 44 / 384 35 / 299 inflammatory, central memory T cells, effector memory T cells, memory T cells, low-avidity T cells, helper T cells, autoregulatory T cells, cytotoxic T cells, natural killer T cells, regulatory T cells, Tr1 cells, suppressor T cells, CD4+ T cells, CD8+ T cells and the like.

[0084] The term “anti-inflammatory T cell” refers to a T cell that promotes an anti-inflammatory response. The anti-inflammatory function of the T cell can be achieved through the production and / or secretion of anti-inflammatory proteins, cytokines, chemokines, and the like. Anti-inflammatory proteins also aim to encompass antiproliferative signals that suppress immune responses. Anti-inflammatory proteins include IL-4, IL-10, IL-13, IL-21, IL-23, IL-27, IFN-α, TGF-β, IL-Ira, G-CSF, and soluble receptors for TNF and IL-6.

[0085] The term “differentiated” refers to when a cell of a first type is induced to develop into a cell of a second type. In some modalities, a cognate T cell is differentiated into a regulatory Tr1 cell. In some modalities, an activated T cell is differentiated into a Tr1 cell. In some modalities, a memory T cell is differentiated into a Tr1 cell. In some modalities, a B cell is differentiated into a regulatory B cell.

[0086] As used in this descriptive report, the term “knob-in-hole” refers to a polypeptidyl architecture that requires a protrusion (or “knob”) at the interface of a first polypeptide and a corresponding cavity (or “hole”) at the interface of a second polypeptide, such that the protrusion can be positioned in the cavity to promote heteromultimer formation. Protrusions are constructed by replacing small amino acid side chains at the interface of the first polypeptide with larger side chains (e.g., phenylalanine or tyrosine). Petition 870250027877, dated 07 / 04 / 2025, page 45 / 384 36 / 299 Cavities of identical or similar size to the bumps are created at the interface of the second polypeptide by replacing larger amino acid side chains with smaller ones (e.g., alanine or threonine). The bumps and cavities can be made by synthetic means, for example, by altering the nucleic acid encoding the polypeptides, or by peptide synthesis, using routine methods for those skilled in the art. In some embodiments, the interface of the first polypeptide is located in an Fc domain in the first polypeptide; and the interface of the second polypeptide is located in an Fc domain in the second polypeptide. Knob-in-hole heteromultimers and methods of their preparation and use are disclosed in U.S. Patents Nos. 5,731,168, 5,807,706, 5,821,333, 7,642,228, 7,695,936, 8,216,805, and 8,679,785, all of which are incorporated by reference in this descriptive report in its entirety.

[0087] As used in this descriptive report, the term MHC-alpha-Fc / MHC-beta-Fc refers to a heterodimer comprising a first polypeptide and a second polypeptide, wherein the first polypeptide comprises an α-chain of MHC class II and an Fc antibody domain; the second polypeptide comprises a β-chain of MHC class II and an Fc antibody domain. An MHC-alpha-Fc / MHC-beta-Fc knob-in-hole further requires that the Fc domains of each polypeptide interface with each other through the complementary positioning of a protrusion in one Fc domain within the corresponding cavity in the other Fc domain.

[0088] The term isolated means separated from cellular and other constituents with which the polynucleotide, peptide, polypeptide, protein, antibody, or fragments thereof, are normally associated in nature. For example, with respect to a polynucleotide, an isolated polynucleotide is one that is separated from the 5' and 3' sequences with the Petition 870250027877, dated 07 / 04 / 2025, p. 46 / 384 37 / 299 which is normally associated on the chromosome. As is evident to those in the art, a non-naturally occurring polynucleotide, peptide, polypeptide, protein, antibody, or fragment(s) thereof, does not need to be isolated to distinguish it from its naturally occurring counterpart. Furthermore, a concentrated, detached, or diluted polynucleotide, peptide, polypeptide, protein, antibody, or fragment(s) thereof is distinguishable from its naturally occurring counterpart to the extent that the concentration or number of molecules per volume is greater (concentrated) or less (detached) than that of its naturally occurring counterpart.A polynucleotide, peptide, polypeptide, protein, antibody, or fragment(s) thereof, which differs from its naturally occurring counterpart in its primary sequence or, for example, in its glycosylation pattern, need not be present in its isolated form, insofar as it is distinguishable from its naturally occurring counterpart by its primary sequence or, alternatively, by another characteristic such as, for example, its glycosylation pattern. A mammalian cell, for example, a T cell, is isolated if it is removed from the anatomical location where it is found in an organism.

[0089] An autoreactive T cell is a T cell that recognizes a self-antigen, which is a molecule produced and contained by the same individual that contains the T cell.

[0090] A pathogenic T cell is a T cell that is harmful to an individual who possesses the T cell. Conversely, a non-pathogenic T cell is not substantially harmful to an individual, and an antipathogenic T cell reduces, enhances, inhibits, or prevents the damage caused by a pathogenic T cell.

[0091] As used in this descriptive report, the terms regulatory B cells or B-regulatory cells (B-regs) mean those cells that are responsible for the anti-inflammatory effect, which is characterized by the expression of CD1d, Petition 870250027877, dated 07 / 04 / 2025, page 47 / 384 38 / 299 B-regs are also identified by Tim-1 expression and can be induced by Tim-1 binding to promote tolerance. The ability to be B-regs has been shown to be driven by many stimulatory factors such as toll-like receptors, CD40 ligand, and others. However, full characterization of B-regs is ongoing. B-regs also express high levels of CD25, CD86, and TGF-β. This subset of B cells is capable of suppressing Th1 proliferation, thus contributing to the maintenance of self-tolerance. Potentiation of B-reg function should become the goal of many immunomodulatory drugs, contributing to better control of autoimmune diseases. See, for example: ncbi.nlm.nih.gov / pubmed / 23707422, last accessed October 31, 2013.

[0092] Type 1 Regulatory T cells (Tr1) are a subset of CD4+ T cells that possess regulatory properties and are capable of suppressing antigen-specific immune responses in vitro and in vivo. These Tr1 cells are defined by their unique cytokine production profile and produce elevated levels of IL-10 and TGF-beta, but do not produce IL-4 or IL-2. The IL-10 and TGF-beta produced by these cells mediate the inhibition of naive primary T cells in vitro. There is also evidence that Tr cells exist in vivo, and the presence of highly IL-10-producing CD4(+) T cells in patients with severe combined immunodeficiency who have received allogeneic stem cell transplants has been documented. Tr1 cells are involved in the regulation of peripheral tolerance and they could potentially be used as a cell therapy to modulate immune responses in vivo. See, for example: ncbi.nlm.nih.gov / pubmed / 10887343, last accessed on October 31, 2013.

[0093] Tr1 cells are defined by their ability Petition 870250027877, dated 07 / 04 / 2025, page 48 / 384 39 / 299 to produce high levels of IL-10 and TGF-beta. Tr1 cells specific for various antigens arise in vivo, but can also differentiate from naive CD4+ T cells in the presence of IL-10 in vitro. Tr1 cells have a low proliferative capacity, which can be overcome by IL-15. Tr1 cells suppress naive and memory T helper type 1 or 2 responses through the production of IL-10 and TGF-beta. Further characterization of Tr1 cells at the molecular level will define their mechanisms of action and clarify their relationship with other Tr cell subsets. The use of Tr1 cells to identify new targets for the development of new therapeutic agents, and as a cell therapy to modulate peripheral tolerance, can be anticipated. See, for example, ncbi.nlm.nih.gov / pubmed / 11722624, last accessed on October 31, 2013.

[0094] The term “an effective amount” is an amount sufficient to achieve the desired objective, examples of which, but not limited to, include: initiation of the immune response, modulation of the immune response, suppression of an inflammatory response, and modulation of T cell activity or T cell populations. In one aspect, the effective amount is that which works to achieve a stated therapeutic objective, for example, a therapeutically effective amount. As described in detail in this descriptive report, the effective amount, or dosage, depends on the purpose and composition, and can be determined in accordance with this disclosure.

[0095] An effective amount of therapeutic composition is determined based on the desired objective. The term “unit dose” or “dosage” refers to the physically distinct units suitable for use in an individual, each unit containing a predetermined amount of the composition calculated to produce the desired responses discussed above in association with its administration, i.e., the route and regimen. Petition 870250027877, dated 07 / 04 / 2025, page 49 / 384 40 / 299 appropriate. The amount to be administered, both according to the number of treatments and the unit dose, depends on the desired outcome and / or protection. The precise amounts of the composition also depend on the professional's assessment and are peculiar to each individual. Factors affecting the dose include the individual's physical and clinical condition, the route of administration, the desired treatment objective (symptom relief versus cure), and the potency, stability, and toxicity of the particular composition. By formulation, the solutions will be administered in a manner compatible with the dosage formulation and in an amount that is therapeutically or prophylactically effective. The formulations are easily administered in various dosage forms, for example, the type of injectable solutions described above.

[0096] An MHC multimer”, as the term is used in this descriptive report, means a complex of two or more, usually four, up to about fifty or more MHC monomers.

[0097] As used in this descriptive report, the term “multimer complex” refers to a complex between a target cell population and one or more pMHC complexes, wherein the MHC protein of the pMHC complex comprises a multimeric form of the MHC protein. In some embodiments, the multimeric form of the MHC protein includes a dimer or a trimer.

[0098] As used in this descriptive report, the phrase “immune response” or its equivalent “immunological response” refers to the development of a cell-mediated response (mediated by antigen-specific T cells or their secretory products). A cellular immune response is evoked by the presentation of polypeptide epitopes in association with MHC Class I or Class II molecules, to treat or prevent a viral infection, expand antigen-specific Breg cells, TC1 cells, CD4+ T-helper cells and / or CD8+ cytotoxic T cells and / or Petition 870250027877, dated 07 / 04 / 2025, page 50 / 384 41 / 299 generated by disease, autoregulatory T cells and B cells, and memory cells. The response may also involve the activation of other components. In some respects, the term immune response can be used to encompass the formation of a regulatory network of immune cells. Thus, the term regulatory network formation can refer to an evoked immune response such that an immune cell, preferably a T cell, more preferably a regulatory T cell, triggers further differentiation of other immune cells, for example, without limitation, B cells or antigen-presenting cells – non-limiting examples of which include dendritic cells, monocytes, and macrophages. In certain modalities, regulatory network formation involves B cells being differentiated into regulatory B cells; in certain modalities, regulatory network formation involves the formation of tolerogenic antigen-presenting cells.

[0099] The term nanosphere, NP, or nanoparticle, as used in this descriptive report, means a small, distinct particle that is administered singly or in plurals to an individual, cell sample, or tissue sample, as appropriate. In certain embodiments, the term nanoparticle, as used in this descriptive report, includes any layers surrounding the nanoparticle core. In certain embodiments, the nanoparticles have a substantially spherical shape. In certain embodiments, the nanoparticle is not a liposome or a viral particle. In further embodiments, the nanoparticle is composed of any suitable material, for example, a solid, a solid core, a metal, a dendrimer, a polymeric micelle, a metal oxide, or a protein, or fragments or combinations thereof. The term substantially spherical, as used in this descriptive report, means that the shape of the particles does not deviate from a sphere by more than about 10%.Various antigen or peptide complexes. Petition 870250027877, dated 07 / 04 / 2025, page 51 / 384 42 / 299 known from the discovery can be applied to the particles. The nanoparticles of this discovery range in size from about 1 nm to about 1 pm and preferably from about 1 nm to about 500 nm or, alternatively, from about 1 nm to about 100 nm or, alternatively, from about 1 nm to about 50 nm or, alternatively, from about 5 nm to about 100 nm and, in some respects, refers to the average or median diameter of several nanoparticles when several nanoparticles are desired. Smaller nanosize particles can be obtained, for example, by the fractionation process, whereby larger particles are allowed to settle in an aqueous solution. The upper portion of the solution is then recovered by methods known to those skilled in the art. This upper portion is enriched in smaller size particles. The process can be repeated until a desired average size is generated.The term nanostructure is generally used to describe structures smaller than about 1 pm.

[00100] The terms inflammatory response and inflammation, as used in this descriptive report, indicate the complex biological response of an individual's vascular tissues to damaging stimuli, for example, pathogens, damaged cells, or irritants, and includes the secretion of cytokines and, more particularly, pro-inflammatory cytokines, i.e., cytokines that are predominantly produced by activated immune cells and that are involved in amplifying inflammatory reactions. Exemplary pro-inflammatory cytokines include, without limitation, IL-1, IL-6, IL-10, TNF-α, IL-17, IL-21, IL-23, IL-27, and TGF-β. Exemplary inflammations include acute inflammation and chronic inflammation. Acute inflammation indicates a short-term process characterized by the classic signs of inflammation (edema, redness, pain, heat, and loss of function) as a consequence of tissue infiltration by plasma and leukocytes. Acute inflammation typically occurs since the stimulus Petition 870250027877, dated 07 / 04 / 2025, page 52 / 384 43 / 299 harmful is present and ceases after the stimulus has been removed, degraded, or isolated by scarring (fibrosis). Chronic inflammation indicates a condition characterized by concomitant active inflammation, tissue destruction, and attempts at repair. Chronic inflammation is not characterized by the classic signs of acute inflammation listed above. Rather, chronically inflamed tissue is characterized by infiltration of mononuclear immune cells (monocytes, macrophages, lymphocytes, and plasma cells), tissue destruction, and attempts at scarring, which include angiogenesis and fibrosis. Inflammation can be inhibited in the present development by affecting, and in particular inhibiting, any of the events that form the complex biological response associated with inflammation in an individual.

[00101] As used in this descriptive report, the term CD49b or “cluster of differentiation 49b” is a protein that is an alpha subunit of integrin and constitutes about half of the alpha2beta1 integrin duplex. In humans, CD49b is encoded by the CD49b gene. CD49b can be found in a wide variety of cell types, including T cells, natural killer cells, fibroblasts, and platelets. In some embodiments, the T cell includes a Tr1 cell. In some embodiments, the expression of CD49b identifies a Tr1 cell. The detection of a cell expressing CD49b can be identified using conventional techniques, for example, the use of an anti-CD49b antibody, which are commercially available, for example, from a vendor such as BioLegend.

[00102] As used in this descriptive report, the term “Lag3” or “lymphocyte activation gene 3” or “CD223” or “cluster of differentiation 223” refers to a protein that is encoded by the Lag3 gene and belongs to the immunoglobulin (Ig) superfamily. Lag3 is a cell surface protein that is expressed on various cell types, including T cells, Petition 870250027877, dated 07 / 04 / 2025, page 53 / 384 44 / 299 natural-killer cells, B cells, and plasmacytoid dendritic cells. In some embodiments, the T cell includes a Tr1 cell. In some embodiments, Lag3 expression identifies a TR1 cell. Detection of a cell expressing Lag3 can be identified using conventional techniques, for example, the use of an anti-Lag3 antibody, which are commercially available, for example, from a vendor such as BioLegend.

[00103] As used in this descriptive report, the term “disease-relevant” antigen means an antigen or fragment thereof selected to treat a selected disease and is involved in the disease process. For example, a diabetes-relevant antigen is an antigen or fragment thereof that, when presented, produces an immune response that serves to treat diabetes; thus, a diabetes-relevant antigen that produces such an effect is selected to treat diabetes. A multiple sclerosis (MS)-relevant antigen is selected to treat MS. A diabetes-relevant antigen would not be selected to treat MS. Similarly, an autoimmunity-related antigen is an antigen that is relevant to an autoimmune disease and would not be selected for the treatment of a disorder or disease other than autoimmunity, for example, cancer.Relevant, non-limiting disease antigens are disclosed in this descriptive report, and furthermore, these antigens can be determined for a particular disease based on techniques, mechanisms, and methods documented in the literature.

[00104] The term “autoimmune disease or disorder” includes diseases or disorders that arise and are directed against the individual’s own tissues or organs or manifestations thereof, or a condition resulting from them. In one embodiment, it refers to a condition that results from, or is aggravated by, the production by T cells that are reactive with normal tissues and antigens of the Petition 870250027877, dated 07 / 04 / 2025, page 54 / 384 45 / 299 body. Examples of autoimmune diseases or disorders include, but are not limited to, arthritis (e.g., acute rheumatoid arthritis, chronic rheumatoid arthritis, gout or gouty arthritis, acute gouty arthritis, acute immune arthritis, chronic inflammatory arthritis, degenerative arthritis, collagen-induced arthritis type II, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, Still's disease, vertebral arthritis and juvenile-onset rheumatoid arthritis, osteoarthritis, chronic progressive arthritis, deforming arthritis, primary chronic polyarthritis, reactive arthritis, and ankylosing spondylitis), hyperproliferative inflammatory skin diseases, psoriasis, e.g., plaque psoriasis, guttate psoriasis, pustular psoriasis, and nail psoriasis, atopy, including atopic diseases such as, for example, hay fever and Job's syndrome, dermatitis, including contact dermatitis, chronic contact dermatitis, exfoliative dermatitis, allergic dermatitisAllergic contact dermatitis, dermatitis herpetiformis, nummular dermatitis, seborrheic dermatitis, nonspecific dermatitis, primary irritant contact dermatitis and atopic dermatitis, X-linked hyper-IgM syndrome, allergic intraocular inflammatory diseases, urticaria such as, for example, chronic allergic urticaria and chronic idiopathic urticaria, including chronic autoimmune urticaria, myositis, polymyositis / dermatomyositis, juvenile dermatomyositis, toxic epidermal necrolysis, scleroderma (including systemic scleroderma), sclerosis such as, for example, systemic sclerosis, multiple sclerosis (MS) such as, for example, spino-optic MS, primary progressive MS (PPMS) and relapsing-remitting MS (RRMS), progressive systemic sclerosis, atherosclerosis, arteriosclerosis, disseminated sclerosis, ataxic sclerosis, disorder of neuromyelitis optica spectrum (NMO, also known as Devic's disease or Devic's syndrome), inflammatory bowel disease (IBD) (e.g., Crohn's disease, Petition 870250027877, dated 07 / 04 / 2025, p. 55 / 384 46 / 299 autoimmune gastrointestinal diseases, colitis such as, for example, ulcerative colitis, ulcerative colitis, microscopic colitis, collagenous colitis, polypous colitis, necrotizing enterocolitis and transmural colitis and autoimmune inflammatory bowel disease), inflammation of the intestine, pyoderma gangrenosum, erythema nodosum, primary sclerosing cholangitis, respiratory distress syndrome, including adult or acute respiratory distress syndrome (ARDS), meningitis, inflammation of all or part of the uvea, iritis, choroiditis, an autoimmune hematological disorder, rheumatoid spondylitis, rheumatoid synovitis, hereditary angioedema, cranial nerve damage as in meningitis, gestational herpes, gestational pemphigoid, scrotal pruritus, autoimmune premature ovarian failure, sudden hearing loss as a consequence of an autoimmune condition, IgE-mediated diseases such as, for example, anaphylaxis and allergic and atopic rhinitis, encephalitis such as, for example,Rasmussen's encephalitis and limbic and / or brainstem encephalitis, uveitis such as, for example, anterior uveitis, acute anterior uveitis, granulomatous uveitis, non-granulomatous uveitis, phagogenic uveitis, posterior uveitis or autoimmune uveitis, glomerulonephritis (GN) with and without nephrotic syndrome such as, for example, chronic or acute glomerulonephritis such as, for example, primary GN, immune-mediated GN, membranous GN (membranous nephropathy), idiopathic membranous GN or idiopathic membranous nephropathy, membrano- or proliferative membranous GN (MPGN), including Type I and Type II and rapidly progressive GN, proliferative nephritis, autoimmune polyglandular endocrine failure, balanitis including circumscribed plasmacellular balanitis, balanoposthitis, erythema annular centrifugal lesion, erythema dyschromicum perstans, erythema multiforme, annular granuloma, lichen nitidus, lichen sclerosus et atrophicus, chronic lichen simplex, lichen spinulosum, lichen planus, lamellar ichthyosis, epidermolytic hyperkeratosis.premalignant keratosis, pyoderma, Petition 870250027877, dated 07 / 04 / 2025, p. 56 / 384 47 / 299 gangrenous, allergic conditions and responses, allergic reaction, eczema, including allergic or atopic eczema, steatotic eczema, dyshidrotic eczema and palmoplantar vesicular eczema, asthma such as bronchial asthma, bronchial asthma and autoimmune asthma, conditions involving T-cell infiltration and chronic inflammatory responses, immune reactions against foreign antigens such as fetal ABO blood groups during pregnancy, chronic inflammatory lung disease, autoimmune myocarditis, leukocyte adhesion deficiency, lupus, including lupus nephritis, lupus cerebritis, pediatric lupus, non-renal lupus, extrarenal lupus, discoid lupus and discoid lupus erythematosus, lupus alopecia, systemic lupus erythematosus (SLE) such as cutaneous SLE or subacute cutaneous SLE, neonatal lupus syndrome (NLE) and systemic lupus erythematosus, Type I diabetes, Type II diabetes, latent autoimmune diabetes in adults (or Type 1 diabetes,5). Also included are immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T lymphocytes, sarcoidosis, granulomatosis, including lymphomatoid granulomatosis, Wegener's granulomatosis, agranulocytosis, vasculitis, including vasculitis, large vessel vasculitis (including polymyalgia rheumatica and giant cell arteritis (of Takayasu)), medium vessel vasculitis (including Kawasaki disease and polyarteritis nodosa / periarteritis nodosa), microscopic polyarteritis, immunovasculitis, CNS vasculitis, cutaneous vasculitis, hypersensitivity vasculitis, necrotizing vasculitis such as systemic necrotizing vasculitis and ANCA-associated vasculitis such as Churg-Strauss (CSS) vasculitis or syndrome and ANCA-associated small vessel vasculitis, temporal arteritis, aplastic anemia, autoimmune aplastic anemia, Coombs-positive anemia, Diamond-Blackfan anemia,hemolytic anemia or immune hemolytic anemia including autoimmune hemolytic anemia (AIHA), Addison's disease, Petition 870250027877, dated 07 / 04 / 2025, page 57 / 384 48 / 299 autoimmune neutropenia, pancytopenia, leukopenia, diseases involving leukocyte diapedesis, inflammatory disorders of the CNS, Alzheimer's disease, Parkinson's disease, multiple organ damage syndrome such as those secondary to septicemia, trauma or hemorrhage, antigen-antibody complex-mediated diseases, antiglomerular basement membrane disease, antiphospholipid antibody syndrome, antiphospholipid syndrome, allergic neuritis, Behcet's disease / syndrome, Castleman's syndrome, Goodpasture's syndrome, Reynaud's syndrome, Sjögren's syndrome, Stevens-Johnson syndrome, pemphigoid such as bullous pemphigoid and cutaneous pemphigoid, pemphigus (including pemphigus vulgaris, pemphigus foliaceus, mucomembranous pemphigoid and pemphigus erythematosus), autoimmune polyendocrinopathies, Reiter's disease or syndrome, thermal injury, preeclampsia, an immune complex disorder such as, for example, immune complex nephritis, antibody-mediated nephritis,Polyneuropathies, chronic neuropathy such as, for example, IgM polyneuropathies or IgM-mediated neuropathy, autoimmune or immune-mediated thrombocytopenia such as, for example, idiopathic thrombocytopenic purpura (ITP), including chronic or acute ITP, acquired thrombocytopenic purpura, scleritis such as, for example, idiopathic keratoscleritis, episcleritis, autoimmune disease of the testes and ovaries, including autoimmune orchitis and oophoritis, primary hypothyroidism, hypoparathyroidism, autoimmune endocrine diseases, including thyroiditis such as, for example, autoimmune thyroiditis, Hashimoto's disease, chronic thyroiditis (Hashimoto's thyroiditis) or subacute thyroiditis, autoimmune thyroid disease, idiopathic hypothyroidism, Graves' disease, polyglandular syndromes such as, for example, autoimmune polyglandular syndromes (or syndromes of polyglandular endocrinopathies), paraneoplastic syndromes, including neurological paraneoplastic syndromes such as, for example,Lambert's myasthenic syndrome, Petition 870250027877, dated 07 / 04 / 2025, page 58 / 384, 49 / 299 Eaton or Eaton-Lambert syndrome, stiff-man syndrome or rigid person syndrome, encephalomyelitis such as, for example, allergic encephalomyelitis or allergic encephalomyelitis and experimental allergic encephalomyelitis (EAE), myasthenia gravis such as, for example, myasthenia gravis associated with thymoma, cerebellar degeneration, neuromyotonia, opsoclonus or myoclonus syndrome (OMS) and sensory neuropathy, multifocal motor neuropathy, Sheehan's syndrome, autoimmune hepatitis, chronic hepatitis, lupus erythematosus, giant cell hepatitis, chronic active hepatitis or chronic autoimmune active hepatitis, lymphoid interstitial pneumonitis (LIP), bronchiolitis obliterans (non-transplant) vs. NSIP, Guillain-Barré syndrome, Berger's disease (IgA nephropathy), idiopathic IgA nephropathy, linear IgA dermatosis, acute febrile neutrophilic dermatosis, subcorneal pustular dermatosis, transient acantholytic dermatosis, cirrhosis such as primary biliary cirrhosis and pneumonocirrhosis.autoimmune enteropathy syndrome, celiac disease, celiac sprue (gluten enteropathy), refractory sprue, idiopathic sprue, cryoglobulinemia, amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), coronary artery disease, autoimmune otologic disease such as, for example, autoimmune inner ear disease (AIED), autoimmune hearing loss, polychondritis such as, for example, refractory or relapsing polychondritis, pulmonary alveolar proteinosis, Cogan's syndrome / non-syphilitic interstitial keratitis, Bell's palsy, Sweet's disease / syndrome, autoimmune rosacea, pain associated with zoster, amyloidosis, a non-cancerous lymphocytosis, a primary lymphocytosis, which includes monoclonal B-cell lymphocytosis (e.g., benign monoclonal gammopathy and monoclonal gammopathy of undetermined significance, MGUS), neuropathy peripheral, paraneoplastic syndrome, channelopathies such as, for example, epilepsy, migraine, arrhythmia, muscle disorders, deafness, blindness,periodic paralysis and, Petition 870250027877, dated 07 / 04 / 2025, p. 59 / 384 50 / 299 CNS channelopathies, autism, inflammatory myopathy, focal or segmental glomerulosclerosis (FSGS), endocrine ophthalmopathy, uveoretinitis, chorioretinitis, autoimmune hepatological disorder, fibromyalgia, multiple endocrine failure, Schmidt's syndrome, adrenalitis, gastric atrophy, presenile dementia, demyelinating diseases such as, for example, autoimmune demyelinating diseases and chronic inflammatory demyelinating polyneuropathy, Dressler's syndrome, alopecia areata, alopecia totalis, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal motility disorder, sclerodactyly and telangiectasia), male and female autoimmune infertility, for example, as a consequence of antisperm antibodies, mixed connective tissue disease, Chagas disease, rheumatic fever, recurrent abortion, farmer's lung, erythema multiforme, post-cardiotomy syndrome, Cushing's syndrome, poultry breeder's lung, allergic granulomatous angiitis,Benign lymphocytic angiitis, Alport syndrome, alveolitis such as allergic alveolitis and fibrosing alveolitis, interstitial lung disease, transfusion reaction, leprosy, malaria, parasitic diseases such as leishmaniasis, trypanosomiasis, schistosomiasis, ascariasis, aspergillosis, Sampter syndrome, Caplan syndrome, dengue fever, endocarditis, endomyocardial fibrosis, diffuse interstitial pulmonary fibrosis, interstitial pulmonary fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endophthalmitis, erythema elevatum et diutinum, erythroblastosis fetalis, eosinophilic fasciitis, Shulman syndrome, Felty syndrome, filariasis, cyclitis such as chronic cyclitis, heterochromic cyclitis, iridocyclitis (acute or chronic) or Fuchs' cyclitis, purpura of Henoch-Schönlein syndrome, human immunodeficiency virus (HIV) infection, SCID, acquired immunodeficiency syndrome (AIDS), echovirus infection, sepsis, endotoxemia, pancreatitis, thyrotoxicosis, infection by, Petition 870250027877, dated 07 / 04 / 2025, p. 60 / 384 51 / 299 parvovirus, rubella virus infection, post-vaccination syndromes, congenital rubella infection, Epstein-Barr virus infection, mumps, Evans syndrome, autoimmune gonadal failure, Sydenham's chorea, post-streptococcal nephritis, thromboangiitis obliterans, thyrotoxicosis, tabes dorsalis, choroiditis, giant cell polymyalgia, chronic hypersensitivity pneumonitis, keratoconjunctivitis sicca, epidemic keratoconjunctivitis, idiopathic nephritic syndrome, minimal change nephropathy, benign familial lesion and ischemia reperfusion, transplanted organ reperfusion, retinal autoimmunity, joint inflammation, bronchitis, chronic obstructive airway / pulmonary disease, silicosis, aphthous ulcers, aphthous stomatitis, arteriosclerotic disorders, spermatogenesis, autoimmune hemolysis, disease of Boeck's disease, cryoglobulinemia, Dupuytren's contracture, phacoanaphylactic endophthalmos, allergic enteritis, erythema nodosum leprosum, idiopathic facial paralysis, chronic fatigue syndrome.Rheumatic fever, Hamman-Rich disease, sensorineural hearing loss, paroxysmal hemoglobinuria, hypogonadism, regional ileitis, leukopenia, infectious mononucleosis, transverse myelitis, primary idiopathic myxedema, nephrosis, sympathetic ophthalmia, granulomatous orchitis, pancreatitis, acute polyradiculitis, pyoderma gangrenosum, De Quervain's thyroiditis, acquired splenic atrophy, non-malignant thymoma, vitiligo, toxic shock syndrome, food poisoning, conditions involving T-cell infiltration, leukocyte adhesion deficiency, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T lymphocytes, diseases involving leukocyte diapedesis, multiple organ damage syndrome, antigen-antibody complex-mediated diseases, antiglomerular basement membrane disease, allergic neuritis, autoimmune polyendocrinopathies, oophoritis, primary myxedema, atrophic gastritis autoimmune, sympathetic ophthalmia, diseases, Petition 870250027877, dated 07 / 04 / 2025, p. 61 / 384 52 / 299 rheumatic diseases, mixed connective tissue disease, nephrotic syndrome, insulitis, polyendocrine failure, autoimmune polyglandular syndrome type I, adult-onset idiopathic hypoparathyroidism (AOIH), cardiomyopathy such as dilated cardiomyopathy, acquired epidermolysis bullosa (EBA), hemochromatosis, myocarditis, nephrotic syndrome, primary sclerosing cholangitis, purulent or non-purulent sinusitis, acute or chronic sinusitis, ethmoid, frontal, maxillary or sphenoid sinusitis, an eosinophil-related disorder such as eosinophilia, eosinophilia with pulmonary infiltration, eosinophilia-myalgia syndrome, Löffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopneumonic aspergillosis, aspergilloma or granulomas containing eosinophils, anaphylaxis, seronegative spondyloarthritis, autoimmune polyendocrine disease, sclerosing cholangitis, scleritis, episcleritis, chronic mucocutaneous candidiasis, Bruton's syndrome.Transient hypogammaglobulinemia of childhood, Wiskott-Aldrich syndrome, ataxia-telangiectasia syndrome, angiectasia, autoimmune disorders associated with collagen disease, rheumatism, neurological disease, lymphadenitis, reduced blood pressure response, vascular dysfunction, tissue injury, cardiovascular ischemia, hyperalgesia, renal ischemia, cerebral ischemia, and disease accompanying vascularization, allergic hypersensitivity disorders, glomerulonephritis, reperfusion injury, ischemic reperfusion disorder, reperfusion injury of the myocardium or other tissues, lymphomatous tracheobronchitis, inflammatory dermatoses, dermatoses with acute inflammatory components, multiple organ failure, bullous diseases, renal cortical necrosis, acute purulent meningitis or other inflammatory disorders of the central nervous system, ocular and orbital inflammatory disorders, syndromes associated with granulocyte transfusion, cytokine-induced toxicity, narcolepsy,serious acute inflammation, inflammation, Petition 870250027877, dated 07 / 04 / 2025, page 62 / 384 53 / 299 chronic intractable, pyelitis, endarterial hyperplasia, peptic ulcer, valvulitis, emphysema, alopecia areata, adipose tissue inflammation / type II diabetes, obesity associated with adipose tissue inflammation / insulin resistance, and endometriosis.

[00105] In some modalities, the autoimmune disorder or disease may include, without limitation, Type I and Type II diabetes mellitus, prediabetes, transplant rejection, multiple sclerosis, a disorder related to multiple sclerosis, premature ovarian failure, scleroderma, Sjögren's disease / syndrome, lupus, vitiligo, alopecia (baldness), polyglandular insufficiency, Graves' disease, hypothyroidism, polymyositis, pemphigus, Crohn's disease, colitis, autoimmune hepatitis, hypopituitarism, myocarditis, Addison's disease, autoimmune skin diseases, uveitis, pernicious anemia, hypoparathyroidism, and / or rheumatoid arthritis.Other indications of interest include, without limitation, asthma, allergic asthma, primary biliary cirrhosis, cirrhosis, neuromyelitis optica spectrum disorder (Devic's disease, optic spinal multiple sclerosis (OSMS)), pemphigus vulgaris, inflammatory bowel disease (IBD), arthritis, rheumatoid arthritis, systemic lupus erythematosus (SLE), celiac disease, psoriasis, autoimmune cardiomyopathy, idiopathic dilated cardiomyopathy (IDCM), myasthenia gravis, uveitis, ankylosing spondylitis, immune-mediated myopathies, prostate cancer, antiphospholipid syndrome (ANCA+), atherosclerosis, dermatomyositis, chronic obstructive pulmonary disease (COPD), emphysema, spinal cord injury, traumatic injury, tobacco-induced lung destruction, ANCA-associated vasculitis, psoriasis, sclerosing cholangitis, primary sclerosing cholangitis, and diseases of the systems central and peripheral nervous systems

[00106] In some forms, the autoimmune disorder or disease may include, but is not limited to, diabetes, multiple sclerosis, celiac disease, primary biliary cirrhosis, pemphigus, Petition 870250027877, dated 07 / 04 / 2025, page 63 / 384 54 / 299 pemphigus foliaceus, pemphigus vulgaris, neuromyelitis optica spectrum disorder, arthritis (including rheumatoid arthritis), allergic asthma, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), systemic lupus erythematosus, atherosclerosis, chronic obstructive pulmonary disease, emphysema, psoriasis, autoimmune hepatitis, uveitis, Sjögren's syndrome, scleroderma, antiphospholipid syndrome, ANCA-associated vasculitis, and stiff-person syndrome.

[00107] As used in this descriptive report, the term “adipose tissue inflammation / type II diabetes” refers to the inflammation of adipose tissue exhibited by an individual suffering from type II diabetes. Adipose tissue inflammation contributes to the development of insulin resistance in the individual.

[00108] As used in this descriptive report, the term “obesity associated with adipose tissue inflammation / insulin resistance” refers to adipose tissue inflammation exhibited by an individual suffering from obesity. Adipose tissue inflammation contributes to the individual's insulin resistance, thereby increasing the likelihood that adipose tissue inflammation will result in the pathogenesis of type II diabetes.

[00109] As used in this descriptive report, the term “canonical sequence” refers to the protein sequence used as a reference for amino acid numbering in the absence of additional guidelines in the disclosure or existing technique. As is evident to those in the art, the termini of antigenic fragments may vary with the reference sequence from which the fragment was mapped. Thus, it should be understood, unless specifically stated otherwise, that fragment identifiers are approximate termini.

[00110] As used in this descriptive report, the term “PPI” refers to all isoforms, variants, and fragments thereof, of a protein associated with the name “pre-proinsulin”. Petition 870250027877, dated 07 / 04 / 2025, page 64 / 384 55 / 299 is a biologically inactive precursor to the biologically active endocrine hormone insulin, or a biological equivalent thereof. The canonical sequence of the PPI isoform is 110 amino acids long: MALWMRRLLPLLALLALWGPDPAAAFVNQHLCGSHLVEALYLVCGERGFFYTPKTRREAEDLQ VGQVELGGGPGAGSLQPLALEGSLQKRGIVEQCCTSICSLYQLENYCN.

[00111] As used in this descriptive report, the term “IGRP” refers to all isoforms, variants, and fragments thereof, of a protein associated with the name “islet-specific glucose-6-phosphatase catalytic subunit-related protein” or “Glucose-6-phosphatase-2,” an important autoantigen for autoimmune type 1 diabetes, or a biological equivalent thereof. The canonical sequence of IGRP is 355 amino acids long: MDFLHRNGVLIIQHLQKDYRAYYTFLNFMSNVGDPRNIFFIYFPLCFQFNQTVGTKMIWVAV IGDWLNLIFKWILFGHRPYWWVQETQIYPNHSSPCLEQFPTTCETGPGSPSGHAMGASCVWY VMVTAALSHTVCGMDKFSITLHRLTWSFLWSVFWLIQISVCISRVFIATHFPHQVILGVIGG MLVAEAFEHTPGIQTASLGTYLKTNLFLFLFAVGFYLLLRVLNIDLLWSVPIAKKWCANPDW IHIDTTPFAGLVRNLGVLFGLGFAINSEMFLLSCRGGNNYTLSFRLLCALTSLTILQLYHFL QIPTHEEHLFYVLSFCKSASIPLTVVAFIPYSVHMLMKQSGKKSQ.

[00112] As used in this descriptive report, the term “GAD” refers to all isoforms, variants, and fragments thereof, of a protein associated with the name “glutamic acid decarboxylase,” an antigen associated with diabetes, or a biological equivalent thereof. GAD may optionally refer to GAD1, GAD2, GAD65, GAD67, or any other glutamic acid decarboxylase relevant to diabetes. The canonical sequence of the GAD2 isoform is 585 amino acids in length and is revealed in the descriptive report below: MASPGSGFWSFGSEDGSGDSENPGTARAWCQVAQKFTGGIGNKLCALLYGDAEKPAESGGSQ PPRAAARKAACACDQKPCSCSKVDVNYAFLHATDLLPACDGERPTLAFLQDVMNILLQYVVK SFDRSTKVIDFHYPNELLQEYNWELADQPQNLEEILMHCQTTLKYAIKTGHPRYFNQLSTGL DMVGLAADWLTSTANTNMFTYEIAPVFVLLEYVTLKKMREIIGWPGGSGDGIFSPGGAISNM Petition 870250027877, dated 07 / 04 / 2025, p. 65 / 384 56 / 299 YAMMIARFKMFPEVKEKGMAALPRLIAFTSEHSHFSLKKGAAALGIGTDSVILIKCDERGKM IPSDLERRILEAKQKGFVPFLVSATAGTTVYGAFDPLLAVADICKKYKIWMHVDAAWGGGLL MSRKHKWKLSGVERANSVTWNPHKMMGVPLQCSALLVREEGLMQNCNQMHASYLFQQDKHYD LSYDTGDKALQCGRHVDVFKLWLMWRAKGTTGFEAHVDKCLELAEYLYNIIKNREGYEMVFD GKPQHTNVCFWYIPPSLRTLEDNEERMSRLSKVAPVIKARMMEYGTTMVSYQPLGDKVNFFR MVISNPAATHQDIDFLIEEIERLGQDL.

[00113] As used in this descriptive report, peripherin refers to all isoforms, variants, and fragments thereof, of a protein associated with that name, or a biological equivalent thereof. An exemplary, non-limiting human peripherin sequence associated with UniProt Reference No. P41219 is disclosed in the descriptive report below: MSHHPSGLRAGFSSTSYRRTFGPPPSLSPGAFSYSSSSRFSSSRLLGSASPSSSVRLGSFRS PRAGAGALLRLPSERLDFSMAEALNQEFLATRSNEKQELQELNDRFANFIEKVRFLEQQNAA LRGELSQARGQEPARADQLCQQELRELRRELELLGRERDRVQVERDGLAEDLAALKQRLEEE TRKREDAEHNLVLFRKDVDDATLSRLELERKIESLMDEIEFLKKLHEEELRDLQVSVESQQV QQVEVEATVKPELTAALRDIRAQYESIAAKNLQEAEEWYKSKYADLSDAANRNHEALRQAKQ EMNESRRQIQSLTCEVDGLRGTNEALLRQLRELEEQFALEAGGYQAGAARLEEELRQLKEEM ARHLREYQELLNVKMALDIEIATYRKLLEGEESRISVPVHSFASLNIKTTVPEVEPPQDSHS RKTVLIKTIETRNGEVVTESQKEQRSELDKSSAHSY.

[00114] As used in this descriptive report, the term aGlia refers to all isoforms, variants, and fragments thereof, of a protein associated with the name Alpha / betagliadin, derived from a member of the wheat family or other allergen related to celiac disease, or a biological equivalent thereof. An exemplary non-limiting alphagliadin sequence expressed in wheat associated with GenBank Accession No. CAA10257.1 is: MKTFLILALLAIVATTATTAVRVPVPQLQPQNPSQQQPQEQVPLVQQQQFLGQQQPFPPQQP YPQPQPFPSQQPYLQLQPFPQPQLPYSQPQPFRPQQPYPQPQPQYSQPQQPISQQQQQQQQQ QQQQQQQQQQQILQQILQQQLIPCMDVVLQQHNIAHGRSQVLQQSTYQLLQELCCQHLWQIP EQSQCQAIHKVVHAIILHQQQKQQQQPSSQVSFQQPLQQYPLGQGSFRPSQQNPQAQGSVQP QQLPQFEEIRNLALQTLPAMCNVYIPPYCTITPFGIFGTN. Petition 870250027877, dated 07 / 04 / 2025, page 66 / 384 57 / 299

[00115] Another exemplary non-limiting alpha-gliadin sequence expressed in wheat is revealed in this descriptive report below: VRVPVPQLQPQNPSQQQPQEQVPLVQQQQFLGQQQPFPPQQPYPQPQPFPSQQPYLQLQPFP QPQLPYSQPQPFRPQQPYPQPQPQYSQPQQPISQQQQQQQQQQQQQQQQQQQQQILQQILQQQ LIPCMDVVLQQHNIAHGRSQVLQQSTYQLLQELCCQHLWQIPEQSQCQAIHKVVHAIILHQQ QKQQQQPSSQVSFQQPLQQYPLGQGSFRPSQQNPQAQGSVQPQQLPQFEEIRNLALQTLPAM CNVYIPPYCTITPFGIFGTN.

[00116] As used in this descriptive report, the term “PDC-E2” refers to all isoforms, variants, and fragments thereof, of a protein associated with the name dihydrolipoamide Acetyltransferase or “DLAT”, an autoantigen of primary biliary cirrhosis, or a biological equivalent thereof.The canonical sequence of PDC-E2 is 647 amino acids long and is revealed in the descriptive report below: MWRVCARRAQNVAPWAGLEARWTALQEVPGTPRVTSRSGPAPARRNSVTTGYGGVRALCGWT PSSGATPRNRLLLQLLGSPGRRYYSLPPHQKVPLPSLSPTMQAGTIARWEKKEGDKINEGDL IAEVETDKATVGFESLEECYMAKILVAEGTRDVPIGAIICITVGKPEDIEAFKNYTLDSSAA PTPQAAPAPTPAATASPPTPSAQAPGSSYPPHMQVLLPALSPTMTMGTVQRWEKKVGEKLSE GDLLAEIETDKATIGFEVQEEGYLAKILVPEGTRDVPLGTPLCIIVEKEADISAFADYRPTE VTDLKPQVPPPTPPPVAAVPPTPQPLAPTPSAPCPATPAGPKGRVFVSPLAKKLAVEKGIDL TQVKGTGPDGRITKKDIDSFVPSKVAPAPAAVVPPTGPGMAPVPTGVFTDIPISNIRRVIAQ RLMQSKQTIPHYYLSIDVNMGEVLLVRKELNKILEGRSKISVNDFIIKASALACLKVPEANS SWMDTVIRQNHVVDVSVAVSTPAGLITPIVFNAHIKGVETIANDVVSLATKAREGKLQPHEF QGGTFTISNLGMFGIKNFSAIINPPQACILAIGASEDKLVPADNEKGFDVASMMSVTLSCDH RVVDGAVGAQWLAEFRKYLEKPITMLL.

[00117] As used in this descriptive report, the term “Insulin” refers to all isoforms, variants, and fragments thereof, of a protein associated with that name, or a biological equivalent thereof. A non-limiting exemplary sequence of human insulin associated with UniProt Reference No. P01308 is disclosed in this descriptive report below: MALWMRRLLPLLALLALWGPDPAAAFVNQHLCGSHLVEALYLVCGERGFFYTPKTRREAEDLQ Petition 870250027877, dated 07 / 04 / 2025, page 67 / 384 58 / 299 VGQVELGGGPGAGSLQPLALEGSLQKRGIVEQCCTSICSLYQLENYCN.

[00118] As used in this descriptive report, the term DG1EC2 refers to all isoforms, variants, and fragments thereof, of a protein associated with the name “desmosomal glycoprotein 1”, or a biological equivalent thereof. The canonical sequence of DG1EC2 is 1,054 amino acids long and is revealed in the descriptive report below: MNWHFLRTATVLLIFLVVVEINSEFRIQVRDYNTKNGTIKWHSIRRQKREWIKFAAACREGE DNSKRNPIAKIHSDCAANQQVTYRISGVGIDQPPYGIFIINQKTGEINITSIVDREITPFFI IYCRALNSLGQDLERPLELRVRVLDINDNPPVFSMSTFVGQIEENSNANTLVMRLNATGADE PNNLNSKIAFKIIRQEPSDSPMFIINRNTGEIRTMNNFLDREQYSQYSLAVRGSDRDGGADG MSAECECNIKILDVNDNIPYMEPSSHMVRIEENALSQNLVEIRVIDLDEEFSANWMAVIFFI SGNEGGWFDIEMNERTNVGILKVIKPLDYEAVQNLQLSLGVRNKADFHHSIMSQYKVTATAI SVTVLNVIEGSVFRPGSKTYVVRSDMGQNYKVGDFVATDLDTGLASTTVRYVMGNNPANLLN VDSKTGVITLRNKVTMEQYEMLNGKYQGTILSIDDALQRTCTGTINIDLQGSGWEKDSEKVT SSQNSGSSTGDSSGGTGGGGRENPSEGDTTTNTGGKTSTDYEDGETQTQSNNNHQELGSNNL SDNVHFGPAGIGLLIMGFLVLGLVPFLLMCCDCGGAPGAGAGFEPVPECSDGAIHSWAVEGPQPLPTDATTVCVPPIPSNNANVIECIDTSGVYTNEYGGREMQDLGGGERTTGFELTEGVKTS GVPEICQEYSGTLRRNSMRECREGGLNMNFMESYFCQKAYAYADEDEGRPSNDCLLIYDIEG VGSPAGSVGCCSFIGEDLDDSFLDTLGPKFKKLADISLGKEVEPDPSWPPESTEPICPQQGT EPIIGGHPPISPHFGTTTVISENTYPSGPGVQHPMPIPDPLGYGNVTVTESYTTSGTLKPTV HVHDNRHASNVVVTERVVGPISGTDLHGMLEMPDLRDGSNVI.

[00119] As used in this descriptive report, the term “DG3” refers to all isoforms, variants, and fragments thereof, of a protein associated with the name “desmoglein 3”, or a biological equivalent thereof. An exemplary non-limiting sequence of human desmoglein 3 associated with UniProt Reference No. P32926-1 is disclosed in the descriptive report below: MMGLFPRTTGALAIFVVVILVHGELRIETKGQYDEEEMTMQQAKRRQKREWVKFAKPCREGE DNSKRNPIAKITSDYQATQKITYRISGVGIDQPPFGIFVVDKNTGDINITAIVDREETPSFL ITCRALNAQGLDVEKPLILTVKILDINDNPPVFSQQIFMGEIEENSASNSLVMILNATDADE PNHLNSKIAFKIVSQEPAGTPMFLLSRNTGEVRTLTNSLDREQASSYRLVVSGADKDGEGLS Petition 870250027877, dated 07 / 04 / 2025, page 68 / 384 59 / 299 TQCECNIKVKDVNDNFPMFRDSQYSARIEENILSSELLRFQVTDLDEEYTDNWLAVYFFTSG NEGNWFEIQTDPRTNEGILKVVKALDYEQLQSVKLSIAVKNKAEFHQSVISRYRVQSTPVTI QVINVREGIAFRPASKTFTVQKGISSKKLVDYILGTYQAIDEDTNKAASNVKYVMGRNDGGY LMIDSKTAEIKFVKNMNRDSTFIVNKTITAEVLAIDEYTGKTSTGTVYVRVPDFNDNCPTAV LEKDAVCSSSPSVVVSARTLNNRYTGPYTFALEDQPVKLPAVWSITTLNATSALLRAQEQIP PGVYHISLVLTDSQNNRCEMPRSLTLEVCQCDNRGICGTSYPTTSPGTRYGRPHSGRLGPAA IGLLLLGLLLLLLAPLLLLTCDCGAGSTGGVTGGFIPVPDGSEGTIHQWGIEGAHPEDKEIT NICVPPVTANGADFMESSEVCTNTYARGTAVEGTSGMEMTTKLGAATESGGAAGFATGTVSG AASGFGAATGVGICSSGQSGTMRTRHSTGGTNKDYADGAISMNFLDSYFSQKAFACAEEDDG QEANDCLLIYDNEGADATGSPVGSVGCCSFIADDLDDSFLDSLGPKFKKLAEISLGVDGEGK EVQPPSKDSGYGIESCGHPIEVQQTGFVKCQTLSGSQGASALSTSGSVQPAVSIPDPLQHGN YLVTETYSASGSLVQPSTAGFDPLLTQNVIVTERVICPISSVPGNLAGPTQLRGSHTMLCTE DPCSRLI.

[00120] As used in this descriptive report, the term “AQP4” refers to all isoforms, variants, and fragments thereof, of a protein associated with the name “aquaporin 4,” which belongs to the aquaporin family of integral membrane proteins that conduct across the cell membrane and is the primary autoimmune target of neuromyelitis optica spectrum disorder, or a biological equivalent thereof. The canonical sequence of AQP4 is 323 amino acids long and is disclosed in this descriptive report below: MSDRPTARRWGKCGPLCTRENIMVAFKGVWTQAFWKAVTAEFLAMLIFVLLSLGSTINWGGT EKPLPVDMVLISLCFGLSIATMVQCFGHISGGHINPAVTVAMVCTRKISIAKSVFYIAAQCL GAIIGAGILYLVTPPSVVGGLGVTMVHGNLTAGHGLLVELIITFQLVFTIFASCDSKRTDVT GSIALAIGFSVAIGHLFAINYTGASMNPARSFGPAVIMGNWENHWIYWVGPIIGAVLAGGLY EYVFCPDVEFKRRFKEAFSKAAQQTKGSYMEVEDNRSQVETDDLILKPGVVHVIDVDRGEEK KGKDQSGEVLSSV.

[00121] As used in this descriptive report, the term “PLP” refers to all isoforms, variants, and fragments thereof, of a protein associated with the name “proteolipid myelin protein,” or a biological equivalent thereof. A non-limiting exemplary sequence of human myelin protein Petition 870250027877, dated 07 / 04 / 2025, page 69 / 384 The proteolipid compound 60 / 299 associated with UniProt Reference No. P60201 is disclosed in the descriptive report below: MGLLECCARCLVGAPFASLVATGLCFFGVALFCGCGHEALTGTEKLIETYFSKNYQDYEYLI NVIHAFQYVIYGTASFFFLYGALLLAEGFYTTGAVRQIFGDYKTTICGKGLSATVTGGQKGR GSRGQHQAHSLERVCHCLGKWLGHPDKFVGITYALTVVWLLVFACSAVPVYIYFNTWTTCQS IAFPSKTSASIGSLADARMYGVLPWNAFPGKVCGSNLLSICKTAEFQMTFHLFIAAFVGAA ATLVSLLTFMIAATYNFAVLKLMGRGTKF.

[00122] As used in this descriptive report, the term MOG refers to all isoforms, variants, and fragments thereof, of a protein associated with the name oligodendrocyte myelin glycoprotein, or a biological equivalent thereof. An exemplary non-limiting human oligodendrocyte myelin glycoprotein sequence associated with UniProt Reference No. Q16653 is disclosed in this descriptive report below: MASLSRPSLPSCLCSFLLLLLLQVSSSYAGQFRVIGPRHPIRALVGDEVELPCRISPGKNAT GMEVGWYRPPFSRVVHLYRNGKDQDGDQAPEYRGRTELLKDAIGEGKVTLRIRNVRFSDEGG FTCFFRDHSYQEEAAMELKVEDPFYWVSPGVLVLLAVLPVLLLQITVGLIFLCLQYRLRGKL RAEIENLHRTFDPHFLRVPCWKITLFVIVPVLGPLVALIICYNWLHRRLAGQFLEELRNPF.

[00123] As used in this descriptive report, MBP refers to all isoforms, variants, and fragments thereof, of a protein associated with the name myelin basic protein, or a biological equivalent thereof. An exemplary non-limiting sequence of human myelin basic protein associated with UniProt Reference No. P02686 is disclosed in this descriptive report below: MGNHAGKRELNAEKASTNSETNRGESEKKRNLGELSRTTSEDNEVFGEADANQNNGTSSQDT AVTDSKRTADPKNAWQDAHPADPGSRPHLIRLFSRDAPGREDNTFKDRPSESDELQTIQEDS AATSESLDVMASQKRPSQRHGSKYLATASTMDHARHGFLPRHRDTGILDSIGRFFGGDRGAP KRGSGKDSHHPARTAHYGSLPQKSHGRTQDENPVVHFFKNIVTPRTPPPSQGKGRGLSLSRF SWGAEGQRPGFGYGGRASDYKSAHKGFKGVDAQGTLSKIFKLGGRDSRSGSPMARR.

[00124] As used in this descriptive report, the term CII refers to all isoforms, variants, and fragments thereof, of a protein associated with the name native collagen. Petition 870250027877, dated 07 / 04 / 2025, p. 70 / 384 61 / 299 type II”, a high molecular weight fibrillar molecule implicated in chronic polyarthritis, or a biological equivalent thereof. An exemplary non-limiting consensus sequence of human collagen II is revealed in the descriptive report below: MRGASVTVAAVRCGDVAGSCVDGRYNDKDVWKCRCVCDTGTVCDDCDVKDCSGCCCTDATAS GGKGKGGDKDVGKGGGAGGRGDRGDKGKGAGRGRDGGTGNGGGGGGGNAAMAGGDKAGGAGV MGMGMGRGGAGAGGGNGGGVSGMGRGGGKGDDGAGKGKAGRGGGARGGTGGVKGHRGYGDGA KGAGAGVKGSGSGNGSGMGRGGRGRTGAGAAGARGNDGGAGGVGAGGGGAGAKGAGTGARGG AGRGGTGSGAGASGNGTDGGAKGSAGAGAGAGGRGGGATGGKGTGGAGKGGKGGAGGAGAGG KRGARGGGVGGGRGAGNRGGDGAGKGAGRGSGAGKGANGDGRGGGGARGTGRGDAGGKVGSGA GDGRGGGARGGVMGGKGANGGKAGKGGAGRGGKDGTGAAGGAGAGRGGAGSGGGGGGGKGDG VGAGAGVGRGRGGRGGSGAGGRGGTGTDGKGASGAGGAGGGMGRGAAGAGKGDRGDVGKGGAG KDGRGRGTGGAGANGKGVGGAGSAGARGAGRGTGGAGAGGADGGAKGGAGKGDAGAGGSGAG GTGVTGKGARGAGGATGGAAGRVGGSNGNGGGSGKDGKGARGDSGGRAGGGAGGKGGDDGSG AGGGAGRGVGGRGRGGSGGKGAGASGDRGGVGGTGAGGGRGSGADGGRDGAAGVKGDRGTGA VGAGAGGSGAGTGKGDRGAGAGMGSGAGARGGGRGDKGAGGRGKGHRGTGGGSGDGASGAG SGRGGVGSGKDGANGGGGRGRSGTGAGGNGGGGGDMSAAGGRKGDYMRADAAGGRHDAVDAT KSNNSRSGSRKNARTCRDKCHWKSGDYWDNGCTDAMKVCNMTGTCVYNANVKKNWWSSKSKK KHWGTNGGHSYGDDNANTANVMTRSTGSNTYHCKNSAYDAAGNKKAGSNDVRAGNSRTYTAK DGCTKHTGKWGKTVYRSKTSRDAMDGGGVDGVC.

[00125] Another exemplary non-limiting sequence of murine collagen II is revealed in this descriptive report below: MIRLGAPQSLVLLTLLIAAVLRCQGQDARKLGPKGQKGEPGDIRDIIGPRGPPGPQGPAGEQ GPRGDRGDKGEKGAPGPRGRDGEPGTPGNPGPAGPPGPPGPPGLSAGNFAAQMAGGYDEKAG GAQMGVMQGPMGPMGPRGPPGPAGAPGPQGFQGNPGEPGEPGVSGPMGPRGPPGPAGKPGDD GEAGKP GKSGERGLP GPQGARGFPGTP GLP GVKGHRGYP GLDGAKGEAGAP GVKGE SGSPGE NGSPGPMGPRGLP GERGRTGPAGAAGARGNDGQP GPAGPPGPVGPAGGP GFPGAP GAKGEAG PTGARGPEGAQGSRGEPGNPGSPGPAGASGNPGTDGIPGAKGSAGAPGIAGAPGFPGPRGPP GPQGATGPLGPKGQAGEPGIAGFKGDQGPKGETGPAGPQGAPGPAGEEGKRGARGEPGGAGP IGPPGERGAPGNRGFPGQDGLAGPKGAPGERGPSGLTGPKGANGDPGRPGEPGLPGARGLTG RP GDAGPQGKVGP S GAP GEDGRPGPP GPQGARGQP GVMGFP GP KGANGEP GKAGEKGLAGAP GLRGLPGKDGETGAAGPPGPSGPAGERGEQGAPGPSGFQGLPGPPGPPGEGGKQGDQGIPGE Petição 870250027877, de 07 / 04 / 2025, pág. 71 / 384 62 / 299 AGAPGLVGPRGERGFPGERGSPGAQGLQGPRGLPGTPGTDGPKGAAGPDGPPGAQGPPGLQG MPGERGAAGIAGPKGDRGDVGEKGPEGAPGKDGGRGLTGPIGPPGPAGANGEKGEVGPPGPS GSTGARGAPGERGETGPPGPAGFAGPPGADGQPGAKGDQGEAGQKGDAGAPGPQGPSGAPGP QGPTGVTGP KGARGAQGP P GATGFPGAAGRVGP P GANGNP GPAGP P GPAGKD GP KGVRGD S G PPGRAGDPGLQGPAGAPGEKGEPGDDGPSGLDGPPGPQGLAGQRGIVGLPGQRGERGFPGLP GPSGEPGKQGAPGASGDRGPPGPVGPPGLTGPAGEPGREGSPGADGPPGRDGAAGVKGDRGE TGALGAPGAPGPPGSPGPAGPTGKQGDRGEAGAQGPMGPSGPAGARGIAGPQGPRGDKGESG EQGERGLKGHRGFTGLQGLPGPPGPSGDQGASGPAGPSGPRGPPGPVGPSGKDGSNGIPGPI GPPGPRGRSGETGPVGPPGSPGPPGPPGPPGPGIDMSAFAGLGQREKGPDPMQYMRADEADS TLRQHDVEVDATLKSLNNQIESIRSPDGSRKNPARTCQDLKLCHPEWKSGDYWIDPNQGCTL DAMKVFCNMETGETCVYPNPATVPRKNWWSSKSKEKKHIWFGETMNGGFHFSYGDGNLAPNT ANVQMTFLRLLSTEGSQNITYHCKNSIAYLDEAAGNLKKALLIQGSNDVEMRAEGNSRFTYT ALKDGCTKHTGKWGKTVIEYRSQKTSRLPIIDIAPMDIGGAEQEFGVDIGPVCFL.

[00126] As used in this descriptive report, the term “DERP-1” refers to all isoforms, variants, and fragments thereof, of a protein associated with the name “p1” of Dermatophagoides pteronyssius and known to cause an allergic reaction in humans, or a biological equivalent thereof. A non-limiting exemplary consensus sequence of DERP-1 is disclosed in this descriptive report below: NEIAXAKIDLRQMRTVTPIXMQGGCGSCWALSGVAATESAYLAYGNXSLDLAEQELVDCASQ HGCHGDTIPRGIEYIQHNGVVQESYYRYVAREQSCRRPNAQRFGISNYCQIYPPNVNKIREA LAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSW DTNWGDNGYGYFAANIDLMMIEEYPYVVIL.

[00127] As used in this descriptive report, the term “DERP2” refers to all isoforms, variants, and fragments thereof, of a protein associated with the name “p2” of Dermatophagoides pteronyssius and known to cause an allergic reaction in humans, or a biological equivalent thereof. A non-limiting exemplary consensus sequence of DERP2 is disclosed in that descriptive report below: MMYKILCLSLLVAAVARDQVDVKDCANHEIKKVLVPGCHGSEPCIIHRGKPFQLEAVFEANQ NTKTAKIEIKASIDGLEVDVPGIDPNACHYMKCPLVKGQQYDIKYTWNVPKIAPKSENVVVT Petition 870250027877, dated 07 / 04 / 2025, p. 72 / 384 63 / 299 VKVMGDDGVLACAIATHAKIRD.

[00128] As used in this descriptive report, the term OVA refers to all isoforms, variants, and fragments thereof, of a protein associated with the name ovalbumin for use in generating an allergic response in mice, or a biological equivalent thereof.

[00129] As used in this descriptive report, BacInt or Bacteroides integrase refers to all isoforms, variants, and fragments thereof, of a protein associated with that name, or a biological equivalent thereof. The canonical sequence of BacInt is 406 amino acids long and is revealed in the descriptive report below: MDKIRYRLVYNRQNTLNRQGTALVQVEAYLNQRKIYLKTNVYLKPECWSREGAQVINHPQSN ELNIMLYEYILYLQGIELGYWKRGIPATLSLLKDAVKKKSAVNISFSTFAKSAIDNSDKKQS TKDNLHSTLAVLHDFRSGLDFKDLTYTFLRDFEQYLREKGNAVNTIAKHMRQLRTLVNEAIN QGYMHADAYPFRKYKIKQEKGRHEFLTPDELKKLETVEVEEESMRHVLDAFLFCCYTGLRYS DFCQLTPENFIRINGKRWLYFKSVKTGVEIRLPLHLLFESRALGILDRYPDIGSFAALPSNC EVNKQLRKLAGLCGIKKRITYHVSRHTCATLLIHQGVAITTVQKLLGHTSVKTTQIYSEVLS STIVRDLKNVQKGKRKVKMFPDKGLRTSDFIDNR.

[00130] As used in this descriptive report, the term CBir, Fla-X and / or Fla-2 refers to all isoforms, variants, and fragments thereof, of a protein associated with one or more bacterial flagellins implicated in colitis, or a biological equivalent thereof. An exemplary, non-limiting sequence of Fla-X is revealed in the descriptive report below: MVVQHNLRAMNSNRMLGITQGSLNKSTEKLSSGYKVNRAADDAAGLSISEKMRKQIRGLSQA SLNAEDGISAVQTAEGALTEVHDMLQRMNELAVKAANGTNSTSDRQTIQDEVDQLLTEIDRV AETTKFNELYTLKGDEDKVTRYLSAHDAGIEGTLTQGATNATFSMDQLKFGDTIMIAGREYH ISGTKAEQAAIITASVKIGQQVTIDGIMYTCSSVSNADKFELKSEDLIAKLDTSSLSIMSVN GKTYYGAGITDDRTVVSSIGAYKLIQKELGLASSIGADGATQASVNAGVDGKTLMKPSFEGK WVFSIDKGSVQVREDIDFSLHVGADADMNNKIAVKIGALDTKGLGIQGLNVKDTTGAAATYA IDSIADAVARISAQRSLLGAVQNRLEHTINNLDNVVENTTAAESQIRDTDMATEMVKYSNNN VLAQAGQSMLAQSNQANQGVLQLLQ. Petition 870250027877, dated 07 / 04 / 2025, page 73 / 384 64 / 299

[00131] An exemplary non-limiting sequence of Fla-2 is revealed in the descriptive report below: MVVQHNLRAMNSNRMLGITQGSLNKSTEKLSSGYKVNRAADDAAGLSISEKMRKQIRGLSQA SLNAEDGISAVQTAEGALTEVHDMLQRMNELAVKAANGTNSTSDRQTIQDEVDQLLTEIDRV AETTKFNELYTLKGDEDKVTRYLSAHDAGIEGTLTQGATNATFSMDQLKFGDTIMIAGREYH ISGTQKQQGEIITSSVKIGQQVTIDGIMYTCTATVSNADKFELTKDDLIAKLDTSSLSIMSV NGKTYYGAGITDDRTVVSSIGAYKLIQKELGLASSIGADGSTQASVNAGVDGKTLKKPSFEG KWVFSIDKGSVQVREDIDFSLHVGADADMNNKIAVKIGALDTKGLGIQGLNVKDTTGAAATY AIDSIADAVARISAQRSLLGAVQNRLEHTINNLDNVVENTTAAESQIRDTDMATEMVKYSNN NVLAQAGQSMLAQSNQANQGVLSLLG.

[00132] As used in this descriptive report, the term “YIDX” refers to all isoforms, variants, and fragments thereof, of a protein associated with that name, is of bacterial origin, and is implicated in the pathogenesis of immune-related disease, or a biological equivalent thereof. A non-limiting exemplary sequence of YIDX is disclosed in this descriptive report below: MKLNFKGFFKAAGLFPLALMLSGCISYALVSHTAKGSSGKYQSQSDTITGLSQAKDSNGTKG YVFVGESLDYLITDGADDIVKMLNDPALNRHNIQVADDARFVLNAGKKKFTGTISLYYYWNN EEEKALATHYGFACGVQHCTRSLENLKGTIHEKNKNMDYSKVMAFYHPFKVRFYEYYSPRGI PDGVSAALLPVTVTLDIITAPLQFLVVYAVNQ.

[00133] Another exemplary non-limiting sequence of YIDX is revealed in this descriptive report below: MKLNFKGFFKAAGLFPLALMLSGCISYALVSHTAKGSSGKYQSQSDTITGLSQAKDSNGTKG YVFVGESLDYLITDGADDIVKMLNDPALNRHNIQVADDARFVLNAGKKKFTGTISLYYYWNN EEEKALATHYGFACGVQHCTRSLENLKGTIHEKNKNMDYSKVMAFYHPFKVRFYEYYSPRGI PDGVSAALLPVTVTLDIITAPLQFLVVYAVNQ.

[00134] As used in this descriptive report, the term “AChR” refers to all isoforms, variants, and fragments thereof, of a protein associated with that name, or a biological equivalent thereof.

[00135] An exemplary non-limiting acetylcholine receptor sequence associated with UniProt Reference No. Q13702 Petition 870250027877, dated 07 / 04 / 2025, page 74 / 384 65 / 299 is revealed in the descriptive report below: MGQDQTKQQIEKGLQLYQSNQTEKALQVWTKVLEKSSDLMGRFRVLGCLVTAHSEMGRYKEM LKFAVVQIDTARELEDADFLLESYLNLARSNEKLCEFHKTISYCKTCLGLPGTRAGAQLGGQ VSLSMGNAFLGLSVFQKALESFEKALRYAHNNDDAMLECRVCCSLGSFYAQVKDYEKALFFP CKAAELVNNYGKGWSLKYRAMSQYHMAVAYRLLGRLGSAMECCEESMKIALQHGDRPLQALC LLCFADIHRSRGDLETAFPRYDSAMSIMTEIGNRLGQVQALLGVAKCWVARKALDKALDAIE RAQDLAEEVGNKLSQLKLHCLSESIYRSKGLQRELRAHVVRFHECVEETELYCGLCGESIGE KNSRLQALPCSHIFHLRCLQNNGTRSCPNCRRSSMKPGFV.

[00136] A non-limiting exemplary acetylcholine receptor sequence associated with UniProt Reference No. Q048441 is disclosed in the descriptive report below: MARAPLGVLLLLGLLGRGVGKNEELRLYHHLFNNYDPGSRPVREPEDTVTISLKVTLTNLIS LNEKEETLTTSVWIGIDWQDYRLNYSKDDFGGIETLRVPSELVWLPEIVLENNIDGQFGVAY DANVLVYEGGSVTWLPPAIYRSVCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFTFAVDNDG KTINKIDIDTEAYTENGEWAIDFCPGVIRRHHGGATDGPGETDVIYSLIIRRKPLFYVINII VPCVLISGLVLLAYFLPAQAGGQKCTVSINVLLAQTVFLFLIAQKIPETSLSVPLLGRFLIF VMVVATLIVMNCVIVLNVSQRTPTTHAMSPRLRHVLLELLPRLLGSPPPPEAPRAASPPRRA SSVGLLLRAEELILKKPRSELVFEGQRHRQGTWTAAFCQSLGAAAPEVRCCVDAVNFVAEST RDQEATGEEVSDWVRMGNALDNICFWAALVLFSVGSSLIFLGAYFNRVPDLPYAPCIQP.

[00137] A non-limiting exemplary acetylcholine receptor sequence associated with UniProt Reference No. P027081 is disclosed in the descriptive report below: MEPWPLLLLFSLCSAGLVLGSEHETRLVAKLFKDYSSVVRPVEDHRQVVEVTVGLQLIQLIN VDEVNQIVTTNVRLKQGDMVDLPRPSCVTLGVPLFSHLQNEQWVDYNLKWNPDDYGGVKKIH IPSEKIWRPDLVLYNNADGDFAIVKFTKVLLQYTGHITWTPPAIFKSYCEIIVTHFPFDEQN CSMKLGTWTYDGSVVAINPESDQPDLSNFMESGEWVIKESRGWKHSVTYSCCPDTPYLDITY HFVMQRLPLYFIVNVIIPCLLFSFLTGLVFYLPTDSGEKMTLSISVLLSLTVFLLVIVELIP STSSAVPLIGKYMLFTMVFVIASIIITVIVINTHHRSPSTHVMPNWVRKVFIDTIPNIMFFS TMKRPSREKQDKKIFTEDIDISDISGKPGPPPMGFHSPLIKHPEVKSAIEGIKYIAETMKSD QE SNNAAAEWKYVAMVMDHILLGVFMLVC11GTLAVFAGRLIE LNQQG.

[00138] A non-limiting exemplary acetylcholine receptor sequence associated with UniProt Reference No. P075101 is disclosed in the descriptive report below: Petition 870250027877, dated 07 / 04 / 2025, page 75 / 384 66 / 299 MHGGQGPLLLLLLLAVCLGAQGRNQEERLLADLMQNYDPNLRPAERDSDVVNVSLKLTLTNL ISLNEREEALTTNVWIEMQWCDYRLRWDPRDYEGLWVLRVPSTMVWRPDIVLENNVDGVFEV ALYCNVLVSPDGCIYWLPPAIFRSACSISVTYFPFDWQNCSLIFQSQTYSTNEIDLQLSQED GQTIEWIFIDPEAFTENGEWAIQHRPAKMLLDPAAPAQEAGHQKVVFYLLIQRKPLFYVINI IAPCVLISSVAILIHFLPAKAGGQKCTVAINVLLAQTVFLFLVAKKVPETSQAVPLISKYLT FLLVVTILIVVNAVVVLNVSLRSPHTHSMARGVRKVFLRLLPQLLRMHVRPLAPAAVQDTQS RLQNGSSGWSITTGEEVALCLPRSELLFQQWQRQGLVAAALEKLEKGPELGLSQFCGSLKQA APAIQACVEACNLIACARHQQSHFDNGNEEWFLVGRVLDRVCFLAMLSLFICGTAGIFLMAH YNRVPALPFPGDPRPYLPSPD.

[00139] A non-limiting exemplary acetylcholine receptor sequence associated with UniProt Reference No. P112301 is disclosed in the descriptive report below: MTPGALLMLLGALGAPLAPGVRGSEAEGRLREKLFSGYDSSVRPAREVGDRVRVSVGLILAQ LISLNEKDEEMSTKVYLDLEWTDYRLSWDPAEHDGIDSLRITAESVWLPDVVLLNNNDGNFD VALDISVVVSSDGSVRWQPPGIYRSSCSIQVTYFPFDWQNCTMVFSSYSYDSSEVSLQTGLG PDGQGHQEIHIHEGTFIENGQWEIIHKPSRLIQPPGDPRGGREGQRQEVIFYLIIRRKPLFY LVNVIAPCILITLLAIFVFYLPPDAGEKMGLSIFALLTLTVFLLLLADKVPETSLSVPIIIK YLMFTMVLVTFSVILSVVVLNLHHRSPHTHQMPLWVRQIFIHKLPLYLRLKRPKPERDLMPE PPHCSSPGSGWGRGTDEYFIRKPPSDFLFPKPNRFQPELSAPDLRRFIDGPNRAVALLPELR EVVSSISYIARQLQEQEDHDALKEDWQFVAMVVDRLFLWTFIIFTSVGTLVIFLDATYHLPP PDPFP

[00140] A non-limiting exemplary acetylcholine receptor sequence associated with UniProt Reference No. Q070011 is disclosed in the descriptive report below: MEGPVLTLGLLAALAVCGSWGLNEEERLIRHLFQEKGYNKELRPVAHKEESVDVALALTLSN LISLKEVEETLTTNVWIEHGWTDNRLKWNAEEFGNISVLRLPPDMVWLPEIVLENNNDGSFQ ISYSCNVLVYHYGFVYWLPPAIFRSSCPISVTYFPFDWQNCSLKFSSLKYTAKEITLSLKQD AKENRTYPVEWIIIDPEGFTENGEWEIVHRPARVNVDPRAPLDSPSRQDITFYLIIRRKPLF YIINILVPCVLISFMVNLVFYLPADSGEKTSVAISVLLAQSVFLLLISKRLPATSMAIPLIG KFLLFGMVLVTMVVVICVIVLNIHFRTPSTHVLSEGVKKLFLETLPELLHMSRPAEDGPSPG ALVRRSSSLGYISKAEEYFLLKSRSDLMFEKQSERHGLARRLTTARRPPASSEQAQQELFNE LKPAVDGANFIVNHMRDQNNYNEEKDSWNRVARTVDRLCLFVVTPVMVVGTAWIFLQGVYNQ PPPQPFPGDPYSYNVQDKRFI. Petition 870250027877, dated 07 / 04 / 2025, page 76 / 384 67 / 299

[00141] As used in this descriptive report, the term “thyroid peroxidase” refers to all isoforms, variants, and fragments thereof, of a protein associated with that name, or a biological equivalent thereof. An exemplary non-limiting human thyroid peroxidase sequence associated with UniProt Reference No. P07202 is disclosed in the descriptive report below: MRALAVLSVTLVMACTEAFFPFISRGKELLWGKPEESRVSSVLEESKRLVDTAMYATMQRNL KKRGILSPAQLLSFSKLPEPTSGVIARAAEIMETSIQAMKRKVNLKTQQSQHPTDALSEDLL SIIANMSGCLPYMLPPKCPNTCLANKYRPITGACNNRDHPRWGASNTALARWLPPVYEDGFS QPRGWNPGFLYNGFPLPPVREVTRHVIQVSNEVVTDDDRYSDLLMAWGQYIDHDIAFTPQST SKAAFGGGADCQMTCENQNPCFPIQLPEEARPAAGTACLPFYRSSAACGTGDQGALFGNLST ANPRQQMNGLTSFLDASTVYGSSPALERQLRNWTSAEGLLRVHARLRDSGRAYLPFVPPRAP AACAPEPPGIPGETRGPCFLAGDGRASEVPSLTALHTLWLREHNRLAALKALNAHWSADAVY QEARKVVGALHQIITLRDYIPRILGPEAFQQYVGPYEGYDSTANPTVSNVFSTAAFRFGHAT IHPLVRRLDASFQEHPDLPGLWLHQAFFSPWTLLRGGGLDPLIRGLLARPAKLQVQDQLMNEELTERLFVLSNSSTLDLASINLQRGRDHGLPGYNEWREFCGLPRLETPADLSTAIASRSVAD KILDLYKHPDNIDVWLGGLAENFLPRARTGPLFACLIGKQMKALRDGDWFWWENSHVFTDAQ RRELEKHSLSRVICDNTGLTRVPMDAFQVGKFPEDFESCDSITGMNLEAWRETFPQDDKCGF PESVENGDFVHCEESGRRVLVYSCRHGYELQGREQLTCTQEGWDFQPPLCKDVNECADGAHP PCHASARCRNTKGGFQCLCADPYELGDDGRTCVDSGRLPRVTWISMSLAALLIGGFAGLTST VICRWTRTGTKSTLPISETGGGTPELRCGKHQAVGTSPQRAAAQDSEQESAGMEGRDTHRLP RAL.

[00142] As used in this descriptive report, the term “thyroid receptor” refers to all isoforms, variants, and fragments thereof, of a protein associated with that name, or a biological equivalent thereof. In some embodiments, “thyroid receptor” includes “thyroid-stimulating hormone receptor”. A non-limiting exemplary sequence of thyroid-stimulating hormone receptor associated with UniProt Reference No. P16473-1 is disclosed in this descriptive report below: MRPADLLQLVLLLDLPRDLGGMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLIET Petition 870250027877, dated 07 / 04 / 2025, page 77 / 384 68 / 299 HLRTIPSHAFSNLPNISRIYVSIDVTLQQLESHSFYNLSKVTHIEIRNTRNLTYIDPDALKE LPLLKFLGIFNTGLKMFPDLTKVYSTDIFFILEITDNPYMTSIPVNAFQGLCNETLTLKLYN NGFTSVQGYAFNGTKLDAVYLNKNKYLTVIDKDAFGGVYSGPSLLDVSQTSVTALPSKGLEH LKELIARNTWTLKKLPLSLSFLHLTRADLSYPSHCCAFKNQKKIRGILESLMCNESSMQSLR QRKSVNALNSPLHQEYEENLGDSIVGYKEKSKFQDTHNNAHYYVFFEEQEDEIIGFGQELKN PQEETLQAFDSHYDYTICGDSEDMVCTPKSDEFNPCEDIMGYKFLRIVVWFVSLLALLGNVF VLLILLTSHYKLNVPRFLMCNLAFADFCMGMYLLLIASVDLYTHSEYYNHAIDWQTGPGCNT AGFFTVFASELSVYTLTVITLERWYAITFAMRLDRKIRLRHACAIMVGGWVCCFLLALLPLV GISSYAKVSICLPMDTETPLALAYIVFVLTLNIVAFVIVCCCYVKIYITVRNPQYNPGDKDT KIAKRMAVLIFTDFICMAPISFYALSAILNKPLITVSNSKILLVLFYPLNSCANPFLYAIFT KAFQRDVFILLSKFGICKRQAQAYRGQRVPPKNSTDIQVQKVTHDMRQGLHNMEDVYELIEN SHLTPKKQGQISEEYMQTVL.

[00143] A non-limiting exemplary thyroid-stimulating hormone receptor sequence associated with UniProt Reference No. Q59GA2-1 is disclosed in this descriptive report below: PRVPWKMRPADLLQLVLLLDLPRDLGGMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQT LKLIETHLRTIPSHAFSNLPNISRIYVSIDVTLQQLESHSFYNLSKVTHIEIRNTRNLTYID PDALKELPLLKFLGIFNTGLKMFPDLTKVYSTDIFFILEITDNPYMTSIPVNAFQGLCNETL TLKLYNNGFTSVQGYAFNGTKLDAVYLNKNKYLTVIDKDAFGGVYSGPSLLDVSQTSVTALP SKGLEHLKELIARNTWTLKKLPLSLSFLHLTRADLSYPSHCCAFKNQKKIRGILESLMCNES SMQSLRQRKSVNALNSPLHQEYEENLGDSIVGYKEKSKFQDTHNNAHYYVFFEEQEDEIIGF GQELKNPQEETLQAFDSHYDYTICGDSEDMVCTPKSDEFNPCEDIMGYKFLRIVVWFVSLLA LLGNVFVLLILLTSHYKLNVPRFLMCNLAFADFCMGMYLLLIASVDLYTHSEYYNHAIDWQT GPGCNTAGFFTVFASELSVYTLTVITLERWYAITFAMRLDRKIRLRHACAIMVGGWVCCFLL ALLPLVGISSYAKVSICLPMDTETPLALAYIVFVLTLNIVAFVIVCCCYVKIYITVRNPQYN PGDKDTKIAKRMAVLIFTDFICMAPISFYALSAILNKPLITVSNSKILLVLFYPLNSCANPF LYAIFTKAFQRDVFILLSKFGICKRQAQAYRGQRVPPKNSTDIQVQKVTHDMRQGLHNMEDV YELIENSHLTPKKQGQISEEYMQTVL.

[00144] A non-limiting exemplary thyroid-stimulating hormone receptor sequence associated with UniProt Reference No. B4E0H2-1 is disclosed in this descriptive report below: Petition 870250027877, dated 07 / 04 / 2025, page 78 / 384 69 / 299 MRPADLLQLVLLLDLPRDLGGMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLIET HLRIVVWFVSLLALLGNVFVLLILLTSHYKLNVPRFLMCNLAFADFCMGMYLLLIASVDLYT HSEYYNHAIDWQTGPGCNTAGFFTVFASELSVYTLTVITLERWYAITFAMRLDRKIRLRHAC AIMVGGWVCCFLLALLPLVGISSYAKVSICLPMDTETPLALAYIVFVLTLNIVAFVIVCCCY VKIYITVRNPQYNPGDKDTKIAKRMAVLIFTDFICMAPISFYALSAILNKPLITVSNSKILL VLFYPLNSCANPFLYAIFTKAFQRDVFILLSKFGICKRQAQAYRGQRVPPKNSTDIQVQKVT HEMRQGLHNMEDVYELIENSHLTPKKQGQISEEYMQTVL.

[00145] As used in this descriptive report, the term “phospholipid antigen” refers to all isoforms, variants, and fragments thereof, of a protein associated with that name, or a biological equivalent thereof. A non-limiting example of a phospholipid antigen is “beta2-glycoprotein I”, whose sequence is revealed in the descriptive report below: MISPVLILFSSFLCHVAIAGRTCPKPDDLPFSTVVPLKTFYEPGEEITYSCKPGYVSRGGMR KFICPLTGLWPINTLKCTPRVCPFAGILENGAVRYTTFEYPNTISFSCNTGFYLNGADSAKC TEEGKWSPELPVCAPIICPPPSIPTFATLRVYKPSAGNNSLYRDTAVFECLPQHAMFGNDTI TCTTHGNWTKLPECREVKCPFPSRPDNGFVNYPAKPTLYYKDKATFGCHDGYSLDGPEEIEC TKLGNWSAMPSCKASCKVPVKKATVVYQGERVKIQEKFKNGMLHGDKVSFFCKNKEKKCSYT EDAQCIDGTIEVPKCFKEHSSLAFWKTDASDVKPC.

[00146] As used in this descriptive report, the term “H4” refers to all isoforms, variants, and fragments thereof, of a protein associated with the name “histone H4”, or a biological equivalent thereof. The canonical sequence of H4 is revealed in this descriptive report below: SGRGKGGKGLGKGGAKRHRKVLRDNIQGITKPAIRRLARRGGVKRISGLIYEETRGVLKVFL ENVIRDAVTYTEHAKRKTVTAMDVVYALKRQGRTLYGFGG.

[00147] As used in this descriptive report, the term “H2B” refers to all isoforms, variants, and fragments thereof, of a protein associated with the name “histone H2B”, or a biological equivalent thereof. The canonical sequence of H2B is revealed in this descriptive report below: PEPAKSAPAPKKGSKKAVTKAQKKDGKKRKRSRKESYSVYVYKVLKQVHPDTGISSKAMGIM NSFVNDIFERIASEASRLAHYNKRSTITSREIQTAVRLLLPGELAKHAVSEGTKAVTKYTSS Petition 870250027877, dated 07 / 04 / 2025, page 79 / 384 70 / 299 K.

[00148] As used in this descriptive report, the term “H1” refers to all isoforms, variants, and fragments thereof, of a protein associated with the name “histone H1”, or a biological equivalent thereof. The canonical sequence of H1 is revealed in this descriptive report below: MTENSTSAPAAKPKRAKASKKSTDHPKYSDMIVAAIQAEKNRAGSSRQSIQKYIKSHYKVGE NADSQIKLSIKRLVTTGVLKQTKGVGASGSFRLAKGDEPKRSVAFKKTKKEVKKVATPKKAA KPKKAASKAPSKKPKATPVKKAKKKPAATPKKAKKPKVVKVKPVKASKPKKAKTVKPKAKSS AKRASKKK.

[00149] As used in this descriptive report, the term “ApoB” refers to all isoforms, variants, and fragments thereof, of a protein associated with the name “apolipoprotein B”, or a biological equivalent thereof. The canonical sequence of ApoB is revealed in the descriptive report below: MGPRKPALRTPLLLLFLLLFLDTSVWAQDEVLENLSFSCPKDATRFKHLRKYVYNYEAESSS GVQGTADSRSATKINCKVELEVPQICGFIMRTNQCTLKEVYGFNPEGKALMKKTKNSEEFAA AMSRYELKLAIPEGKQIVLYPDKDEPKYILNIKRGIISALLVPPETEEDQQELFLDTVYGNC STQVTVNSRKGTVPTEMSTERNLQQCDGFQPISTSVSPLALIKGLVHPLSTLISSSQTCQYT LDPKRKHVSEAVCDEQHLFLPFSYKNKYGIMTRVTQKLSLEDTPKINSRFFSEGTNRMGLAF ESTKSTSSPKQADAVLKTLQELKKLSISEQNAQRANLFNKLVTELRGLTGEAITSLLPQLIE VSSPITLQALVQCGQPQCYTHILQWLKTEKAHPLLVDIVTYLMALIPNPSTQRLQEIFNTAK EQQSRATLYALSHAVNSYFDVDHSRSPVLQDIAGYLLKQIDNECTGNEDHTFLILRVIGNMG RTMEQVMPALKSSVLSCVRSTKPSLLIQKAALQALRKMELEDEVRTILFDTFVNGVAPVEKR LAAYLLLMKNPSSSDINKIAQLLQWEQSEQVKNFVASHIANILNSEELYVQDLKVLIKNALE NSQFPTIMDFRKFSRNYQISKSASLPMFDPVSVKIEGNLIFDPSSYLPRESLLKTTLTVFGLASLDLFEIGLEGKGFEPTLEALFGKQGFFPDSVNKALYWVNGRVPDGVSKVLVDHFGYTTDG KHEQDMVNGIMPIVDKLIKDLKSKEIPEARAYLRILGKELSFVRLQDLQVLGKLLLSGAQTL QGIPQMVVQAIREGSKNDLFLHYIFMDNAFELPTGAGLQLQVSSSGVFTPGIKAGVRLELAN IQAELVAKPSVSLEFVTNMGIIIPDFAKSSVQMNTNFFHESGLEARVALKAGQLKVIIPSPK RPVKLFSGSNTLHLVSTTKTEVIPPLVENRQSWSTCKPLFTGMNYCTTGAYSNASSTESASY YPLTGDTRYELELRPTGEVEQYSATATYELLKEDKSLVDTLKFLVQAEGVQQSEATVLFKYN RRSRTLSSEVLIPGFDVNFGTILRVNDESAKDKNTYKLILDIQNKITEVSLVGHLSYDKKG Petition 870250027877, de 07 / 04 / 2025, pág. 80 / 384 71 / 299 DGKIKGVVSIPRLQAEARSEVHTHWSSTKLLFQMDSSATAYGSTISKRVTWRYDNEIIEFDW NTGTNVDTKKVASNFPVDLSHYPRMLHEYANGLLDHRVPQTDVTFRDMGSKLIVATNTWLQM ATRGLPYPQTLQDHLNSLSELNLLKMGLSDFHIPDNLFLKTDGRVKYTMRNKINIDIPLPL GGKSSKDLKMPESVRTPALNFKSVGFHLPSREVQVPTFTIKPTHQLQVPLLGVLDSTNVYS NLYNWSASYTGGNTSRDHFSLQAQYRMKTDSVVDLFSYSVQGSGETTYDSKNTFTLSCDGSL HHKFLDSKFKVSHVEKFGNSPVSKGLLTFETSSALGPQMSATVHLDSKKKQHLYVKDIKVDG QFRASSFYAQGKYGLSCERDVTTGQLSGESNMRFNSTYFQGTNQIVGMYQDGALSITSTSDL QDGIFKNTASLKYELTLKSDSSGQYENFAASNKLDVTFSTQSALLRSEHQANYKSLRLV TLLSGSLTSQGVELNADILGTDKINTGAHKATLKIARDGLSTSATTNLKYSPLLLENELNAE LGLSGASMKLSTNGRFKEHHAKFSLDGRAALTEVSLGSIYQAMILGADSKNIFNFKLSREGL RLSNDLMGSYAEMKLDHTHSLNIAGLSDFFSKMDNIYSGDKFYKQNFNLQLQPYSFITTLS NDLRYGALDLTNNGRFRLEPLKLNVGGNFKGTYQNNELKHIYTISYTDLVVASYRADTVAKV QGVEFSHRLNADIEGLTSSVDVTTSYNSDPLHFNNVFHFSLAPFTLGIDTHTSGDGKLSFWG EHTGQLYSKFLLKAEPLALIVSHDYKGSTSHSLPYESSISTALEHTVSALLTPAEQTSTWKF KTKLNDKVYSQDFEAYNTKDKIGVELSGRADLSGLYSPIKLPFFYSEPVNVLNGLEVNDAVDKPQEFTIIAVVKYDKNQDVHTINLPFFKSLPDYLERNRRGMISLLEAMRGELQRLSVDQFVR KYRAALSRLPQQIHHYLNASDWERQVAGAKEKITSFMENYRITDNDVLIAIDSAKINFNEKL SQLETYAIQFDQYIKDNYDPHDLKRTIAEIIDRIIEKLKILDEQYHIRVNLAKSIHNLYLFV ENVDLNQVSSSNTSWIQNVDSNYQVRIQIQEKLQQLRTQIQNIDIQQLAAEVKRQMDAIDVT MHLDQLRTAILFQRISDIIDRVKYFVMNLIEDFKVTEKINTFRVIVRELIEKYEVDQHIQVL MDKSVELAHRYSLSEPLQKLSNVLQRIEIKDYYEKLVGFIDDTVEWLKALSFKNTIEELNRL TDMLVKKLKAFDYHQFVDKTNSKIREMTQRINAEIQALKLPQKMEALKLLVEDFKTTVSNSL ERLKDTKVTVVIDWLQDILTQMKDHFQDTLEDVRDRIYQMDIQRELEHFLSLVNQVYSTLVT YMSDWWTLTAKNITDFAEQYSIQNWAESIKVLVEQGFIVPEMQTFLWTMPAFEVSLRALQEG NFQTPVFIVPLTDLRIPSIRINFKMLKNIKIPLRFSTPEFTLLNTFHVHSFTIDLLEIKAKI IRTIDQILSSELQWPLPEMYLRDLDVVNIPLARLTLPDFHVPEITIPEFTIPNVNLKDLHVP DLHIPEFQLPHLSHTIEIPAFGKLKIQSPLFILDANANIQNVTTSGNKAEIVASVTAK GESQFEALNFDFQAQAQFLELNPHPPVLKESMNFSSKHVRMEHEGEIVFDGKAIEGKSDTVA SLHTEKNEVEFNNGMTKVVNQLTLDSHTKYFHKLSVPRLDFSSKASLNNEIKTLLEAGHVA LTSSGTGSWNWACPNFSDEGHIHSSQISFTVDGPIAFVGLSNNINGKHLRVIQKLTYESGFLNYSKFEVESKVESQHVGSSILTANGRALLKDAKAEMTGEHNANLNGKVIGTLKNSLFFSAQPF ​​EITASTNNEGNLKVGFPLKLTGKIDFLNNYALFLSPRAQQASWQASTRFNQYKYNQNFSAIN NEHNIEASIGMNGDANLDFLNIPLTIPEINLPYTEFKTPLLKDFSIWEETGLKEFLKTTKQS Petition 870250027877, dated 07 / 04 / 2025, page 81 / 384 72 / 299 FDL SVKAQYKKN SDKHSIVVP LGMFYEFILNNVNSWDRKFEKVRNNALHF LTTSYNEAKIKV DKYKTENSLNQPSGTFQNHGYTIPVVNIEVSPFAVETLASSHVIPTAISTPSVTIPGPNIMV PSYKLVLPPLELPVFHGPGNLFKFFLPDFKGFNTIDNIYIPAMGNFTYDFSFKSSVITLNTN AGLYNQSDIVAHFLSSSSFVTDALQYKLEGTSRLMRKRGLKLATAVSLTNKFVKGSHDSTIS LTKKNMEASVRTTANLHAPIFSMNFKQELNGNTKSKPTVSSSIELNYDFNSSKLHSTATGGI DHKFSLESLTSYFSIESFTKGNIKSSFLSQEYSGSVANEANVYLNSKGTRSSVRLQGASKVD GIWNVEVGENFAGEATLQRIYTTWEHNMKNHLQVYSYFFTKGKQTCRATLELSPWTMSTLLQ VHVSQLSSLLDLHHFDQEVILKANTKNQKISWKGGVQVESRVLQHNAQFSNDQEEIRLDLAG SLDGQLWDLEAIFLPVYGKSLQELLQMDGKRQYLQASTSLLYTKNPNGYLLSLPVQELADRF IIPGIKLNDFSGVKIYKKLSTSPFALNLTMLPKVKFPGIDLLTQYSTPEGSSVPIFEATIPE IHLTVSQFTLPKSLPVGNTVFDLNKLANMIADVDLPSVTLPEQTIVIPPLEFSVPAGIFIPF FGELTARAGMASPLYNVTWSAGWKTKADHVETFLDSMCTSTLQFLEYALKVVETHKIEEDLL TYNIKGTLQHCDFNVEYNEDGLFKGLWDWQGEAHLDITSPALTDFHLYYKEDKTSLSASAAS STIGTVGLDSSTDDQSVELNVYFHPQSPPEKKLSIFKTEWRYKESDGERYIKINWEEEAASR LLGSLKSNVPKASKAIYDYANKYHLEYVSSELRKSLQVNAEHARRMVDEMNMSFQRVARDTYQNLYEEMLAQKSLSIPENLKKRVLDSIVHVTQKYHMAVMWLMDSFIHFLKFNRVQFPGYAGT YTVDELYTIVMKETKKSLSQLFNGLGNLLSYVQNQVEKSRLINDITFKCPFFSKPCKLKDLI LIFREELNILSNIGQQDIKFTTILSSLQGFLERVLDIIEEQIKCLKDNESTCVADHINMVFK IQVPYAFKSLREDIYFVLGEFNDFLQSILQEGSYKLQQVHQYMKALREEYFDPSMVGWTVKY YEIEENMVELIKTLLVSFRDVYSEYSVTAADFASKMSTQVEQFVSRDIREYLSMLTDINGKW MEKIAELSIVAKETMKSWVTAVAKIMSDYPQQFHSNLQDFSDQLSSYYEKFVGESTRLIDLS IQNYHVFLRYITELLRKLQVATANNVSPYIKLAQGELMITF.

[00150] As used in this descriptive report, the term ApoE refers to all isoforms, variants, and fragments thereof, of a protein associated with the name apolipoprotein E, or a biological equivalent thereof. An exemplary non-limiting human apoE sequence associated with UniProt Reference No. P02649 is disclosed in the descriptive report below: MKVLWAALLVTFLAGCQAKVEQAVETEPEPELRQQTEWQSGQRWELALGRFWDYLRWVQTLS EQVQEELLSSQVTQELRALMDETMKELKAYKSELEEQLTPVAEETRARLSKELQAAQARLGA DMEDVCGRLVQYRGEVQAMLGQSTEELRVRLASHLRKLRKRLLRDADDLQKRLAVYQAGARE GAERGLSAIRERLGPLVEQGRVRAATVGSLAGQPLQERAQAWGERLRARMEEMGSRTRDRLD EVKEQVAEVRAKLEEQAQQIRLQAEAFQARLKSWFEPLVEDMQRQWAGLVEKVQAAVGTSAA Petition 870250027877, dated 07 / 04 / 2025, page 82 / 384 73 / 299 PVPSDNH.

[00151] As used in this descriptive report, the term NMDAR refers to all isoforms, variants, and fragments thereof, of a protein associated with the name “N-methyl-D-aspartate receptor, or a biological equivalent thereof. A non-limiting exemplary sequence of N-methyl-D-aspartate receptor associated with UniProt Reference No. Q13224-1 is disclosed in this descriptive report below: MKPRAECCSPKFWLVLAVLAVSGSRARSQKSPPSIGIAVILVGTSDEVAIKDAHEKDDFHHL SVVPRVELVAMNETDPKSIITRICDLMSDRKIQGVVFADDTDQEAIAQILDFISAQTLTPIL GIHGGSSMIMADKDESSMFFQFGPSIEQQASVMLNIMEEYDWYIFSIVTTYFPGYQDFVNKI RSTIENSFVGWELEEVLLLDMSLDDGDSKIQNQLKKLQSPIILLYCTKEEATYIFEVANSVG LTGYGYTWIVPSLVAGDTDTVPAEFPTGLISVSYDEWDYGLPARVRDGIAIIITTAASDMLSE HSFIPEPKSSCYNTHEKRIYQSNMLNRYLINVTFEGRNLSFSEDGYQMHPKLVIILLNKERK WERVGKWKDKSLQMKYYVWPRMCPETEEQEDDHLSIVTLEEAPFVIVESVDPLSGTCMRNTV PCQKRIVTENKTDEEPGYIKKCCKGFCIDILKKISKSVKFTYDLYLVTNGKHGKKINGTWNG MIGEVVMKRAYMAVGSLTINEERSEVVDFSVPFIETGISVMVSRSNGTVSPSAFLEPFSADVWVMMFVMLLIVSAVAVFVFEYFSPVGYNRCLADGREPGGPSFTIGKAIWLLWGLVFNNSVPV QNPKGTTSKIMVSVWAFFAVIFLASYTANLAAFMIQEEYVDQVSGLSDKKFQRPNDFSPPFR FGTVPNGSTERNIRNYAEMHAYMGKFNQRGVDDALLSLKTGKLDAFIYDAAVLNYMAGRDE GCKLVTIGSGKVFASTGYGIAIQKDSGWKRQVDAILQLFGDGEMEELEALWLTGICHNEKN EVMSSQLDIDNMAGVFYMLGAAMALSLITFICEHLFYWQFRHCFMGVCSGKPGMVFSISRGI YSCIHGVAIEERQSVMNSPTATMNNTHSNILRLLRTAKNMANLSGVNGSPQSALDFIRRESS VYDISEHRRSFTHSDCKSYNNPPCEENLFSDYISEVERTFGNLQLKDSNVYQDHYHHHHRPH SIGSASSIDGLYDCDNPPFTTQSRSISKKPLDIGLPSSKHSQLSDLYGKFSFKSDRYSGHDD LIRSDVSDISTHTVTGYGNIEGNAAKRRKQQYKDSLKKRPASAKSRREFDEIELAYRRRPRS PDHKRYFRDKEGLRDFYLDQFRTENSPHWEHVDLTDIYKERSDDFKRDSVSGGGPCTNRSHI KHGTGDKHGVVSGVPAPWEKNLTNVEWEDRSGGNFCRSCPSKLHNYSTTVTGQNSGRQACIR CEACKKAGNLYDISEDNSLQELDQPAAPVAVTSNASTTKYPQSPTNSKAQKKNRNKLRRQHS YDTFVDLQKEEALAPRSVSLKDKGRFMDGSPYAHMFEMSAGESTFANNKSSVPTAGHHHHNN PGGGYLSKSLYPDRVTQNPFIPTFGDDQCLLHGSKSYFFRQPTVAGASKARPDFRALVTNKP VSALHGAVPARFQKDICIGNQSNPCVPNNKNPRAFNGSSNGHVYEKLSSIESDV.

[00152] As used in this descriptive report, the term Petition 870250027877, dated 07 / 04 / 2025, page 83 / 384 74 / 299 “Voltage-dependent potassium channel” generally refers to a specific transmembrane channel for potassium that is sensitive to changes in the voltage of a cell's membrane potential. During action potentials, these channels play a crucial role in returning the depolarized cell to a resting state.An exemplary non-limiting voltage-dependent potassium channel sequence associated with UniProt Reference No. P22459-1 is disclosed in the descriptive report below: MEVAMVSAESSGSNCHMPYGYAAQARARERERLAHSRAAAAAAVAAATAAVEGSGGSGGGSH HHHQSRGACTSHDPQSSRGSRRRRRQRSEKKKAHYRQSSFPHCSDLMPSGSEEKILRELSEE EEDEEEEEEEEEEGRFYYSEDDHGDECSYTDLLPQDEGGGGYSSVRYSDCCERVVINVSGLR FETQMKTLAQFPETLLGDPEKRTQYFDPLRNEYFFDRNRPSFDAILYYYQSGGRLKRPVNVP FDIFTEEVKFYQLGEEALLKFREDEGFVREEEDRALPENEFKKQIWLLFEYPESSSPARGIA IVSVLVILISIVIFCLETLPEFRDDRDLVMALSAGGHGGLLNDTSAPHLENSGHTIFNDPFF IVETVCIVWFSFEFVVRCFACPSQALFFKNIMNIIDIVSILPYFITLGTDLAQQQGGGNGQQ QQAMSFAILRIIRLVRVFRIFKLSRHSKGLQILGHTLRASMRELGLLIFFLFIGVILFSSAV YFAEADEPTTHFQSIPDAFWWAVVTMTTVGYGDMKPITVGGKIVGSLCAIAGVLTIALPVPV IVSNFNYFYHRETENEEQTQLTQNAVSCPYLPSNLLKKFRSSTSSSLGDKSEYLEMEEGVKE SLCAKEEKCQGKGDDSETDKNNCSNAKAVETDV.

[00153] As used in this descriptive report, the term “Elastin” refers to all isoforms, variants, and fragments thereof, of a protein associated with that name, or a biological equivalent thereof. The canonical sequence of elastin is 786 amino acids long and is revealed in the descriptive report below: MAGLTAAAPRPGVLLLLLSILHPSRPGGVPGAIPGGVPGGVFYPGAGLGALGGGALGPGGKP LKPVPGGLAGAGLGAGLGAFPAVTFPGALVPGGVADAAAAYKAAKAGAGLGGVPGVGGLGVS AGAVVPQPGAGVKPGKVPGVGLPGVYPGGVLPGARFPGVGVLPGVPTGAGVKPKAPGVGGAF AGIPGVGPFGGPQPGVPLGYPIKAPKLPGGYGLPYTTGKLPYGYGPGGVAGAAGKAGYPTGT GVGPQAAAAAAAKAAAKFGAGAAGVLPGVGGAGVPGVPGAIPGIGGIAGVGTPAAAAAAAAA AKAAKYGAAAGLVP GGP GF GP GVVGVP GAGVP GVGVP GAGIPVVP GAGIP GAAVP GVVSPEA AAKAAAKAAKYGARPGVGVGGIPTYGVGAGGFPGFGVGVGGIPGVAGVPGVGGVPGVGGVPG VGISPEAQAAAAAKAAKYGAAGAGVLGGLVP GP QAAVP GVP GTGGVP GVGTPAAAAAKAAAK Petition 870250027877, dated 07 / 04 / 2025, page 84 / 384 75 / 299 AAQFGLVP GVGVAP GVGVAP GVGVAP GVGLAP GVGVAP GVGVAP GVGVAP GIGP GGVAAAAK SAAKVAAKAQLRAAAGLGAGIPGLGVGVGVPGLGVGAGVPGLGVGAGVPGFGAGADEGVRRS LSPELREGDPSSSQHLPSTPSSPRVPGALAAAKAAKYGAAVPGVLGGLGALGGVGIPGGVVG AGPAAAAAAAKAAAKAAQFGLVGAAGLGGLGVGGLGVPGVGGLGGIPPAAAAKAAKYGAAGL GGVLGGAGQFPLGGVAARPGFGLSPIFPGGACLGKACGRKRK.

[00154] As used in this descriptive report, the term “IRBP” refers to all isoforms, variants, and fragments thereof, of a protein associated with the name “interphotoreceptor retinoid-binding protein,” or a biological equivalent thereof.

[00155] As used in this descriptive report, the term “human retinal stop antigen S” refers to all isoforms, variants, and fragments thereof, of a protein associated with that name, or a biological equivalent thereof. A non-limiting exemplary sequence is disclosed in this descriptive report below: MAASGKTSKSEPNHVIFKKISRDKSVTIYLGNRDYIDHVSQVQPVDGVVLVDPDLVKGKKVY VTLTCAFRYGQEDIDVIGLTFRRDLYFSRVQVYPPVGAASTPTKLQESLLKKLGSNTYPFLL TFPDYLPCSVMLQPAPQDSGKSCGVDFEVKAFATDSTDAEEDKIPKKSSVRLLIRKVQHAPL EMGPQPRAEAAWQFFMSDKPLHLAVSLNKEIYFHGEPIPVTVTVTNNTEKTVKKIKAFVEQV ANVVLYSSDYYVKPVAMEEAQEKVPPNSTLTKTLTLLPLLANNRERRGIALDGKIKHEDTNL ASSTIIKEGIDRTVLGILVSYQIKVKLTVSGFLGELTSSEVATEVPFRLMHPQPEDPAKESY QDANLVFEEFARHNLKDAGEAEEGKRDKNDVDE.

[00156] As used in this descriptive report, the term “myosin” refers to all isoforms, variants, and fragments thereof, of a protein associated with that name, or a biological equivalent thereof. A non-limiting exemplary myosin sequence associated with UniProt Reference No. P35580-1 is disclosed in this descriptive report below: MAQRTGLEDPERYLFVDRAVIYNPATQADWTAKKLVWIPSERHGFEAASIKEERGDEVMVEL AENGKKAMVNKDDIQKMNPPKFSKVEDMAELTCLNEASVLHNLKDRYYSGLIYTYSGLFCVV INPYKNLPIYSENIIEMYRGKKRHEMPPHIYAISESAYRCMLQDREDQSILCTGESGAGKTE NTKKVIQYLAHVASSHKGRKDHNIPGELERQLLQANPILESFGNAKTVKNDNSSRFGKFIRI Petition 870250027877, dated 07 / 04 / 2025, page 85 / 384 76 / 299 NFDVTGYIVGANIETYLLEKSRAVRQAKDERTFHIFYQLLSGAGEHLKSDLLLEGFNNYRFL SNGYIPIPGQQDKDNFQETMEAMHIMGFSHEEILSMLKVVSSVLQFGNISFKKERNTDQASM PENTVAQKLCHLLGMNVMEFTRAILTPRIKVGRDYVQKAQTKEQADFAVEALAKATYERLFR WLVHRINKALDRTKRQGASFIGILDIAGFEIFELNSFEQLCINYTNEKLQQLFNHTMFILEQ EEYQREGIEWNFIDFGLDLQPCIDLIERPANPPGVLALLDEECWFPKATDKTFVEKLVQEQG SHSKFQKPRQLKDKADFCIIHYAGKVDYKADEWLMKNMDPLNDNVATLLHQSSDRFVAELWK DVDRIVGLDQVTGMTETAFGSAYKTKKGMFRTVGQLYKESLTKLMATLRNTNPNFVRCIIPN HEKRAGKLDPHLVLDQLRCNGVLEGIRICRQGFPNRIVFQEFRQRYEILTPNAIPKGFMDGK QACERMIRALELDPNLYRIGQSKIFFRAGVLAHLEEERDLKITDIIIFFQAVCRGYLARKAF AKKQQQLSALKVLQRNCAAYLKLRHWQWWRVFTKVKPLLQVTRQEEELQAKDEELLKVKEKQ TKVEGELEEMERKHQQLLEEKNILAEQLQAETELFAEAEEMRARLAAKKQELEEILHDLESR VEEEEERNQILQNEKKKMQAHIQDLEEQLDEEEGARQKLQLEKVTAEAKIKKMEEEILLLED QNSKFIKEKKLMEDRIAECSSQLAEEEEEKAKNLAKIRNKQEVMISDLEERLKKEEKTRQELE KAKRKLDGETTDLQDQIAELQAQIDELKLQLAKKEEELQGALARGDDETLHKNNALKVVREL QAQIAELQEDFESEKASRNKAEKQKRDLSEELEALKTELEDTLDTTAAQQELRTKREQEVAELKKALEEETKNHEAQDMRQRHATALEELSEQLEQLEQKRFKANLEKNKQGLETDNKELACEV KVLQQVKAESEHKRKKLDAQVQELHAKVSEGDRLRVELAEKASKLQNELDNVSTLLLEEAEKK GIKFAKDAASLESQLQDTQELLQEETRQKLNLSSRIRQLEEEKNSLQQQEEEEEARKNLEK QVLALQSQLADTKKKVDDDLGTIESLEEAKKKLLKDAEALSQRLEEKALAYDKLECTKNRLQ KELDDLTVDLDHQRQVASNLEKKKKFDQLLAEXISARYAEERDRAEAEAREKETKALSL ARALEEALEAKEEFNKQLRADMEDLMSSKDDVGKNVHELEKSCRALEQVEEMRTQLEE LEDELQATEDAKLRLEVNMQAMKAQFERKDLQLEQLEKREKERKERKERKERKERKERKREAK ALAVASKKKMEIDKDLEAQIEAANKARDEVIKQLRKLQAQMKDYQRELEEARASRDEIFAQ SKESEKKLKSLEAEILQLQEELASSERARRHAEQERDELADEITNSASGKSALLDEKRRLEA RIAQLEEELEEEQSNMELLNDRFRKTTLQVDTLNAELAAERSAAQKSDNARQQLERQNKELK AKLQELEGAVKSKFKATISALEAKIGQLEEQLEQLEEQEAKERAAANKLVRRTEKKLKEIFMQVED ERRHADQYKEQMEKANARMKQLQRQLQRRANEQLEDLEQLEQLEKLEKLEKLEKLEK TLKNRLRRGGPISFSSSRSGRRQLHLEGASLELSDDDTESKTSDVNETQPPQSE.

[00157] Another exemplary non-limiting sequence of myosin is disclosed in this descriptive report below: MTDAQMADFGAAAQYLRKSEKERLEAQTRPFDIRTECFVPDDKEEFVKAKILSREGGKVIAE TENGKTVTVKEDQVLQQNPPKFDKIEDMAMLTFLHEPAVLFNLKERYAAWMIYTYSGLFCVT VNPYKWLPVYNAEVVAAYRGKKRSEAPPHIFSISDNAYQYMLTDRENQSILITGESGAGKTV Petition 870250027877, dated 07 / 04 / 2025, page 86 / 384 77 / 299 NTKRVIQYFASIAAIGDRGKKDNANANKGTLEDQIIQANPALEAFGNAKTVRNDNSSRFGKF IRIHFGATGKLASADIETYLLEKSRVIFQLKAERNYHIFYQILSNKKPELLDMLLVTNNPYD YAFVSQGEVSVASIDDSEELMATDSAFDVLGFTSEEKAGVYKLTGAIMHYGNMKFKQKQREE QAEPDGTEDADKSAYLMGLNSADLLKGLCHPRVKVGNEYVTKGQSVQQVYYSIGALAKAVYE KMFNWMVTRINATLETKQPRQYFIGVLDIAGFEIDFNSFEQLCINFTNEKLQQFFNHHMFV LEQEEYKKEGIEWTFIDFGMDLQACIDLIEKPMGIMSILEEECMFPKATDMTFKAKLYDNHL GKSNNFQKPRNIKGKPEAHFSLIHYAGTVDYNILGWLEKNKDPLNETVVGLYQKSSLKLMAT LFSSYATADTGDSGKSKGKKKGSSFQTVSALHRENLNKLMTNLRTTHPHFVRCIIPNERKA PGVMDNPLVMHQLRCNGVLEGIRICRKGFPNRILYGDFRQRYRILNPVAIPEGQFIDSRKGA EKLLSSLDIDHNQYKFGHTKVFFKAGLLGLLEEMRDERLSRIITRIQAQARGQLMRIEFKKI VERRDALLVIQWNIRAFMGVKNWPWMCLYFKIKPLLKSAETEKEMATMKEEFGRIKETLEKS EARRKELEEKMVSLLQEKNDLQLQVQAEQDNNLNDAEERCDQLIKNKIQLEAKVKEMNERLED EEEMNAELTAKKRKLEDECSELKKDIDDLETLAKVEKEKHATENKVKNLTEEMAGLDEIIA KLTKEKKALQEAHQQALDDLQAEEDKVNTLSSKVKLEQQVDDLEGSLEQEKKVRMDLERAK RKLEGDLKLTQESIMDLENDKLQLEEKLKKEFDINQQNSKIEDEQVLALQLQKKLKENQARIEELEELEAERTARAKVEKLRSDLSRELEEISERLEEAGGATSVQIEMNKKREAEFQKMRR DLEEATLQHEATAALRKKHADSVAELGEQIDNLQRVKQKLEKEKSEFKLELDDVTSNMEQI IKAKANLEKVSRTLEDQANEYRVKLEEAQRSLNDFTTQRAKLQTENGELSRQLEEKEALISQ LTRGKLSYTQMEDLKRQLEEEGKAKNALAHALQSARHDCDLLREQYEEETEAKAELQRVLS KANSEVAQCRTKYETDAIQRTEELEEAKKKRLQDAEEAVEAVNAKCSSLEKKHRLQNE IEDLMVDVERSNAAAALDKKQRNFDKILAEWKQKYEESQSELESSQKEARSLSTELFKLKN AYEESLEHLETFKRENKNLQEEISDLTEQLGEGGKNVHELEKVRKQLEVEKLQSALEEAE ASLEHEEGKILRAQLEFNQIKAEIERKLAEKDEEMEQAKRNHQRVVDSLQTSLDAETRSRNE VLRVKKKMEGDLNEMEIQLSHANRMAAEQKVKSLQSLLKDTQIQLDDAVRANDDLKENIA IVERRNNLLQAELEELRAVVEQTERSRKLADRELIETSERVQLLHSQNTSLINQKKKMDADL SQLQSEVEEAVQECRNAEEKKAITSAQKKKKKKKKKKHRMDADL LDEAEQIALKGGKQLQKLEARVRELEGELEAEQKRNAESVKGMRKSERRIKELTYQTEEDK KNLLRLQDLVDKLQLKVKAYKRQAEEAEEQANTNLSKFRKVQHELDEAEERADIAESQVNKL RAKSRDIGAKQKMHDEE.

[00158] As used in this descriptive report, the term “CD1d-binding lipid antigens” generally refers to lipid antigens that bind to non-classical MHC CD1d.

[00159] As used in this descriptive report, the term Petition 870250027877, dated 07 / 04 / 2025, page 87 / 384 78 / 299 “HSP” refers to all isoforms, variants, and fragments thereof, of a protein associated with the name “heat shock protein,” or a biological equivalent thereof. In some embodiments, heat shock proteins include heat shock protein 60.An exemplary non-limiting sequence of heat shock protein 60 associated with UniProt Reference No. P10809-1 is disclosed in the descriptive report below: MLRLPTVFRQMRPVSRVLAPHLTRAYAKDVKFGADARALMLQGVDLLADAVAVTMGPKGRTV IIEQSWGSPKVTKDGVTVAKSIDLKDKYKNIGAKLVQDVANNTNEEAGDGTTTATVLARSIA KEGFEKISKGANPVEIRRGVMLAVDAVIAELKKQSKPVTTPEEIAQVATISANGDKEIGNII SDAMKKVGRKGVITVKDGKTLNDELEIIEGMKFDRGYISPYFINTSKGQKCEFQDAYVLLSE KKISSIQSIVPALEIANAHRKPLVIIAEDVDGEALSTLVLNRLKVGLQVVAVKAPGFGDNRK NQLKDMAIATGGAVFGEEGLTLNLEDVQPHDLGKVGEVIVTKDDAMLLKGKGDKAQIEKRIQ EIIEQLDVTTSEYEKEKLNERLAKLSDGVAVLKVGGTSDVEVNEKKDRVTDLNATRAAVEE GIVLGGGCALLRCIPALDSLTPANEDQKIGIEIIKRTLKIPAMTIAKNAGVEGSLIVEKIMQ SSSEVGYDAMAGDFVNMVEKGIIDPTKVVRTALLDAAGVASLLTTAEVVVTEIPKEEKDPGM GAMGGMGGGMGGGMF.

[00160] Multiple sclerosis (MS) is also known as “disseminated sclerosis,” “disseminated encephalomyelitis,” or “allergic encephalomyelitis.” MS is an inflammatory disease in which the fatty myelin sheaths surrounding the axons of the brain and spinal cord are damaged, leading to demyelination and scarring, as well as a wide spectrum of signs and symptoms. Disorders related to multiple sclerosis include, for example, neuromyelitis optica (NMO) spectrum disorder, uveitis, neuropathic pain, and the like.

[00161] It is believed that “oligodendrocyte myelin glycoprotein” (MOG) is an important glycoprotein in the myelination process of nerves in the central nervous system (CNS). In humans, this protein is encoded by the MOG gene. It is speculated to serve as an “adhesion molecule” necessary to provide structural integrity to the myelin sheath and is known to later develop in the oligodendrocyte. The Numbers Petition 870250027877, dated 07 / 04 / 2025, p. 88 / 384 GenBank Accession Numbers NM_001008228.2 and NP_001008229.1 represent the mRNA and protein sequence, respectively, of the MOG gene. The sequence associated with each of these GenBank Accession Numbers is incorporated by reference for all purposes.

[00162] As used in this descriptive report, the terms cancer and cancerous refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, without limitation, carcinoma, lymphoma, blastoma, sarcoma, and leukemia, and metastases thereof. A metastasis means the transfer of disease-producing organisms or malignant or cancerous cells to other parts of the body through blood or lymphatic vessels or membranous surfaces.Non-limiting examples of these cancers include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell carcinoma of the lung, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, and various types of head and neck cancer.

[00163] As used in this descriptive report, the term diabetes means a variable disorder of carbohydrate metabolism caused by a combination of hereditary and environmental factors and is typically characterized by inadequate insulin secretion or utilization, excessive urine production, excessive amounts of sugar in the blood and urine, and thirst, hunger, and weight loss. Diabetes is characterized by Type 1 diabetes and Type 2 diabetes. The non-obese mouse Petition 870250027877, dated 07 / 04 / 2025, page 89 / 384 The 80 / 299 diabetic (NOD) model is an accepted animal model for the study and treatment of diabetes. Type 1 diabetes (T1D) in mice is associated with autoreactive CD8+ T cells. Non-obese diabetic (NOD) mice develop a form of T1D, very similar to human T1D, resulting from the selective destruction of pancreatic β-cells by T cells that recognize a growing list of autoantigens. Although the onset of T1D clearly requires the contribution of CD4+ cells, there is strong evidence that T1D is CD8+ T cell-dependent. A significant fraction of islet-associated CD8+ cells in NOD mice have been found to use Va17-Ja42+ CDR3-invariant TCRs, termed '8.3-TCR-like'.These cells, which recognize the NRP-A7 mimotope (defined using combinatorial peptide libraries) in the context of the Kdda MHC molecule, are already a significant component of the earliest CD8+ islet infiltrates in NOD, are diabetogenic, and target a peptide of the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), a protein of unknown function. CD8+ cells that recognize this peptide (IGRP206-214, similar to NRP-A7) are exceptionally frequent in circulation (>1 / 200 CD8+ cells). Notably, the progression of insulitis to diabetes in NOD mice is invariably accompanied by cyclic expansion of the circulating pool of CD8+IGRP206-214-reactive cells, and by avid maturation of its islet-associated counterpart. More recently, it has been shown that CD8+ islet-associated cells in NOD mice recognize multiple IGRP epitopes, indicating that IGRP is a dominant autoantigen for CD8+ cells, at least in murine T1D.CD8+ cells associated with the NOD islet, particularly those found early in the disease process, also recognize an insulin epitope (Ins B15-23).

[00164] As used in this descriptive report, the term pre-diabetes means an asymptomatic period preceding Petition 870250027877, dated 07 / 04 / 2025, page 90 / 384 81 / 299 is a diabetic condition characterized by subclinical beta cell damage, in which the patient exhibits normal plasma glucose levels. It is also characterized by the presence of islet cell autoantibodies (ICAs) and, when near the onset of clinical symptoms, may be accompanied by glucose intolerance.

[00165] As used in this descriptive report, the term “multiple sclerosis-related disorder” means a disorder that also presents with a susceptibility to or with MS. Non-limiting examples of these include neuromyelitis optica spectrum disorder (NMO), uveitis, sclerosis with neuropathic pain, atherosclerosis, arteriosclerosis, disseminated sclerosis, systemic sclerosis, spino-optic MS, primary progressive MS (PPMS) and relapsing-remitting MS (RRMS), progressive systemic sclerosis, and ataxic sclerosis.

[00166] The terms “epitope” and “antigenic determinant” are used interchangeably to refer to a site on an antigen to which B and / or T cells respond or recognize. B cell epitopes can be formed by either contiguous amino acids or non-contiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed by contiguous amino acids are typically retained upon exposure to denaturing solvents, while epitopes formed by tertiary folding are typically lost upon treatment with denaturing solvents. An epitope typically includes at least 3 and, more commonly, at least 5 or 8–20 amino acids in a unique spatial conformation. Methods for determining the spatial conformation of epitopes include, for example, X-ray crystallography and two-dimensional nuclear magnetic resonance. See, for example, Glenn E. Morris, “Epitope Mapping Protocols” (1996).T cells recognize continuous epitopes of about nine amino acids for CD8 cells or about 13-15 amino acids for CD4 cells. T cells that... Petition 870250027877, dated 07 / 04 / 2025, page 91 / 384 Cells 82 / 299 that recognize the epitope can be identified by in vitro assays that measure antigen-dependent proliferation, as determined by incorporation of 3H-thymidine by sensitized T cells in response to an epitope (Burke et al., J. Inf. Dis., 170: 1110-1119, 1994), by antigen-dependent death (cytotoxic T lymphocyte assay, Tigges et al., J. Immunol., 156 (10): 390-13910, 1996) or by cytokine secretion. The presence of a cell-mediated immune response can be determined by proliferation assays (CD4+ T cells) or CTL (cytotoxic T lymphocyte) assays.

[00167] Optionally, an antigen, or preferably an epitope of an antigen, may be chemically conjugated to, or expressed as, a fusion protein with other proteins such as, for example, MHC and MHC-related proteins.

[00168] As used in this descriptive report, the terms patient and individual are used synonymously and refer to a mammal. In some embodiments, the patient is a human. In other embodiments, the patient is a mammal in need of veterinary medicine or is a mammal commonly used in a laboratory. In some embodiments, the mammal is a mouse, rat, ape, canine, feline, bovine, equine, or ovine.

[00169] As used in this disclosure, the term polynucleotide refers to a nucleic acid molecule that is recombinant or has been isolated free of total genomic nucleic acid. Included within the term polynucleotide are oligonucleotides (nucleic acids 100 residues or less in length), recombinant vectors including, for example, plasmids, cosmids, phages, viruses, and the like. Polynucleotides include, in certain respects, regulatory sequences isolated substantially distant from their genes or naturally occurring protein-coding sequences. Polynucleotides can be RNA, DNA, analogs thereof, or a Petition 870250027877, dated 07 / 04 / 2025, page 92 / 384 83 / 299 combination of these. A nucleic acid encoding all or part of a polypeptide may contain a contiguous nucleic acid sequence encoding all or a portion of such a polypeptide of the following lengths: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 441, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1.010, 1.02 0, 1.030, 1.040, 1.050, 1.060, 1 .070, 1.080, 1. 090, 1.095 , 1. 100, 1.500 , 2.000, 2.500, 3.000, 3 .500, 4.000, 4. 500, 5.000 , 5. 500, 6.000 , 6.500, 7.000, 7.500, 8 .000, 9,000, 10,000, or more nucleotides, nucleosides, or base pairs. It is also contemplated that a particular polypeptide of a certain species may be encoded by nucleic acids containing natural variations that have slightly different nucleic acid sequences, but nevertheless encode the same protein, polypeptide, or peptide, or a substantially similar protein, polypeptide, or peptide.

[00170] A polynucleotide is composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); thymine (T); and uracil (U) for thymine when the polynucleotide is RNA. Thus, the term "polynucleotide sequence" is the alphabetical representation of a polynucleotide molecule. This alphabetical representation can be entered into databases on a computer that has a central processing unit and used for bioinformatics applications such as functional genomics and homology research.

[00171] The term “isolated” or “recombinant,” as used in this descriptive report, with respect to nucleic acids, Petition 870250027877, dated 07 / 04 / 2025, p. 93 / 384 84 / 299 For example, DNA or RNA refers to molecules separated from other DNAs or RNAs, respectively, that are present in the natural source of the macromolecule, as well as polypeptides. The term “isolated or recombinant nucleic acid” aims to include nucleic acid fragments that are not naturally occurring as fragments and would not be found in the natural state. The term “isolated” is also used in this descriptive report to refer to polynucleotides, polypeptides, and proteins that are isolated from other cellular proteins and aims to encompass both purified and recombinant polypeptides. In other embodiments, the term “isolated or recombinant” means separated from cellular and other constituents with which the cell, tissue, polynucleotide, peptide, polypeptide, protein, antibody, or fragments thereof, are normally associated in nature. For example, an isolated cell is a cell that is separated from tissue or cells of dissimilar phenotype or genotype.An isolated polynucleotide is separated from the contiguous 3' and 5' nucleotides with which it is normally associated in its native or natural environment, for example, on the chromosome. As is evident to those in the art, a non-naturally occurring polynucleotide, peptide, polypeptide, protein, antibody, or fragments thereof, does not need to be “isolated” to distinguish it from its naturally occurring counterpart.

[00172] A polynucleotide or polynucleotide region (or a polypeptide or polypeptide region) that has a certain percentage (e.g., 80%, 85%, 90%, or 95%) of “sequence identity” to another sequence means that, when aligned, those percentages of bases (or amino acids) are the same when comparing the two sequences. Alignment and percentage of homology or sequence identity can be determined using software known in the art, for example, those described in “Current Protocols in Molecular Petition 870250027877, dated 07 / 04 / 2025, page 94 / 384 85 / 299 Biology” (Ausubel et al., eds. 1987) Supplement 30, Section 7.7.18, Table 7.7.1. Preferably, standard parameters are used for alignment. One such alignment program is BLAST, using standard parameters. In particular, certain programs are BLASTN and BLASTP, using the following standard parameters: Genetic code = default; filter = none; strand = both; cutoff value = 60; expected = 10; Matrix = BLOSUM62; Descriptions = 50 sequences; sorted by = HIGHEST SCORE; Databases = non-redundant, CDS GenBank + EMBL + DDBJ + PDB + GenBank + SwissProtein + SPupdate + PIR translations. Details of these programs can be found at the following internet address: ncbi.nlm.nih.gov / cgi-bin / BLAST.

[00173] It should be inferred without explicit citation and unless otherwise desired, that when the present disclosure relates to an antigen, polypeptide, protein, polynucleotide, or antibody, an equivalent or biological equivalent thereof is included within the scope of this disclosure. As used in this descriptive report, the term “biological equivalent thereof” is intended to be synonymous with “equivalent thereof” when referring to a reference antigen, protein, antibody, fragment, polypeptide, or nucleic acid, and means those possessing minimal homology while maintaining the desired structure or functionality. Unless specifically stated in this descriptive report, it is contemplated that any polynucleotide, polypeptide, or protein mentioned in this descriptive report also includes equivalents thereof.In one aspect, an equivalent polynucleotide is one that hybridizes under stringent conditions to the polynucleotide or complement of the polynucleotide as described in this descriptive report for use in the methods described. In another aspect, an equivalent antibody or antigen-binding polypeptide means one that binds with at least 70% or, alternatively, at least 75%. Petition 870250027877, dated 07 / 04 / 2025, page 95 / 384 86 / 299 alternatively, at least 80% or, alternatively, at least 85% or, alternatively, at least 90% or, alternatively, at least 95% affinity or higher affinity for a reference antibody or antigen-binding fragment. In another aspect, the equivalent of this competes with the binding of the antibody or antigen-binding fragment to its antigen under a competitive ELISA assay. In another aspect, an equivalent means at least about 80% homology or identity and, alternatively, at least about 85% or, alternatively, at least about 90% or, alternatively, at least about 95% or, alternatively, 98% homology or identity and exhibits substantially equivalent biological activity to the reference protein, polypeptide, or nucleic acid.

[00174] The term hybridization refers to a reaction in which one or more polynucleotides react to form a complex that is stabilized by hydrogen bonding between the bases of the nucleotide residues. Hydrogen bonding can occur through Watson-Crick base pairing, Hoogstein bonding, or any other sequence-specific method. The complex may comprise two strands forming a duplex structure, three or more strands forming a multistranded complex, a single self-hybridizing strand, or any combination thereof. A hybridization reaction may constitute a step in a larger process, for example, the initiation of a polymerase chain (PC) reaction, or the enzymatic cleavage of a polynucleotide by a ribozyme.

[00175] Examples of stringent hybridization conditions include: incubation temperatures from about 25°C to about 37°C; hybridization buffer concentrations from about 6x SSC to about 10x SSC; formamide concentrations from about 0% to about 25%; and washing solutions from about 4x SSC to about 8x SSC. Examples of moderate hybridization conditions Petition 870250027877, dated 07 / 04 / 2025, p. 96 / 384 Examples of strict conditions include: incubation temperatures of about 40°C to about 50°C; buffer concentrations of about 9x SSC to about 2x SSC; formamide concentrations of about 30% to about 50%; and washing solutions of about 5x SSC to about 2x SSC. Examples of strict conditions include: incubation temperatures of about 55°C to about 68°C; buffer concentrations of about 1x SSC to about 0.1x SSC; formamide concentrations of about 55% to about 75%; and washing solutions of about 1x SSC, 0.1x SSC, or deionized water. In general, hybridization incubation times are from 5 minutes to 24 hours, with 1, 2, or more washing steps, and washing incubation times are approximately 1, 2, or 15 minutes. SSC is 0.15 M NaCl and 15 mM citrate buffer. It is understood that equivalents of SSC using other buffer systems may be employed.

[00176] The term homology or identity or similarity refers to the similarity of sequences between two peptides or between two nucleic acid molecules. Homology can be determined by comparing a position in each sequence that can be aligned for comparison purposes. When a position in the compared sequence is occupied by the same base or amino acid, then the molecules are homologous at that position. A degree of homology between sequences is a function of the number of homologous combinations or positions shared by the sequences. An unrelated or non-homologous sequence shares less than 40% identity or, alternatively, less than 25% identity with one of the sequences of the present disclosure.

[00177] The term homology or identity or similarity can also refer to two nucleic acid molecules that hybridize under strict conditions.

[00178] As used in this descriptive report, the terms dealing with, treatment and similar terms are used in this Petition 870250027877, dated 07 / 04 / 2025, page 97 / 384 88 / 299 descriptive report to signify the achievement of a desired pharmacological and / or physiological effect. The effect may be therapeutic in terms of a partial or complete cure for a disorder and / or an adverse effect attributable to the disorder. In one aspect, treatment indicates a reduction in the signs of the disease with the use of an established scale.

[00179] As used in this descriptive report, the term treatment or treating, when related to oncology, means any treatment of a disease or associated condition or disorder in a patient, including inhibition of the disease or condition, i.e., interruption or suppression of the development of clinical symptoms, for example, cancer cachexia; and / or relief of the disease or condition causing regression of clinical symptoms, for example, increased overall survival or reduction of tumor burden.

[00180] In some respects, the term refers to an improvement in final clinical outcomes. The term final clinical outcome refers to any clinical observation or measurement regarding a patient's response to a therapy. Non-limiting examples of final clinical outcomes include tumor response (TR), overall survival (OS), progression-free survival (PFS), disease-free survival, time to tumor recurrence (TTR), time to tumor progression (TTP), relative risk (RR), toxicity, or side effect. The term overall survival (OS) means a prolongation of life expectancy when compared to treatment-naive or untreated individuals or patients. The term progression-free survival (PFS) or time to tumor progression (TTP) indicates the length of time during and after treatment in which the cancer does not grow.Progression-free survival includes the amount of time patients have had a complete or partial response, as well as the amount of time patients have had stable disease. The term tumor recurrence... Petition 870250027877, dated 07 / 04 / 2025, page 98 / 384 89 / 299, as used in this descriptive report and as defined by the National Cancer Institute, is cancer that has recurred (returned), usually after a period of time during which the cancer could not be detected. The cancer may return in the same place as the original (primary) tumor or in another place in the body. It is then called recurrent cancer. The term "time to tumor recurrence" (TTR) is defined as the time from the date of cancer diagnosis to the date of the first recurrence, death, or to the last contact, if the patient was free of any tumor recurrence at the time of the last contact. If a patient did not have a recurrence, then the TTR was considered at the time of death or the last follow-up. The term "relative risk" (RR), in statistics and mathematical epidemiology, refers to the risk of an event (or of developing a disease) in relation to exposure.Relative risk is the ratio of the probability of an event occurring in an exposed group versus an unexposed group.

[00181] The term “composition” is intended to mean a combination of an active agent and another compound or composition, either inert (e.g., a detectable agent or marker) or active, e.g., an adjuvant. In certain embodiments, the composition does not contain an adjuvant.

[00182] The term “pharmaceutical composition” aims to include the combination of an active agent with a carrier, inert or active, making the composition suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo.

[00183] The term “functionally equivalent codon” is used in this descriptive report to refer to codons that code for the same amino acid, for example, the six codons for arginine or serine, and also refers to codons that code for biologically equivalent amino acids (see Table 2).

[00184] As used in this descriptive report, the terms “protein” or “polypeptide” or “peptide” refer to a Petition 870250027877, dated 07 / 04 / 2025, page 99 / 384 90 / 299 molecule comprising at least five amino acid residues.

[00185] Other objectives, features, and advantages of the present disclosure will become apparent from the following detailed description. Additional definitions are also provided in this descriptive report. It should be understood, however, that the detailed description and specific examples, while indicating specific embodiments of the disclosure, are provided only as illustrations, insofar as various alterations and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. DESCRIPTIVE MODALITIES

[00186] Autoimmune diseases such as, for example, type 1 diabetes (T1D), multiple sclerosis, and rheumatoid arthritis, result from chronic autoimmune responses involving T cells and B cells that recognize numerous antigenic epitopes in incompletely defined lists of autoantigens (Santamaria, P. (2010) Immunity 32: 437-445; Babbe, H. et al. (2000) J. Exp. Med. 192: 393-404; Firestein, GS (2003) Nature 423: 356-361). Elimination or suppression of all (known and unknown) autoreactive polyclonal T cell specificities in each individual autoimmune disorder without compromising systemic immunity is not currently possible.

[00187] Adoptive transfer of ex vivo expanded FOXP3+CD4+CD25+ polyclonal regulatory T cells (Tregs) has been proposed as an alternative therapeutic approach (Sakaguchi, S. et al. (2006) Immunol. Rev. 212: 8-27). The potential for assistive immunosuppression, the lack of effective strategies for in vitro expansion of antigen-specific Treg cells, and the instability of the FOXP3+ Treg cell line have prevented the clinical translation of this approach (Zhou, X. et al. (2009) Nature Immunol. 10: 1000-1007; Komatsu, N. et al. (2014) Nature Med. Petition 870250027877, dated 07 / 04 / 2025, page 100 / 384 91 / 299 20: 62-68; Bailey-Bucktrout, SL et al. (2013) Immunity 39: 949-962). Tr1 FOXP3-CD4+CD25- T cells, which produce the cytokines IL-10 and IL-21 and express the surface markers CD49b and LAG-3 and the transcription factor c-Maf8, constitute another subset of regulatory T cells recently explored for the treatment of human inflammatory diseases (McLarnon, A. (2012) Nature Rev. Gastroenterol. Hepatol. 9: 559; Desreumaux, P. et al. (2012) Gastroenterologia 143: 1207-1217; Roncarolo, MG et al.). However, as with FOXP3+ Treg cells, there are no pharmacological approaches that can expand autoantigen- or disease-specific TR1-like cells in vivo.

[00188] Thus, regulatory T cells are promising as targets for therapeutic intervention in autoimmunity, but approaches capable of expanding antigen-specific regulatory T cells in vivo are not currently available. Here, the Applicant shows that systemic release of nanoparticles coated with autoimmune disease-relevant peptides linked to major histocompatibility complex class II (pMHCII) molecules triggers the generation and expansion of antigen-specific CD4+ type 1 (TR1)-like regulatory T cells in different mouse models, including humanized mice with patient lymphocytes, leading to the resolution of established autoimmune phenomena. Ten pMHCII-based nanomedicines show similar biological effects, regardless of genetic background, prevalence of cognate T cell population, or MHC restriction.These nanomedicines promote the differentiation of disease-sensitized autoreactive T cells into TR1-like cells, which, in turn, suppress self-antigen-laden antigen-presenting cells and direct the differentiation of cognate B cells into disease-suppressing regulatory B cells, without compromising immunity. Petition 870250027877, dated 07 / 04 / 2025, page 101 / 384 92 / 299 systemic. Thus, pMHCII-based nanomedicines represent a new class of drugs, potentially useful for the treatment of a broad spectrum of autoimmune conditions in a disease-specific manner.

[00189] The Applicant previously discovered that systemic release of nanoparticles (NPs) coated with T1D-relevant class I pMHC complexes (pMHC-NPs) could halt T1D progression by expanding subsets of CD8+ T cells with regulatory potential but conventional memory-like phenotype (Tsai, S. et al. (2010) Immunity 32: 568-580). Because the nanoparticles could be coated with different class I pMHC complexes, the Applicant reasoned that pMHC-NP therapy might utilize a naturally occurring negative feedback regulatory loop, whereby chronic autoantigen exposure (and exposure to pMHC-NPs) could trigger the differentiation of autoreactive T cells into a progeny of regulatory T cells. Based on this reasoning, the Applicant predicted and demonstrated in this descriptive report that NPs coated with disease-relevant pMHCII complexes may be able to expand disease-specific CD4+ regulatory T cells in vivo.

[00190] This revelation is based on those initial observations regarding the supply of pMHC-NPs, their compositions and methods for production, as well as their use. Substrates / Particles

[00191] The terms particles, nanoparticles, microparticles, globule, microsphere and grammatical equivalents used in this descriptive report mean small distinct particles that are manageable to an individual. In certain embodiments, the particles have a substantially spherical shape. The term substantially spherical, as used in this descriptive report, means that the shape of the particles does not deviate from a sphere by more than Petition 870250027877, dated 07 / 04 / 2025, page 102 / 384 93 / 299 which is about 10%. Several known antigen or peptide complexes of the development can be applied to the particles.

[00192] The pMHC-NP nanoparticle core comprises, or basically consists of, or even consists of a core, for example, a solid core, a metal core, a dendrimer core, a polymeric micelle nanoparticle core, a nanorod, a fullerene, a nanoshell, a core-shell, a protein-based nanostructure, or a lipid-based nanostructure. In some aspects, the nanoparticle core is bioabsorbable and / or biodegradable. In some aspects, the nanoparticle core is a dendrimer nanoparticle core comprising, or alternatively consisting of, or even consists of a highly branched macromolecule having a tree-like structure growing from a core. In further aspects, the dendrimer nanoparticle core may comprise, or alternatively consisting of, or even consist of a poly(amidoamine)-based dendrimer or a poly-L-lysine-based dendrimer.In certain aspects, the nanoparticle core is a polymeric micelle core comprising, or alternatively consisting basically of, or consisting of an amphiphilic block copolymer assembled in a nanoscale core-shell structure. In further aspects, the polymeric micelle core comprises, or alternatively consists basically of, or consists of a polymeric micelle produced using a polyethylene glycol-diastearoylphosphatidylethanolamine block copolymer. In yet another aspect, the nanoparticle core comprises, or alternatively consists basically of, or consists of a metal. In another aspect, the nanoparticle core is not a liposome. Additional examples of core materials include, without limitation, standard and specialty glasses, silica, polystyrene, polyester, polycarbonate, acrylic polymers, polyacrylamide, polyacrylonitrile, polyamide, fluoropolymers. Petition 870250027877, dated 07 / 04 / 2025, page 103 / 38494 / 299 silicone, cellulose, silicon, metals (e.g., iron, gold, silver), minerals (e.g., ruby), nanoparticles (e.g., gold nanoparticles, colloidal particles, metal oxides, metal sulfides, metal selenides, and magnetic materials such as, for example, iron oxide), and composites thereof. In some embodiments, an iron oxide nanoparticle core comprises iron(II, III) oxide. The core could be of homogeneous composition, or a composite of two or more classes of material, depending on the desired properties. In certain aspects, metal nanoparticles will be used. These metal particles or nanoparticles may be formed from Au, Pt, Pd, Cu, Ag, Co, Fe, Ni, Mn, Sm, Nd, Pr, Gd, Ti, Zr, Si, and In, precursors, their binary alloys, their ternary alloys, and their intermetallic compounds. See U.S. Patent 6,712,997, which is incorporated into this descriptive report by reference in its entirety.In certain embodiments, the core and layer compositions (described below) may vary, provided the nanoparticles are biocompatible and bioabsorbable. The core could be of homogeneous composition, or a composite of two or more material classes, depending on the desired properties. In certain embodiments, metal nanospheres will be used. These metal nanoparticles may be formed of Fe, Ca, Ga, and the like. In certain embodiments, the nanoparticle comprises, or alternatively consists of, basically, or even consists of a core comprising metal or metal oxide such as, for example, gold or iron oxide.

[00193] The particles typically consist of a substantially spherical core and, optionally, one or more layers or coatings. The core may vary in size and composition, as described in this descriptive report. In addition to the core, the particle may have one or more layers to provide functionalities appropriate to the applications of interest. The thicknesses of the layers, if present, may vary depending Petition 870250027877, dated 07 / 04 / 2025, page 104 / 384 95 / 299 of the needs of specific applications. For example, layers can transmit useful optical properties.

[00194] The layers can also impart chemical or biological functionalities, referred to in this descriptive report as chemically active or biologically active layers. These layers are typically applied to the outer surface of the particle and can impart functionalities to the pMHC-NPs. The layer or layers can typically vary in thickness from about 0.001 micrometers (1 nanometer) to about 10 micrometers or more (depending on the desired particle diameter) or from about 1 nm to 5 nm or, alternatively, from about 1 nm to about 10 nm or, alternatively, from about 1 nm to about 40 nm, or from about 15 nm to about 25 nm or about 20 nm, and ranges between these values.

[00195] The layer or coating may comprise, or alternatively consist primarily of, or even consist of, a sugar or other biodegradable polymer. Examples of biodegradable layers include, without limitation, dextran; poly(ethylene glycol); poly(ethylene oxide); mannitol; poly(esters) based on polylactide (PLA), polyglycolide (PGA), polycaprolactone (PCL); poly(hydroxyalkanoate) of the PHB-PHV class; and other modified polysaccharides such as, for example, starch, cellulose, and chitosan. Additionally, the nanoparticle may include a layer with surfaces suitable for the adhesion of chemical functionalities to chemical bonding or coupling sites.

[00196] Layers can be produced on nanoparticles by various methods known to those skilled in the art. Examples include sol-gel chemistry techniques, for example, as described in Iler, “Chemistry of Silica”, John Wiley and Sons, 1979; Brinker and Scherer, “Sol-gel Science”, Academic Press, (1990). Additional approaches to producing layers on nanoparticles include chemistry of Petition 870250027877, dated 07 / 04 / 2025, page 105 / 384 96 / 299 surface and encapsulation techniques, for example, as described in Partch and Brown, J. Adhesion, 67: 259-276, 1998; Pekarek et al., Nature, 367: 258, (1994); Hanprasopwattana, Langmuir, 12: 3173-3179, (1996); Davies, Advanced Materials, 10: 1264-1270, (1998); and references cited therein. Vapor deposition techniques may also be used; see, for example, Golman and Shinohara, Trends Chem. Engin., 6:1-6, (2000); and US Patent No. 6,387,498. Still other approaches include layer-by-layer self-assembly techniques, for example, as described in Sukhorukov et al., Polymers Adv. Tech., 9 (10-11): 759-767, (1998); Caruso et al., Macromolecules, 32 (7): 2,317-2,328, (1998); Caruso et al., J. Amer. Chem. Soc., 121 (25): 6,039-6,046, (1999); US Patent No. 6,103,379 and references cited therein.

[00197] In some aspects, the nanoparticle core is a dendrimer nanoparticle core comprising or, alternatively, consisting basically of or consisting of a highly branched macromolecule having a tree-like structure growing from a core. In further aspects, the dendrimer nanoparticle may comprise or, alternatively, consist basically of or consisting of a poly(amidoamine)-based dendrimer or a poly-L-lysine-based dendrimer. In certain aspects, the nanoparticle core is a polymeric micelle core comprising or, alternatively, consisting basically of or consisting of an amphiphilic block copolymer assembled into a nanoscale core-shell structure.In further aspects, the polymeric micelle core may comprise, or alternatively consist basically of, or even consist of, a polymeric micelle produced using a polyethylene glycol-diastearoylphosphatidylethanolamine block copolymer. The dendrimer core or polymeric micelle core may also comprise an outer coating or layer, as described. Petition 870250027877, dated 07 / 04 / 2025, page 106 / 384 97 / 299 in this descriptive report.

[00198] In certain embodiments, specific means of synthesizing dendrimer nanoparticles or nanoparticles with a dendrimer nanoparticle core may require that metal ions be extracted from within dendrimers and then subsequently chemically reduced to generate nearly monodisperse particles having dimensions of less than 3 nm, for example, the method disclosed in Crooks et al., “Synthesis, Characterization, and Applications of Dendrimer-Encapsulated Nanoparticles.

[00199] The size of the nanoparticle core can vary from about 1 nm to about 1 μm. In certain embodiments, the nanoparticle core is less than about 1 μm in diameter. In other embodiments, the nanoparticle core is less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 200 nm, less than about 100 nm, or less than about 50 nm in diameter. In further embodiments, the nanoparticle core is from about 1 nm to about 10 nm, 15 nm, 20 nm, 25 nm, 30 nm, 40 nm, 50 nm, 75 nm, or 100 nm in diameter.In specific embodiments, the nanoparticle core has a diameter of about 1 nm to about 100 nm; about 1 nm to about 75 nm; about 1 nm to about 50 nm; about 1 nm to about 25 nm; about 1 nm to about 25 nm; about 5 nm to about 100 nm; about 5 nm to about 50 nm; or about 5 nm to about 25 nm, or about 15 nm to about 25 nm or about 20 nm. In some embodiments, the core of the... Petition 870250027877, dated 07 / 04 / 2025, p. 107 / 384 98 / 299 nanoparticles have a diameter of about 25 nm to about 60 nm, or about 25 nm to about 50 nm, or about 20 nm to about 40 nm, or about 15 nm to about 50 nm, or about 15 nm to about 40 nm, or about 15 nm to about 35 nm, or about 15 nm to about 30 nm, or about 15 nm to about 25 nm, or alternatively, about 15 nm or about 20 nm or about 25 nm or about 30 nm or about 35 nm or about 40 nm.

[00200] The size of the pMHC-NP, with or without the layer, can vary from about 5 nm to about 1 μm in diameter. In certain embodiments, the pMHC-NP complex is less than about 1 μm or, alternatively, less than 100 nm in diameter. In other embodiments, the pMHC-NP complex is less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 200 nm, less than about 100 nm, or less than about 50 nm in diameter.In additional embodiments, the complex has a diameter of about 5 nm or 10 nm up to about 50 nm, or from about 5 nm up to about 75 nm, or from about 5 nm up to about 50 nm, or from about 5 nm up to about 60 nm, or from about 10 nm up to about 50 nm, or from about 10 nm up to about 60 nm, or from about 10 nm up to about 70 nm, or from about 10 nm up to about 75 nm, or from about 20 nm up to about 50 nm, or from about 20 nm up to about 60 nm, or from about 20 nm up to about 70 nm, or from about 20 nm up to about 75 nm, or from about 30 nm up to about 50 nm, or from about 30 nm up to about 60 nm, or from about 30 nm up to about 70 nm, or from about 30 nm to about 75 nm, or, in one aspect, about 55 nm in diameter. In specific embodiments, the pMHC-NP complex is from about 35 nm to about 60 nm, or from about 35 nm to about 70 nm, or from about 35 nm to about 75 nm in diameter.In one aspect, the pMHC-NP complex is approximately 30 nm to approximately 50 nm in diameter. Antigen-MHC complexes Petition 870250027877, dated 07 / 04 / 2025, p. 108 / 384 99 / 299

[00201] The nanoparticle complexes of this discovery comprise a nanoparticle core, with or without a layer, coupled to an antigen-MHC complex (pMHC). The selection of the antigen will depend on the disease or condition to be treated, as noted above. The individual polypeptide (e.g., MHC) and the antigenic components (e.g., peptide) form a complex through covalent or non-covalent bonding (e.g., through hydrogen bonds, ionic bonds, or hydrophobic bonds). The preparation of these complexes may require varying degrees of manipulation, and these methods are well known in the literature. In some respects, the antigenic components may be non-covalently associated with the pocket portion of the MHC component, for example, by mixing the MHC and the antigenic components; this is based on the natural binding affinity between an MHC and an antigen.Alternatively, in some respects, the MHC component can be covalently linked to the antigenic component using standardized procedures, for example, without limitation, the introduction of known coupling agents or photoaffinity labeling (see, for example, Hall et al., Biochemistry 24: 5702-5711 (1985)). In certain respects, an antigenic component can be operatively coupled to the MHC component via peptide bonds or by other methods discussed in the literature including, without limitation, adhesion via carbohydrate groups in glycoproteins including, for example, the carbohydrate portions of the alpha and / or beta chains. In particular embodiments, the antigenic component can be attached to the N-terminal or C-terminal end of an appropriate MHC molecule.Alternatively, in certain embodiments, the MHC complex can be recombinantly formed by incorporating the antigenic component sequence into a sequence encoding an MHC, such that both retain their functional properties. Petition 870250027877, dated 07 / 04 / 2025, page 109 / 384 100 / 299

[00202] Multiple antigen-MHC complexes can be coupled to the same nanoparticle core; these complexes, MHCs and / or antigens can be the same or different from each other.

[00203] Valence is defined as the number of pMHC complexes per nanoparticle core. In certain embodiments, the nanoparticle valence may vary from about 1 pMHC complex to 1 nanoparticle core to about 6,000 pMHC complexes to 1 nanoparticle core or, alternatively, from about 10:1 to about 6,000:1 or, alternatively, from about 11:1 to about 6,000:1 or, alternatively, from about 12:1 to about 6,000:1 or, alternatively, at least 2:1 or, alternatively, at least 8:1 or, alternatively, at least 9:1 or, alternatively, at least 10:1 or, alternatively, at least 11:1 or, alternatively, at least 12:1.

[00204] In some respects, the valence is from about 10:1 to about 6,000:1, or from about 20:1 to about 5,500:1 or, alternatively, from about 10:1 to about 5000:1 or, alternatively, from about 10:1 to about 4000:1 or, alternatively, from about 10:1 to about 3500:1 or, alternatively, from about 10:1 to about 3000:1 or, alternatively, from about 10:1 to about 2500:1 or, alternatively, from about 10:1 to about 2000:1 or, alternatively, from about 10:1 to about 1500:1 or, alternatively, from about 10:1 to 1000:1 or, alternatively, from about 10:1 to about 500:1 or, alternatively, from about 10:1 to about 100:1 or, alternatively, from about 20:1 to about 50:1 or, alternatively, from about 25:1 to about 60:1; alternatively from about 30:1 to about 50:1 or, alternatively, from about 35:1 to about 45:1 or, Alternatively, approximately 40:1. Petition 870250027877, dated 07 / 04 / 2025, page 110 / 384 101 / 299

[00205] The Applicant has found that the pMHC density in the nanoparticle regulates the ability of pMHC-NPs to trigger or differentiate the formation of Tr1 cells in a dose-independent manner. The density is calculated as the number of complexes per unit surface area of ​​the nanoparticle. The surface area of ​​the nanoparticle can be determined with or without the layers, including, without limitation, linkers that conjugate the pMHC complex to the nanoparticle. For the purposes of calculating the density, the relevant surface area value is based on the final diameter of the particle construct without the pMHC complex, with or without the outer layer in the nanoparticle core.

[00206] It is determined and disclosed in this descriptive report that the density of pMHC complexes in the nanoparticle contributes to the therapeutic benefit in a dose-independent manner. Thus, as disclosed in this descriptive report, the nanoparticle may have a defined density of pMHC in the range of about 0.01 pMHC or, alternatively, 0.025 pMHC molecules per 100 nm² of nanoparticle surface area, including the layer or complex, assuming at least 2 MHC molecules or, alternatively, at least 8 or, alternatively, at least 9 or, alternatively, at least 10 or, alternatively, at least 11 or, alternatively, at least 12 pMHC molecules in complex with the nanoparticle up to about 100 pMHC molecules per 100 nm² of surface area.In one aspect, the nanoparticle has a pMHC density of about 0.05 pMHC per 100 nm2 to about 76 pMHC / 100 nm2 or, alternatively, from 0.1 pMHC / 100 nm2 to about 50 pMHC / 100 nm2 or, alternatively, from about 0.3 pMHC / 100 nm2 to about 25 pMHC / 100 nm2 or, alternatively, from about 0.35 pMHC / 100 nm2 to about 25 pMHC / 100 nm2 or, alternatively, from about 0.4 pMHC / 100 nm2 to about 50 pMHC / 100 nm2 or, alternatively, from about 0.4 pMHC / 100 nm2 to about 25 pMHC / 100 nm2 or, alternatively, from about. Petition 870250027877, dated 07 / 04 / 2025, p. 111 / 384 102 / 299 0.4 pMHC / 100 nm2 to about 20 pMHC / 100 nm2, 0.4 pMHC / 100 nm2 to about 10 pMHC / 100 nm2, 0.4 pMHC / 100 nm2 to about 5 pMHC / 100 nm2 or, alternatively, from about 0.5 pMHC / 100 nm2 to about 20 pMHC / 100 nm2 or, alternatively, from about 0.5 pMHC / 100 nm2 to about 10 pMHC / 100 nm2 or, alternatively, from about 0.6 pMHC / 100 nm2 to about 20 pMHC / 100 nm2 or, alternatively, from about 1.0 pMHC / 100 nm2 to about 20 pMHC / 100 nm2 or, alternatively, from about 10 pMHC / 100 nm2 up to about 20 pMHC / 100 nm2 or, alternatively, at least about 0.4 or, alternatively, at least about 0.406 or, alternatively, at least about 0.5 or, alternatively, at least about 1.0 or, alternatively, at least about 5.0 or, alternatively, at least about 10.0 or, alternatively, at least about 15.0 pMHC / 100 nm2 or, alternatively, less than about 76 pMHC / 100 nm2 or, alternatively, less than about 50 pMHC / 100 nm2 or, alternatively,less than about 47.75 pMHC / 100 nm2 or, alternatively, less than about 25 pMHC / 100 nm2 or, alternatively, less than about 20 pMHC / 100 nm2.

[00207] In certain embodiments, the pMHC density per nanoparticle is from about 0.4 pMHC / 100 nm2 to about 25 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 20 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 15 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 14 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 13 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 12 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 11.6 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 11.5 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 11 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 10 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 9 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 8 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 7 Petition 870250027877, dated 07 / 04 / 2025, page 112 / 384 103 / 299 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 6 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 5 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 4 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 3 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 2.5 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 2 pMHC / 100 nm2, or from about 0.4 pMHC / 100 nm2 to about 1.5

[00208] In further embodiments, the nanoparticle may have a pMHC density of about 0.22 pMHC / 100 nm2 to about 10 pMHC / 100 nm2, about 9 pMHC / 100 nm2, about 8 pMHC / 100 nm2, about 7 pMHC / 100 nm2, about 6 pMHC / 100 nm2, about 5 pMHC / 100 nm2, about 4 pMHC / 100 nm2, about 3 pMHC / 100 nm2, about 2 pMHC / 100 nm2, or from about 0.22 pMHC / 100 nm2 to or from about 0.22 pMHC / 100 nm2 to or from about 0.22 pMHC / 100 nm2 to or from about 0.22 pMHC / 100 nm2 to or from about 0.22 pMHC / 100 nm2 to or from about 0.22 pMHC / 100 nm2 to or from about 0.22 pMHC / 100 nm2 to or from about 0.22 pMHC / 100 nm2 to about 1.5 pMHC / 100 nm2.In some respects, the nanoparticle has a pMHC density of about 0.22 pMHC / 100 nm2 to about 10 pMHC / 100 nm2, or 0.24 pMHC / 100 nm2 to about 9 pMHC / 100 nm2, or about 0.26 pMHC / 100 nm2 to about 8 pMHC / 100 nm2, or about 0.28 pMHC / 100 nm2 to about 7 pMHC / 100 nm2, or about 0.24 pMHC / 100 nm2 to about 4 pMHC / 100 nm2, or about 0.5 pMHC / 100 nm2 to about 3 pMHC / 100 nm2, or about 0.6 pMHC / 100 nm2 to about 1.5 pMHC / 100 nm2. In some embodiments, the nanoparticle has a pMHC density of about 0.4 pMHC / 100 nm2 to about 1.3 pMHC / 100 nm2 or, alternatively, from about 0.5 pMHC / 100 nm2 to about 0.9 pMHC / 100 nm2 or, alternatively, from about 0.6 pMHC / 100 nm2 to about 0.8 pMHC / 100 nm2.

[00209] Still in additional modalities, the nanoparticle Petition 870250027877, dated 07 / 04 / 2025, p. 113 / 384 104 / 299 It can have a density of approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4,7, 4,8, 5,9, 6,0, 6,1, 6,2, 6, 3, 6,4, 6,5, 6,6, 6,7, 6,8, 6,9, 7,0, 7,1, 7,2, 7,3, 7,4, 7,5, 7, 6, 7,7, 7,8, 7, 9, 8,0, 8,1, 8,2, 8,3, 8,4, 8,5, 8,6, 8,7, 8,8, 8, 9, 9,0, 9,1, 9,2, 9,3, 9,4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, or 12.0 pMHC / 100 nm2. In specific embodiments, the nanoparticle has a density of approximately 0.4 pMHC / 100 nm2 to approximately 1.5 pMHC / 100 nm2 or approximately 0.4 pMHC / 100 nm2 to approximately 6 pMHC / 100 nm2 or approximately 0.4 pMHC / 100 nm2 to approximately 11 pMHC / 100 nm2.

[00210] In some aspects, this descriptive report provides a complex comprising a nanoparticle core, wherein various disease-relevant antigen-MHC (pMHC) complexes are coupled to the core; the diameter of the core is from about 15 nm to about 25 nm; and wherein the pMHC density in the nanoparticle is from about 0.4 pMHC / 100 nm² to about 6 pMHC / 100 nm² of the nanoparticle surface area. In some embodiments, the complex further comprises an outer layer on the nanoparticle core, wherein the pMHC complex is coupled to the nanoparticle core and / or the outer layer, and wherein the diameter of the nanoparticle core and the outer layer is from about 35 nm to about 45 nm.

[00211] The term “operatively coupled” or “coated,” as used in this descriptive report, refers to a situation in which the individual polypeptide (e.g., MHC) and antigenic components (e.g., peptide) are combined to form the active complex before binding to the target site, e.g., an immune cell. This includes the situation in which the individual components of the polypeptide complex are Petition 870250027877, dated 07 / 04 / 2025, page 114 / 384 105 / 299 recombinantly synthesized or expressed and subsequently isolated and combined to form a complex, in vitro, prior to administration to an individual; the situation in which a chimeric or fusion polypeptide (i.e., each distinct protein component of the complex is contained within a single polypeptide chain) is recombinantly synthesized or expressed as an intact complex. Typically, polypeptide complexes are added to nanoparticles to generate nanoparticles with adsorbed or coupled polypeptide complexes that have a number of molecules / number of nanoparticles ratio of about, at least about, or at most about 0.1, 0.5, 1, 3, 5, 7, 10, 15, 20, 25, 30, 35, 40, 50, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1.500 or more to / 1, most typically 0.1:1, 1:1 to 50:1 or 300:1, and intermediate ranges, where the ratios provide the selected endpoints of each range. The polypeptide content of the nanoparticles can be determined using standardized techniques. MHC molecules

[00212] As used in this descriptive report and unless specifically noted, the term MHC in the context of a pMHC complex means a classical or non-classical MHC class I protein and / or a classical or non-classical MHC class II protein, any loci of HLA DR, HLA DQ, HLA DP, HLA-A, HLA-B, HLA-C, HLA-E, CD1d, or a fragment or biological equivalent thereof, double-stranded or single-stranded constructs, dimers (Fc fusions), tetramers, multimeric forms, and a polymeric form of MHC1 or MHC2. In some embodiments, the pMHC may be a single-stranded construct. In some embodiments, the pMHC may be a double-stranded construct.

[00213] In some embodiments, the MHC protein can be a dimer or a multimer.

[00214] In some modalities, the MHC protein can Petition 870250027877, dated 07 / 04 / 2025, page 115 / 384 106 / 299 comprise a knob-in-hole based MHC-alpha-Fc / MHCbeta-Fc heterodimer or multimer.

[00215] As noted above, knob-in-hole is a polypeptide architecture that requires a protrusion (or knob) at the interface of a first polypeptide and a corresponding cavity (or hole) at the interface of a second polypeptide, such that the protrusion can be positioned in the cavity to promote heteromultimer formation. Protrusions are constructed by replacing small amino acid side chains at the interface of the first polypeptide with larger side chains (e.g., phenylalanine or tyrosine). Cavities of identical or similar size to the protrusions are created at the interface of the second polypeptide by replacing larger amino acid side chains with smaller ones (e.g., alanine or threonine).The bumps and pits can be made by synthetic means, for example, by altering the nucleic acid that encodes the polypeptides or by peptide synthesis, using routine methods for those skilled in the art. In some embodiments, the interface of the first polypeptide is located in an Fc domain in the first polypeptide; and the interface of the second polypeptide is located in an Fc domain in the second polypeptide.

[00216] As noted above, MHC-alpha-Fc / MHC-beta-Fc is a heterodimer comprising a first polypeptide and a second polypeptide, wherein the first polypeptide comprises an α-chain of MHC class II and an Fc antibody domain; the second polypeptide comprises a β-chain of MHC class II and an Fc antibody domain. An MHC-alpha-Fc / MHC-beta-Fc knobin-hole further requires that the Fc domains of each polypeptide interface with each other through the complementary positioning of a protrusion in one Fc domain within the corresponding cavity in the other Fc domain. Petition 870250027877, dated 07 / 04 / 2025, page 116 / 384 107 / 299

[00217] In certain modes of revelation, a particular antigen is identified and presented in the antigen-MHC-nanoparticle complex within the context of an appropriate MHC class I or II polypeptide. Antigen presentation to T cells is mediated by two distinct classes of molecules, MHC class I (MHC-I) and MHC class II (MHC-II), which utilize distinct antigen processing pathways. Peptides derived from intracellular antigens are presented to CD8+ T cells by MHC class I molecules, which are expressed on virtually all cells, while peptides derived from extracellular antigens are presented to CD4+ T cells by MHC-II molecules. However, there are certain exceptions to this dichotomy. Several studies have demonstrated that peptides generated from endocytosed particulate or soluble proteins are presented on MHC-I molecules in macrophages as well as in dendritic cells.In certain aspects, an individual's genetic makeup can be assessed to determine which MHC polypeptide should be used for a particular patient and a particular set of peptides. In certain embodiments, the MHC class I component may comprise, consist primarily of, or alternatively, consist wholly or in part of an HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, HLAG, or CD-1 molecule. In embodiments where the MHC component is an MHC class II component, the MHC class II component may comprise, consist primarily of, or alternatively, consist wholly or in part of an HLA-DR, HLA-DQ, or HLA-DP molecule. In certain embodiments, MHC may comprise HLA DRB1, HLA DRB3, HLA DRB4, HLA DRB5, HLA DQB1, HLA DQA1, IAg7, I-Ab, I-Ad, HLA-DQ, HLA-DP, HLA-A, HLA-B, HLA-C, HLA-E or CD1d.

[00218] Non-classical MHC molecules are also contemplated for use in MHC complexes for development. In some embodiments, non-classical MHC molecules are non-polymorphic, conserved across species, and possess pockets of Petition 870250027877, dated 07 / 04 / 2025, page 117 / 384 108 / 299 narrow, deep hydrophobic ligand binding pockets. These binding pockets are capable of presenting glycolipids and phospholipids to Natural Killer (NKT) T cells. NKT cells represent a unique lymphocyte population that co-expresses NK cell markers and a semi-invariant T cell receptor (TCR). They are implicated in the regulation of immune responses associated with a wide range of diseases.

[00219] As noted above, the term MHC can be used interchangeably with the term human leukocyte antigen (HLA) when used in reference to human MHC; thus, MHC refers to all HLA subtypes including, without limitation, the classical MHC genes disclosed above: HLA-A, HLA-B, HLA-C, HLA-DP, HLA-DQ and HLA-DR, as well as all variants, isoforms, isotypes, and other biological equivalents thereof.

[00220] MHCs for use in accordance with the present disclosure may be produced, isolated, or purified by means of methodologies known in the art. Common protocols for obtaining MHCs involve steps such as, for example, without limitation, electrophoresis or other charge- or size-based separation techniques, biotinylation or other labeling and purification methods, or transfection and induction of vector constructs expressing MHC proteins. Purified animal antibodies are also available from commercially available sources, including retailers such as, for example, eBioscience, Biolegend, or Tonbo Biosciences.

[00221] In certain embodiments, the MHC of antigen-MHC complexes may be classical MHC1, non-classical MHC1, classical MHC2, non-classical MHC2, dimers (Fc fusions), MHC tetramers, or a polymeric form of MHC. In some embodiments, MHC multimers are generated according to well-documented methods in the art; see, for example, Bakker et al. MHC Multimer Technology: Current Status and Future Prospects, Current Opinion in Immunology, Vol. 17, No. 4, pages 428-433. Petition 870250027877, dated 07 / 04 / 2025, p. 118 / 384 109 / 299 (2005) and references cited therein. Non-limiting exemplary methods include the use of a biotinylation agent such as, for example, without limitation, streptavidin or avidin, to link MHC monomers, creating a multimeric structure with the agent as a scaffold. MHC dimers, specifically, can alternatively be produced by fusion with constant regions or Fc regions of antibody; this can be achieved by operative coupling directly or by means of a linker, for example, a cysteine ​​linker. Components of a co-stimulatory molecule

[00222] In certain aspects, NPs additionally comprise or, alternatively, consist basically of, or even consist of at least one costimulatory molecule. Costimulatory molecules are molecules that produce a secondary signal in vivo that serves to activate naive T cells into antigen-specific T cells capable of producing an immune response to cells possessing said specific antigen. The present disclosure is not limited to any specific costimulatory molecule. The various costimulatory molecules are well known in the art. Some non-limiting examples of costimulatory molecules are 4-IBBL, OX40L, CD40, IL-15 / IL15Ra, CD28, CD80, CD86, CD30L, and ICOSL. Only one specific costimulatory molecule may be coupled to a nanoparticle, or several costimulatory molecules may be coupled to the same nanoparticle.In certain embodiments, the costimulatory molecule is a protein, such as an antibody, that is capable of being an agonist for a costimulatory receptor on a T cell. In this case, the antibody is able to induce a costimulatory signal that is necessary to activate naive T cells and induce an immune response in an antigen-specific manner. Additionally or alternatively, the term "costimulatory molecule," as used in this descriptive report, may also refer to an agent capable of generating a signal. Petition 870250027877, dated 07 / 04 / 2025, p. 119 / 384 110 / 299 costimulatory because it has an agonist effect on a native costimulatory signaling molecule, for example, anti-CD28 or CD28 ligand, generating a CD28 costimulatory response.

[00223] In specific embodiments, the costimulatory molecules of the present disclosure can be one or more of the following molecules: B7-1 / CD80, BTLA, B7-2 / CD86, CD28, B7-H1 / PDL1, CTLA-4, B7-HVIST / B7-H1 / PDL1, CTLA-4, B7-HVIST / HVIST / H15, Gib B7-H3, ICOS, B7-H4, PD-1, B7-H6, PD-L2 / B7-DC, B7-H7, PDCD6, LILRA3 / CD85e, LILRB2 / CD85d / ILT4, LILRA4 / CD85g / ILT7, LILRB3 / CD85a / ILT15 / ILT2, LILRB3 / ILT15 / ILT2, LILRB4 / CD85k / ILT3, 4-1BB / TNFRSF9 / CD137, GITR / TNFSF18 Binder, 4-1BB / TNFSF9 Binder, HVEM / TNFRSF14, BAFF / BLyS / TNFSF13B, LIGHT / TNFSF14, BAFF / TNFSF13, RNFSF13 Lymphotoxin-alpha / TNF-beta, CD27 / TNFRSF7, OX40 / TNFRSF4, CD27 / TNFSF7 ligand, OX40 / TNFSF4 ligand, CD30 / TNFRSF8, RELT / TNFRSF19L, CD30 / TNFSFT8 ligand, OX40 / TNFRSF13, CD40 / TNFRSF5, TL1A / TNFSF15, CD40 / TNFSF5 ligand, TNF-alpha, DR3 / TNFRSF25, TNF RII / TNFRSF1B, GITR / TNFRSF18, 2B4 / CD244 / SLAMF4, CD84 / SLAMF5, BLAMFS / LAMF / SLAMF4, CD84 / 2998 CD2, CRACC / SLAMF7, CD2F-10 / SLAMF9, NTB-A / SLAMF6, CD48 / SLAMF2, SLAM / CD150, CD58 / LFA-3, CD7, DPPIV / CD26, CD96, EphB6, CD160,Integrin alpha 4 beta 1, CD200, Integrin alpha 4 beta 7 / LPAM-1, CD300a / LMIR1, LAG-3, CRTAM, TIM-1 / KIM-1 / HAVCR, DAP12, TIM-4, Dectin-1 / CLEC7A, TSLP R, ICOSL, and / or biological equivalents thereof.

[00224] The co-stimulatory molecule can be coupled to the nanoparticle in the same way as the pMHC complex. In one embodiment of the present disclosure, the co-stimulatory molecule and the antigen / MHC complex are attached separately to the nanoparticle. In another embodiment of the disclosure, the co-stimulatory molecule and the pMHC complex are first complexed together and are then subsequently complexed with the nanoparticle. Multiple co-stimulatory molecules can be coupled to the nanoparticle; these can be multiples of the same Petition 870250027877, dated 07 / 04 / 2025, p. 120 / 384 111 / 299 co-stimulatory molecule or multiple different co-stimulatory molecules. Typically, polypeptide complexes are added to nanoparticles to generate nanoparticles with adsorbed or coupled polypeptide complexes that have a ratio of the number of co-stimulatory molecules / number of nanoparticles of about 1 to 6,000 molecules per nanoparticle or, alternatively, at least about or at most about 0.1, 0.5, 1, 10, 100, 500, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000 or more to 1, and ranges between these values, typically from about 0.1:1 to about 50:1. In another aspect, the ratio of the costimulatory molecule to the pMHC complex can be about 0.1, 0.5, 1, 2, 5, 10, 50 or more to 1, preferably a ratio of 1:1, 1:2, 1:9, 1:10, 1:100, 2:1, 9:1, 10:1 or 100:1 of costimulatory molecule / pMHC complex is obtained.Similarly, the density of co-stimulatory molecules relative to the nanoparticle surface area can be calculated using the same relative formula as for pMHC complexes. In certain embodiments, the density of co-stimulatory molecules per unit surface area of ​​the nanoparticle ranges from approximately 0.0022 co-stimulatory molecules / 100 nm² to approximately 13.26 co-stimulatory molecules / 100 nm². In some embodiments, the density range of co-stimulatory molecules may be the same as or different from the density range for pMHC complexes.

[00225] In some embodiments, in which the nanoparticle comprises one or more co-stimulatory molecules and does not comprise a pMHC complex, the nanoparticle has a co-stimulatory molecule density of approximately 0.2 molecules. co-stimulatory molecules / 100 nm2 up to approximately 6.5 co-stimulatory molecules / 100 nm2, or from approximately 0.2 co-stimulatory molecules / 100 nm2 up to approximately 6 co-stimulatory molecules / 100 nm2, or from approximately 0.2 co-stimulatory molecules / 100 nm2 up to approximately 5.8 molecules Petition 870250027877, dated 07 / 04 / 2025, p. 121 / 384 112 / 299 co-stimulatory molecules / 100 nm2, or from about 0.2 co-stimulatory molecules / 100 nm2 to about 5.75 co-stimulatory molecules / 100 nm2, or from about 0.2 co-stimulatory molecules / 100 nm2 to about 5.5 co-stimulatory molecules / 100 nm2, or from about 0.2 co-stimulatory molecules / 100 nm2 to about 5 co-stimulatory molecules / 100 nm2, or from about 0.2 co-stimulatory molecules / 100 nm2 to about 4.5 co-stimulatory molecules / 100 nm2, or from about 0.2 co-stimulatory molecules / 100 nm2 to about 4 co-stimulatory molecules / 100 nm2, or from about 0.2 co-stimulatory molecules / 100 nm2 to about from 3.5 co-stimulatory molecules / 100 nm2, or from about 0.2 co-stimulatory molecules / 100 nm2 to about 3 co-stimulatory molecules / 100 nm2, or from about 0.2 co-stimulatory molecules / 100 nm2 to about 2.5 co-stimulatory molecules / 100 nm2, or from about 0.2 co-stimulatory molecules / 100 nm2 to about 2 co-stimulatory molecules / 100 nm2, or from about 0.2 co-stimulatory molecules / 100 nm2 up to about 1.5 co-stimulatory molecules / 100 nm2, or from about 0.2 co-stimulatory molecules / 100 nm2 up to about 1.25 co-stimulatory molecules / 100 nm2, or from about 0.2 co-stimulatory molecules / 100 nm2 up to about 1 co-stimulatory molecule / 100 nm2, or from about 0.2 co-stimulatory molecules / 100 nm2 up to about 0.75 molecules, co-stimulatory / 100 nm2.

[00226] In another aspect, the nanoparticle may have a co-stimulatory molecule density of about 0.11 molecules co-stimulatory molecules / 100 nm2 up to approximately 5 co-stimulatory molecules / 100 nm2, or from approximately 0.11 co-stimulatory molecules / 100 nm2 up to approximately 4.5 co-stimulatory molecules / 100 nm2, or from approximately 0.11 molecules Petition 870250027877, dated 07 / 04 / 2025, p. 122 / 384 113 / 299 co-stimulatory molecules / 100 nm² up to approximately 4 co-stimulatory molecules / 100 nm², or from approximately 0.11 co-stimulatory molecules / 100 nm² up to approximately 3.5 co-stimulatory molecules / 100 nm², or from approximately 0.11 co-stimulatory molecules / 100 nm² up to approximately 3 co-stimulatory molecules / 100 nm², or from approximately 0.11 co-stimulatory molecules / 100 nm² up to approximately 2.5 co-stimulatory molecules / 100 nm², or from approximately 0.11 co-stimulatory molecules / 100 nm² up to approximately 2 co-stimulatory molecules / 100 nm², or from approximately 0.11 co-stimulatory molecules / 100 nm² up to approximately 1.5 co-stimulatory molecules / 100 nm², or from approximately 0.11 co-stimulatory molecules co-stimulatory molecules / 100 nm² up to approximately 1 pMHC / 100 nm², or from approximately 0.11 co-stimulatory molecules / 100 nm² to approximately 0.75 co-stimulatory molecules / 100 nm². In some aspects, the nanoparticle core has a co-stimulatory molecule density of approximately 0.11 co-stimulatory molecules / 100 nm² up to approximately 5 co-stimulatory molecules / 100 nm², or 0.12 co-stimulatory molecules / 100 nm² up to approximately 4.5 co-stimulatory molecules / 100 nm². co-stimulatory molecules / 100 nm2, or from about 0.13 co-stimulatory molecules / 100 nm2 to about 4 co-stimulatory molecules / 100 nm2, or from about 0.14 co-stimulatory molecules / 100 nm2 to about 3.5 co-stimulatory molecules / 100 nm2, or from about 0.12 co-stimulatory molecules / 100 nm2 to about 2 co-stimulatory molecules / 100 nm2, or from about 0.25 co-stimulatory molecules / 100 nm2 to about 1.5 co-stimulatory molecules / 100 nm2, or from about 0.3 co-stimulatory molecules / 100 nm2 to about 0.75 co-stimulatory molecules / 100 nm2. In a further aspect, the nucleus of The nanoparticle has a co-stimulatory molecule density of approximately 0.2 co-stimulatory molecules / 100 nm² up to approximately 0.65 co-stimulatory molecule / 100 nm2 or, alternatively, of Petition 870250027877, dated 07 / 04 / 2025, p. 123 / 384 114 / 299 approximately 0.25 co-stimulatory molecules / 100 nm2 to approximately 0.45 co-stimulatory molecules / 100 nm2 or, alternatively, from approximately 0.3 co-stimulatory molecules / 100 nm2 to approximately 0.4 co-stimulatory molecules / 100 nm2.

[00227] In some embodiments, in which the nanoparticle comprises a pMHC complex and one or more molecules co-stimulatory molecules: the nanoparticle has a co-stimulatory molecule density of approximately 0.4 co-stimulatory molecules / 100 nm² to approximately 13 co-stimulatory molecules / 100 nm², or from approximately 0.4 co-stimulatory molecules / 100 nm² to approximately 12 co-stimulatory molecules / 100 nm², or from approximately 0.4 co-stimulatory molecules / 100 nm² to approximately 11.6 co-stimulatory molecules / 100 nm², or from approximately 0.4 co-stimulatory molecules / 100 nm² to approximately 11.5 co-stimulatory molecules / 100 nm², or from approximately 0.4 co-stimulatory molecules / 100 nm² to approximately 11 co-stimulatory molecules / 100 nm², or from approximately 0.4 co-stimulatory molecules / 100 nm² to approximately 11 co-stimulatory molecules / 100 nm². co-stimulatory molecules / 100 nm2 up to approximately 10 co-stimulatory molecules / 100 nm2, or from approximately 0.4 co-stimulatory molecules / 100 nm2 up to approximately 9 co-stimulatory molecules / 100 nm2, or from approximately 0.4 co-stimulatory molecules / 100 nm2 up to approximately 8 co-stimulatory molecules / 100 nm2, or from approximately 0.4 co-stimulatory molecules / 100 nm2 up to about 7 co-stimulatory molecules / 100 nm2, or from about 0.4 co-stimulatory molecules / 100 nm2 up to about 6 co-stimulatory molecules / 100 nm2, or from about 0.4 co-stimulatory molecules / 100 nm2 up to about 5 co-stimulatory molecules / 100 nm2, or from about 0.4 co-stimulatory molecules / 100 nm2 up to about 4 co-stimulatory molecules / 100 nm2, or from about 0.4 co-stimulatory molecules / 100 nm2 up to about 3 molecules, Petition 870250027877, dated 07 / 04 / 2025, page 124 / 384 115 / 299 co-stimulatory molecules / 100 nm2, or from about 0.4 co-stimulatory molecules / 100 nm2 to about 2.5 co-stimulatory molecules / 100 nm2, or from about 0.4 co-stimulatory molecules / 100 nm2 to about 2 co-stimulatory molecules / 100 nm2, or from about 0.4 co-stimulatory molecules / 100 nm2 to about 1.5 co-stimulatory molecules / 100 nm2 co-stimulatory / 100 nm2.

[00228] In another aspect, the nanoparticle may have a co-stimulatory molecule density of about 0.22 molecules co-stimulatory molecules / 100 nm² up to approximately 10 co-stimulatory molecules / 100 nm², or from approximately 0.22 co-stimulatory molecules / 100 nm² up to approximately 9 co-stimulatory molecules / 100 nm², or from approximately 0.22 co-stimulatory molecules / 100 nm² up to approximately 8 co-stimulatory molecules / 100 nm², or from approximately 0.22 co-stimulatory molecules / 100 nm² up to approximately 7 co-stimulatory molecules / 100 nm², or from approximately 0.22 co-stimulatory molecules / 100 nm² up to approximately 6 co-stimulatory molecules / 100 nm², or from approximately 0.22 co-stimulatory molecules / 100 nm² up to approximately 5 co-stimulatory molecules / 100 nm², or from approximately 0.22 co-stimulatory molecules co-stimulatory molecules / 100 nm² up to approximately 4 co-stimulatory molecules / 100 nm², or from approximately 0.22 co-stimulatory molecules / 100 nm² up to approximately 3 co-stimulatory molecules / 100 nm², or from approximately 0.22 co-stimulatory molecules / 100 nm² up to approximately 2 pMHC / 100 nm², or approximately from 0.22 co-stimulatory molecules / 100 nm² to approximately 1.5 co-stimulatory molecules / 100 nm². In some aspects, the nanoparticle core has a co-stimulatory molecule density of approximately 0.22 co-stimulatory molecules / 100 nm² to approximately 10 co-stimulatory molecules / 100 nm², or 0.24 co-stimulatory molecules / 100 nm² to approximately 9 co-stimulatory molecules / 100 nm², or approximately 0.26 co-stimulatory molecules / 100 nm². Petition 870250027877, dated 07 / 04 / 2025, p. 125 / 384 116 / 299 co-stimulatory molecules / 100 nm² up to approximately 8 co-stimulatory molecules / 100 nm², or from approximately 0.28 co-stimulatory molecules / 100 nm² up to approximately 7 co-stimulatory molecules / 100 nm², or from approximately 0.24 co-stimulatory molecules / 100 nm² up to approximately 4 co-stimulatory molecules / 100 nm², or from approximately 0.5 co-stimulatory molecules / 100 nm² up to approximately 3 co-stimulatory molecules / 100 nm², or from approximately 0.6 co-stimulatory molecules / 100 nm² up to approximately 1.5 co-stimulatory molecules / 100 nm² co-stimulatory / 100 nm2. In a further aspect, the nanoparticle has a co-stimulatory molecule density of about 0.4 co-stimulatory molecules / 100 nm2 to about 1.3 co-stimulatory molecules / 100 nm2 or, alternatively, from about 0.5 co-stimulatory molecules / 100 nm2 to about 0.9 co-stimulatory molecules / 100 nm2 or, alternatively, from about 0.6 co-stimulatory molecules / 100 nm2 to about 0.8 co-stimulatory molecules / 100 nm2. Cytokines

[00229] In a certain aspect, NPs still comprise, or alternatively consist basically of, or still consist of at least one cytokine molecule. As used in this descriptive report, the term cytokine encompasses low molecular weight proteins secreted by various cells in the immune system that act as signaling molecules for the regulation of a wide range of biological processes within the body at the molecular and cellular levels. Cytokines include individual immunomodulatory proteins that fall within the class of lymphokines, interleukins, or chemokines.

[00230] Non-limiting examples are disclosed in this descriptive report: for example, IL-1A and IL-1B are two distinct members of the human interleukin-1 (IL-1) family. Mature IL-1A is an 18 kDa protein, also known as fibroblast activating factor (FAF), lymphocyte activating factor. Petition 870250027877, dated 07 / 04 / 2025, page 126 / 384 117 / 299 (LAF), B-cell activating factor (BAF), leukocyte endogenous mediator (LEM), etc. IL-4 is a cytokine that induces T helper-2 (Th2) cell differentiation and is closely related to and has similar functions to IL-13. IL-5 is produced by Th2 cells and mast cells. It acts to stimulate B cell growth and increase immunoglobulin secretion. It is also involved in eosinophil activation. IL-6 is an interleukin that can act as a pro-inflammatory or anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate the immune response to trauma or other tissue damage that leads to inflammation. IL-6 is also produced by muscle in response to muscle contraction. IL-8 is a chemokine produced by macrophages and other cell types such as epithelial and endothelial cells, and acts as an important mediator of the immune reaction in the innate immune system response.IL-12 is involved in the differentiation of naive T cells into helper T cells (Th1 or Th2). As a heterodimeric cytokine, IL-12 is formed after two subunits encoded by two separate genes, IL-12A (p35) and IL-12B (p40), dimerize after protein synthesis. IL-12p70 indicates this heterodimeric composition. IL-13, a cytokine secreted by many cell types, especially Th2 cells, is an important mediator of inflammation and allergic disease. IL-17 is a cytokine produced by helper T cells and is induced by IL-23, resulting in destructive tissue damage in delayed-type reactions. IL-17 functions as a pro-inflammatory cytokine that responds to immune system invasion by extracellular pathogens and induces destruction of the pathogen's cellular matrix. IP-10, or interferon-induced protein gamma-10, also known as CXC motif chemokine 10 (CXCL10) or small inducible cytokine B10.As a small cytokine belonging to the CXC family of chemokines, IP-10 is secreted by various cell types (including monocytes, endothelial cells, and fibroblasts). Petition 870250027877, dated 07 / 04 / 2025, p. 127 / 384 118 / 299 response to IFN-γ. Macrophage Inflammatory Proteins (MIPs) belong to the chemokine family. There are two main forms of human MIP, MIP-1a and MIP-1e, which are also known as chemokine ligand (CC motif) 3 (CCL3) and CCL4, respectively. Both are produced by macrophages after stimulation with bacterial endotoxins. Granulocyte colony-stimulating factor (G-CSF or GCSF), also known as colony-stimulating factor 3 (CSF 3), is a colony-stimulating factor hormone. G-CSF is a glycoprotein, growth factor, and cytokine produced by several different tissues to stimulate the bone marrow to produce granulocytes and stem cells. G-CSF also stimulates the survival, proliferation, differentiation, and function of neutrophil precursors and mature neutrophils.Epidermal growth factor, or EGF, is a growth factor that plays an important role in regulating cell growth, proliferation, and differentiation by binding with high affinity to its receptor EGFR. Vascular endothelial growth factor (VEGF) is a family of growth factors that are important signaling proteins involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature).

[00231] The cytokine or cytokines can be coupled to the nanoparticle in the same way as the pMHC complex. In one embodiment of the present disclosure, the cytokine or cytokines and the pMHC complex are attached separately to the nanoparticle. In another embodiment of the disclosure, the cytokine molecule or cytokines and the pMHC complex are first complexed together and are then subsequently complexed with the nanoparticle. Multiple cytokines can be coupled to the nanoparticle; these can be several of the same cytokine or different cytokines.

[00232] In some modalities, the cytokine is complexed Petition 870250027877, dated 07 / 04 / 2025, p. 128 / 384 119 / 299 with an anti-cytokine antibody to form a cytokine / anti-cytokine antibody complex, which complex is subsequently complexed with the nanoparticle. In some embodiments, the cytokine / anti-cytokine antibody complex includes, without limitation, IL-2 / anti-IL-2 complexes. The IL-2 / anti-IL-2 complexes may have agonistic or antagonistic properties.

[00233] In some embodiments, the cytokine is complexed with a cytokine receptor to form a cytokine / cytokine receptor complex, which complex is subsequently complexed with the nanoparticle. In some embodiments, the cytokine / cytokine receptor complex includes, without limitation, IL15 / IL-15Ra and / or IL-1 / IL-2Ra. In some embodiments, the IL15 / IL-15Ra complex can function as a T cell co-stimulator.

[00234] Typically, polypeptide complexes are added to nanoparticles to generate nanoparticles with adsorbed or coupled polypeptide complexes that have a cytokine / nanoparticle number ratio of about 1 to 5,999 molecules per nanoparticle or, alternatively, at least about or at most about 0.1, 0.5, 1, 10, 100, 500, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000 or more to :1, and ranges between these values, for example, from about 0.1:1 to about 50:1. In other respects, the cytokine to antigen / MHC complex ratio can be approximately 0.1, 0.5, 1, 2, 5, 10, 50 or more to 1, preferably a ratio of 1:1, 1:2, 1:9, 1:10, 1:100, 2:1, 9:1, 10:1 or 100:1 of cytokine / antigen / MHC complex is obtained. Similarly, the density of cytokines relative to the surface area of ​​the nanoparticle can be calculated according to the same relative formula as the antigen / MHC complexes.In certain embodiments, the density of cytokines per unit surface area of ​​the nanoparticle ranges from approximately 0.0022 cytokines / 100 nm2 to approximately... Petition 870250027877, dated 07 / 04 / 2025, page 129 / 384 120 / 299 of 13.26 cytokines / 100 nm2. In some modalities, the cytokine density range may be the same as or different from the density range for antigen / MHC complexes. Antigenic components

[00235] Certain aspects of the discovery include methods and compositions relating to antigenic compositions that include segments, fragments, or epitopes of polypeptides, peptides, nucleic acids, carbohydrates, lipids, and other molecules that evoke or induce an antigenic response, generally referred to as antigens. In particular, autoantigens, or antigenic segments or fragments of these autoantigens, which lead to the destruction of a cell through an autoimmune response, can be identified and used in the production of a peptide-MHC / nanoparticle complex described in this descriptive report.

[00236] Although specific examples of antigens and antigenic components are revealed in this descriptive report, the disclosure is not limited by them.Unless specifically stated otherwise, included in this descriptive report are equivalents of isolated or purified polypeptide antigens comprising, or consisting basically of, or still consisting of the amino acid sequences as described in this descriptive report, or a polypeptide having at least about 80% sequence identity or, alternatively, at least 85% or, alternatively, at least 90% or, alternatively, at least 95% or, alternatively, at least 98% sequence identity for the amino acid sequences of the antigens, or polynucleotide-encoded polypeptides having about 80% sequence identity or, alternatively, at least 85% or, alternatively, at least 90% or, alternatively, at least 95% or, alternatively, at least 98% sequence identity for the polynucleotide that. Petition 870250027877, dated 07 / 04 / 2025, page 130 / 384 121 / 299 encodes the amino acid sequences of the antigen, or its complement, or a polypeptide encoded by a polynucleotide that hybridizes under moderate to high rigor conditions to a polynucleotide that encodes the amino acid sequence of the antigens, or their complement. Also provided are isolated and purified polynucleotides encoding the antigen polypeptides disclosed in this descriptive report, or amino acids that have at least about 80% sequence identity to them or, alternatively, at least 85% or, alternatively, at least 90% or, alternatively, at least 95% or, alternatively, at least 98% sequence identity to the disclosed sequences, or an equivalent, or a polynucleotide that hybridizes under rigorous conditions to the polynucleotide, its equivalent or its complement, and isolated or purified polypeptides encoded by these polynucleotides.Polypeptides and polynucleotides can be combined with non-naturally occurring substances with which they are not associated in nature, for example, carriers, pharmaceutically acceptable carriers, vectors, and MHC molecules. Modified peptides and equivalents thereof

[00237] Antigenic polypeptides, proteins, and fragments thereof can be modified by various amino acid deletions, insertions, and / or substitutions. In particular embodiments, modified polypeptides and / or peptides are capable of modulating an immune response in an individual. As used in this descriptive report, the term protein or polypeptide or peptide refers to a molecule comprising at least five amino acid residues. In some embodiments, a wild-type version of a protein or peptide is employed; however, in many embodiments of the development, a modified protein or polypeptide is employed to generate a peptide / MHC / nanoparticle complex. A complex Petition 870250027877, dated 07 / 04 / 2025, page 131 / 384 122 / 299 peptide / MHC / nanoparticle can be used to generate an immune response and / or to modify the immune system's T cell population (i.e., re-educate the immune system). The terms described above may be used interchangeably in this descriptive report. A “modified protein” or “modified polypeptide” or “modified peptide” refers to a protein or polypeptide whose chemical structure, particularly its amino acid sequence, is altered relative to the wild-type protein or polypeptide. In some embodiments, a modified protein or polypeptide or peptide has at least one modified activity or function (recognizing that proteins or polypeptides or peptides may have multiple activities or functions).It is specifically contemplated that a modified protein or polypeptide or peptide may be altered with respect to one activity or function, while retaining wild-type activity or function in other aspects such as, for example, immunogenicity or ability to interact with other cells of the immune system, when in the context of an MHC / nanoparticle complex.

[00238] In certain embodiments, the size of a protein or polypeptide (wild type or modified), including any complex of a protein or peptide of interest and, in particular, an MHC / peptide fusion, may comprise, without limitation, 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, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210 220, 230, 240, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1100, 1200, 1300, 1400 Petition 870250027877, dated 07 / 04 / 2025, page 132 / 384 123 / 299 1,500, 1,750, 2,000, 2,250, 2,500 amino acid molecules or greater, including any range or value derivable from these values, or derived from them. In certain respects, 5, 6, 7, 8, 9, 10 or more contiguous amino acids, including derivatives thereof, and fragments of an autoantigen such as, for example, those amino acid sequences disclosed and cited in this descriptive report, may be used as antigens. It is contemplated that polypeptides may be mutated by truncation, which makes them shorter than their corresponding wild-type form, but they may also be altered by fusion or conjugation of a heterologous protein sequence with a particular function (e.g., for presentation as a protein complex, for increased immunogenicity, etc.).

[00239] As used in this descriptive report, the term “amino molecule” refers to any amino acid, amino acid derivative, or amino acid mimetic known in the art. In certain embodiments, the residues of the proteinaceous molecule are sequential, without any non-amino molecule interrupting the sequence of amino molecule residues. In other embodiments, the sequence may comprise one or more portions of a non-amino molecule. In particular embodiments, the sequence of residues of the proteinaceous molecule may be interrupted by one or more portions of a non-amino molecule.

[00240] Consequently, the term “proteinaceous composition” encompasses sequences of amino molecules comprising at least one of the 20 amino acids common in naturally synthesized proteins, or at least one modified or uncommon amino acid.

[00241] Proteinaceous compositions may be made by any methodology known to those skilled in the art, including (i) the expression of proteins, polypeptides or peptides by means of standardized molecular biological techniques, (ii) the isolation of proteinaceous compounds from Petition 870250027877, dated 07 / 04 / 2025, page 133 / 384 124 / 299 natural sources, or (iii) the chemical synthesis of proteinaceous materials. The nucleotide, as well as the protein, polypeptide, and peptide sequences for various genes have been previously disclosed and can be found in recognized computerized databases. One such database is the “National Center for Biotechnology Information’s GenBank” and the “GenPept” databases (on the Internet at ncbi.nlm.nih.gov / ). All or part of the coding regions for these genes can be amplified and / or expressed using the techniques disclosed in this descriptive report or as would be known to those skilled in the art.

[00242] Variants in the amino acid sequence of autoantigenic epitopes and other polypeptides of these compositions may be variants by substitution, insertion, or deletion. A modification in a developing polypeptide may affect 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, 50 , 51, 52, 53, 54, 55 , 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 , 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82 , 83, 84, 85, 86, 87 , 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220,221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247 Petition 870250027877, dated 07 / 04 / 2025, pp. 134 / 384 125 / 299 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447,448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500 or more non-contiguous amino acids, or contiguous of a peptide or polypeptide, when compared to the wild type. A peptide or polypeptide that results in an autoimmune response, and in particular a pathological autoimmune response, is contemplated for use in the discovery methods.

[00243] Deletion variants typically lack one or more residues from the native or wild-type amino acid sequence. Individual residues may be deleted, or several contiguous amino acids may be deleted. A stop codon may be introduced (by substitution or insertion) into a nucleic acid coding sequence to generate a truncated protein. Insertion mutants typically involve the addition of material at a non-terminal point in the polypeptide. This may include the insertion of one or more residues. Additions Petition 870250027877, dated 07 / 04 / 2025, page 135 / 384 126 / 299 terminals, called fusion proteins, can also be generated.

[00244] Substitution variants typically involve the exchange of one amino acid for another at one or more sites within the protein, and may be designed to modulate one or more properties of the polypeptide, with or without the loss of other functions or properties. Substitutions may be conservative, meaning an amino acid is substituted with a similar shape and charge.Conservative substitutions are well known in the art and include, for example, the following changes: alanine to serine; arginine to lysine; asparagine to glutamine or histidine; aspartate to glutamate; cysteine ​​to serine; glutamine to asparagine; glutamate to aspartate; glycine to proline; histidine to asparagine or glutamine; isoleucine to leucine or valine; leucine to valine or isoleucine; lysine to arginine; methionine to leucine or isoleucine; phenylalanine to tyrosine, leucine, or methionine; serine to threonine; threonine to serine; tryptophan to tyrosine; tyrosine to tryptophan or phenylalanine; and valine to isoleucine or leucine. Alternatively, the substitutions may be non-conservative, so that a function or activity of a polypeptide or peptide is affected, such as avidity or affinity for a cellular receptor (or receptors).Non-conservative modifications typically involve the substitution of a residue with one that is chemically dissimilar, for example, a polar or charged amino acid for a non-polar or uncharged amino acid, and vice versa.

[00245] Revelation proteins can be recombinant, or synthesized in vitro. Alternatively, a recombinant protein can be isolated from bacteria or another host cell.

[00246] The term “functionally equivalent codon” is used in this descriptive report to refer to codons that Petition 870250027877, dated 07 / 04 / 2025, p. 136 / 384 127 / 299 code for the same amino acid, for example, the six codons for arginine or serine, and also refers to codons that code for biologically equivalent amino acids (see Table 2).

[00247] It will also be understood that amino acid and nucleic acid sequences may include additional residues, for example, N- or C-terminal amino acids, or additional 5' or 3' nucleic acid sequences, respectively, and still be essentially as described in one of the sequences disclosed in this descriptive report, provided that the sequence meets the criteria described above, including maintaining the biological activity of the protein (e.g., immunogenicity). The addition of terminal sequences particularly applies to nucleic acid sequences that may, for example, include several non-coding sequences flanking the 5' or 3' portions of the coding region. Disease-relevant antigens

[00248] Nanoparticles are useful in therapeutic methods, as described in this descriptive report. The pMHC-NP pMHC complex is selected for use based on the disease to be treated. For example, a diabetes-relevant antigen is an antigen or fragment thereof that is expressed in the targeted cell, tissue, or organ in that autoimmune disease and that is exposed to the immune system after cell, tissue, or organ damage caused by the autoimmune response, even if the antigen is not the trigger of the disease process or a crucial participant in its pathogenesis, and when presented, produces an immune response that serves to treat diabetes; thus, a diabetes-relevant antigen that meets this definition is selected to treat diabetes. A MS-relevant antigen is selected to treat MS. A diabetes-relevant antigen would not be selected to treat MS.Relevant, non-limiting disease antigens are disclosed in this descriptive report, and furthermore, these antigens can be determined. Petition 870250027877, dated 07 / 04 / 2025, page 137 / 384 128 / 299 for a particular disease based on techniques, mechanisms and methods well documented in the literature.

[00249] Non-limiting examples of diseases of interest include, without limitation, asthma, type I and type II diabetes mellitus, prediabetes, multiple sclerosis, peripheral neuropathy, allergic asthma, primary biliary cirrhosis, cirrhosis, neuromyelitis optica spectrum disorder, autoantibody-associated neurological syndromes such as stiff-person syndrome, autoimmune encephalitis, narcolepsy, pemphigus vulgaris, pemphigus foliaceus, psoriasis, Sjögren's disease / syndrome, inflammatory bowel disease (IBD), arthritis, rheumatoid arthritis, systemic lupus erythematosus (SLE), scleroderma, ANCA-associated vasculitis, Goodpasture's syndrome, Kawasaki disease, celiac disease, autoimmune cardiomyopathy, idiopathic dilated cardiomyopathy (IDCM), myasthenia gravis, autoimmune uveitis, ankylosing spondylitis, Graves' disease, immune-mediated myopathies, antiphospholipid syndrome (ANCA+), atherosclerosis, autoimmune hepatitis, sclerosing cholangitis, primary sclerosing cholangitis.Dermatomyositis, chronic obstructive pulmonary disease, spinal cord injury, traumatic injury, tobacco-induced lung destruction, emphysema, pemphigus, uveitis, any other cancer and / or diseases of the central and peripheral nervous systems. Cancer / tumor relevant antigens

[00250] In certain respects, the disease-relevant antigen is a cancer-relevant antigen. In further respects, cancer is carcinoma, sarcoma, myeloma, leukemia, lymphoma, and / or mixed types of metastases from these or other cancers. Cancer-relevant antigens or exemplary tumors include, without limitation, those disclosed in Table 5 below. Table 5. Lys Ile Ser Val Ser Leu Pro Leu Ser Leu Ser Gln Ser Val Cys Petition 870250027877, dated 07 / 04 / 2025, page 138 / 384 129 / 299 Gln Leu Ser Lys Asp Thr Ser Val Leu Thr Phe Thr Phe Cys Cys Ser Asp Ala His Pro Gly Asp Ser Ser Gly Asp Ser Ser Gly Leu Asn Arg Gly Glu Val Arg Gln Phe Thr With Arg His Trp With Lys Val Gly Asp Tyr and Asp Glu Ala Leu Trp Asn LysCys Gly Lys Val Ile Asp Asp Asp Asp His Leu Serves Gln GluIle Cys Leu Met Ala Asn Ser Thr Trp Gly Tyr Pro Phe His AspGly Leu Asn Val Val Pro Trp Asn Leu Thr Leu Phe Ser IleLeu Thr His Ser Phe Thr Ala Phe Lys Arg His ValCys Asn To Be Your Pro To Be Your Be Your Best IleCys Glu Arg Pro Ser Ser Val Leu Thr Tyr Asp and GlyIle Gln Cys How To Clean Clean Tire Thr Donkey Clean Glue Arg Pro Ser Ser Val Thr Val Glu Pro Glu Thr Gly Asp Pro Val Thr Leu Arg Leu Cys How To Serve Lys Arg Ala Asp Lys Glu Asn Gly Thr Lys Leu Leu Where Did You Go Val Leu Pro Ser Val Ala Met PheLeu Leu Val Leu Gly Phe Ile Ile AlaLeu Lys Val Val Thr Ser Ser Phe ValVal Leu Val Pro Gly Thr Lys Phe TyrIle Leu Leu Pro Ile Arg Thr Leu ProLeu Tyr Leu Val Lys Lys Gly Thr AlaThr Ser Leu Phe Ala Glu Thr Ile TrpVal Met Leu Ile Ala Met Tyr Phe Tyr Thr Petition 870250027877, dated 07 / 04 / 2025, page 139 / 384 130 / 299 Leu Met Trp Thr Leu Pro Val Met Leu Met Leu Ile Val Tyr Ile Phe Glu Cys Tyr Ile Phe Glu Cys Ala Ser Cys Ile Leu Val Leu Met Leu Ile Val Tyr Ile Ala Leu Cys Arg Arg Arg Ser Met Val Leu Leu Ser Gly Leu Ser Leu Phe Ala Phe Leu Leu Val Val Gly Leu Ile Val Leu Val Val Gly Leu Ile Val Ala Leu Lys Val Val Lys Ser Asp Phe Val Val Thr Leu Pro Val Gln Thr Leu Pro Leu Asp Leu His Val Ile Ser Asn Asp Val Val Leu Val His Pro Gln Trp Val Leu Phe Leu Arg Pro Gly Asp Asp Ser Ser Ala Leu Gly Thr Thr Cys Tyr Ala Ser Lys Leu Gln Cys Val Asp Leu His Val Glu Leu Ala His Tyr Asp Val Leu Leu Asn Leu Asn Gly Ala Gly Asp Pro Leu Thr Leu Arg Val Asp Cys Thr Pro Leu Met Met Asn Asp Gln Leu Met Phe Leu Ala Leu Phe Asp Ile Glu Ser Lys Val Leu Leu His Glu Thr Asp Ser Ala Val Val Leu Ala Lys Glu Leu Lys Phe Val Ile Leu Leu Trp Gln Pro Ile Pro Val Asp Leu Phe Gly Ile Trp Ser Lys Val Pro Leu Glu Arg Phe Ala Glu Leu Val Lys Gln Gly Asn Phe Asn Ala Trp Val Asn Leu Leu Arg Arg Met Trp Val Thr Asn Leu Phe Glu Thr Pro Ile Leu Ala Asn Leu Phe Glu Thr Pro Val Glu Ala Petition 870250027877, dated 04 / 07 / 2025, page 140 / 384 131 / 299 Gly Leu Gln His Trp Val Pro Glu Leu Val Gln Phe Val Ala Ser Tyr Lys Val Arg Leu Leu Ala Ala Leu Cys Gly Ala Leo Leo Leo Leo Thr Val Leo Thr Val Leo Leo Leo Thr Val Leo Thr Val Val Phe Leu Ser Phe His Ile Ser Asn Leu Leo Leo Val Leo Val Cys Val Leo Val Ala Leu Leu Val Leu Val Cys Val Leu Serum Leu Serum Tyr Thr Asn Pro Ala Val Asn Leu Thr Ile Ser Asp Val Ser Val Ala Leo Ala Ser Thr Ala Pro Pro Val Ala Ile Leu Cys Trp Thr Phe Trp Val Phe Ile Leu Met Phe Ile Val Tyr Ala Leu Thr Ala Glu Cys Ile Phe Phe Val Met Leu Gln Asp Asn Cys Cys Gly Val Ile Leu Cys Trp Thr Phe Trp Val Leu Lys Ile Leu Leu Ala Tyr Phe Ile Leu Phe Val Gly Ile Cys Leu Phe Cys Leu Val Leu Leu Ser Val Ala Met Phe Leu Leu Leu Ser Val Ala Met Phe Leu Leu Ile Leu Gly Ser Leu Pro Phe Phe Leu Ile Leu Asn Ala Tyr Leu Val Arg Val Phe Leo Leo Val Gly Phe Ala Gly Ala Asn Leu Gln Pro Gln Leu Ala Ser Val Cys Met Phe Asp Ser Lys Glu Ala Leu Tyr Leu Tyr Val Leu Val Asp Ser Winger Tyr Met Asp Gly Thr Met Ser Gln Val Lys Met Ala Arg Phe Ser Tyr Ser Val Gly Leu Val Met Asp Glu His Leu Val Petition 870250027877, dated 07 / 04 / 2025, page 141 / 384 132 / 299 Phe Leu Pro Gly Cys Asp Gly Leu Val Cys Met Leu Gly Ser Phe Cys Ala Cys Tyr Leu Ala Phe Arg Asp Asp Ser Ile Trp Leu Pro Lys Lys Cys Ser Leu Cys Cys Leu Asn Gly Gly Thr Cys Met Leu Met Leu Val Gly Ile Cys Leu Ser Ile Phe Glu Leu Gly Leu Val Ala Gly Leu Lys Met Val Arg Phe Ser Tyr Ser Val Cys Leu Asn Glu Gly Thr Cys Met Leu Met Leu Ala Gly Ile Cys Leu Ser Ile Arg Leu Leu Phe Phe Leu Leu Phe Leu Thr Leu Ala Tyr Leu Ile Phe Cys Leu Leu Leu Phe Leu Thr Pro Met Glu Val Lys Leu Met Ser Pro Lys Leu Tyr Val Leu Leu Phe Phe Leu Leu Phe Leu Val Ser Leu Phe Leu Gly Ile Leu Ser Val Ala Ile Ser Gly Met Ile Leu Ser Ile Phe Ile Arg Ala His Thr Pro Tyr Ile Ser Leu Asn Phe Ile Arg Ala His Thr Leu Lys Met Glu Ser Leu Asn Phe Ile Ser His Phe Leu Lys Met Glu Ser Leu Tyr Leu Phe Leu Gly Ile Leu Ser Val

[00251] Other cancer-relevant antigens include those summarized in the Tables in this online database http: / / cancerimmunity.org / peptide / and incorporated into this descriptive report by reference, last accessed on May 6, 2015. Antigens relevant to autoimmune disease

[00252] In certain respects, the disease-relevant antigen contained in the antigen-MHC complex is selected from a Petition 870250027877, dated 07 / 04 / 2025, page 142 / 384 133 / 299 an antigen relevant to autoimmune disease, an antigen relevant to inflammation, or an antigen relevant to allergic disease. In further aspects, an antigen relevant to immune inflammation is one or more selected from the group of an antigen relevant to asthma, an antigen relevant to diabetes, an antigen relevant to prediabetes, an antigen relevant to multiple sclerosis, an antigen relevant to allergic asthma, an antigen relevant to primary biliary cirrhosis, an antigen relevant to cirrhosis, an antigen relevant to a neuromyelitis optica spectrum disorder (Devic's disease, NMO), an antigen relevant to autoimmune encephalitis, an antigen relevant to autoantibody-mediated neurological syndromes, an antigen relevant to stiff-person syndrome, an antigen relevant to paraneoplastic disease, antigens relevant to other diseases of the central and peripheral nervous systems, an antigen relevant to pemphigus vulgaris,Relevant antigen for inflammatory bowel disease (IBD), relevant antigen for Crohn's disease, relevant antigen for ulcerative colitis, a relevant antigen for arthritis, a relevant antigen for rheumatoid arthritis, a relevant antigen for systemic lupus erythematosus (SLE), a relevant antigen for celiac disease, a relevant antigen for psoriasis, a relevant antigen for alopecia areata, a relevant antigen for acquired thrombocytopenic purpura, a relevant antigen for autoimmune cardiomyopathy, a relevant antigen for idiopathic dilated cardiomyopathy (IDCM), a relevant antigen for myasthenia gravis, a relevant antigen for uveitis, a relevant antigen for ankylosing spondylitis, a relevant antigen for Graves' disease, a relevant antigen for Hashimoto's thyroiditis, a relevant antigen for immune-mediated myopathies, a relevant antigen for antiphospholipid syndrome (ANCA+), a relevant antigen for atherosclerosis,an antigen relevant to, Petition 870250027877, dated 07 / 04 / 2025, page 143 / 384 134 / 299 scleroderma, a relevant antigen for autoimmune hepatitis, a relevant antigen for dermatomyositis, a relevant antigen for chronic obstructive pulmonary disease, a relevant antigen for spinal cord injury, a relevant antigen for traumatic injury, a relevant antigen for tobacco-induced lung destruction, a relevant antigen for chronic obstructive pulmonary disease (COPD), a relevant antigen for pulmonary emphysema, a relevant antigen for sclerosing cholangitis, a relevant antigen for peripheral neuropathy, a relevant antigen for narcolepsy, a relevant antigen for Goodpasture's syndrome, a relevant antigen for Kawasaki disease, a relevant antigen for autoimmune uveitis, a relevant antigen for colitis, a relevant antigen for emphysema, a relevant antigen for pemphigus, a relevant antigen for pemphigus foliaceus, a relevant antigen for arthritis, a relevant antigen for Sjögren's syndrome,an antigen relevant to ANCA-associated vasculitis, an antigen relevant to primary sclerosing cholangitis, an antigen relevant to adipose tissue inflammation / type II diabetes, or an antigen relevant to obesity-associated adipose tissue inflammation / insulin resistance.

[00253] In certain aspects, the disease-relevant antigen is derived from one or more of the following groups: PPI, IGRP, GAD, peripherin, aGlia, PDC-E2, Insulin, DG1EC2, DG3, AQP4, PLP, MOG, MBP, CII, DERP-1, DERP2, OVA, BacInt, CBir, Fla-X, Fla-2, YIDX, AChR, thyroid peroxidase, thyroid receptor, phospholipid antigen, H4, H2B, H1, DNA, ApoB, ApoE, NMDAR, voltage-dependent potassium channel, Elastin, Arrestin, Myeloperoxidase PERM_HUMAN, Myeloblastin PRTN3_HUMAN, Cytochrome P450 2D6CP2D6_HUMAN, O-phosphoseryl-tRNA(Sec) SPCS_HUMAN, selenium transferase, peptide cathelicidin antimicrobial CAMP_HUMAN, DNA topoisomerase I, CENP-C, Beta-2glycoprotein 1APOH_HUMAN, SS-A / Ro 60 kDa ribonucleoprotein Petition 870250027877, dated 07 / 04 / 2025, page 144 / 384 135 / 299 RO60_HUMAN, lupus protein La LA_HUMAN, IRBP, myosin, lipid-binding antigens of CD1d, Cap18, CP2D6, SPCS, RO60, RO52, LA, APOH, MPO, PRTN3, or HSP.

[00254] In some modalities, the disease-relevant antigen is: a) an antigen relevant to diabetes and is derived from an antigen selected from one or more of the following groups: preproinsulin (PPI), glucose-6-phosphatase-specific (IGRP), glutamate decarboxylase (GAD), islet cell autoantigen-2 (ICA2), insulin, proinsulin, or a fragment or equivalent of each of these; (b) an antigen relevant to multiple sclerosis and is derived from an antigen selected from one or more of the following groups: myelin basic protein, myelin-associated glycoprotein, myelin oligodendrocyte protein, proteolipid protein, myelin oligodendrocyte oligoprotein, myelin-associated oligodendrocyte basic protein, oligodendrocyte-specific protein, heat shock proteins, oligodendrocyte-specific proteins, NOGO A, Po glycoprotein, peripheral myelin protein 22, 2'3'-cyclic nucleotide 3'phosphodiesterase, or a fragment or equivalent of each of these; c) an antigen relevant to celiac disease and is derived from gliadin or a fragment or equivalent thereof; d) an antigen relevant to primary biliary cirrhosis and is derived from PDC-E2 or a fragment or equivalent thereof; (e) an antigen relevant to pemphigus foliaceus and / or an antigen relevant to pemphigus vulgaris and is derived from an antigen selected from one or more of the following groups: DG1, DG3, or a fragment or equivalent of each of these; f) an antigen relevant to a neuromyelitis optica spectrum disorder and is derived from AQP4 or a fragment or equivalent thereof; Petition 870250027877, dated 07 / 04 / 2025, pp. 145 / 384 136 / 299 (g) an antigen relevant to arthritis and is derived from an antigen selected from one or more of the following groups: heat shock proteins, immunoglobulin-binding protein, heterogeneous nuclear RNPs, annexin V, calpastatin, type II collagen, glucose-6-phosphate isomerase, human cartilage elongation factor gp39, mannose-binding lectin, citrullinated vimentin, type II collagen, fibrinogen, alpha enolase, anti-carbamylated protein (anti-CarP), peptidyl arginine deiminase type 4 (PAD4), BRAF, fibrinogen gamma chain, inter-alpha-trypsin H1 heavy chain inhibitor, alpha-1 antitrypsin, plasma protease C1 inhibitor, gelsolin, alpha 1-B glycoprotein, ceruloplasmin, inter-alpha-trypsin H4 heavy chain inhibitor, complement factor H, alpha 2 macroglobulin, serum amyloid, protein C-reactive protein, serum albumin, beta-chain fibrinogen, serum transferrin, alpha 2 HS glycoprotein, vimentin, Complement C3,or a fragment or an equivalent of each of these; h) an antigen relevant to allergic asthma and is derived from an antigen selected from one or more of the following groups: DERP1, DERP2, or a fragment or equivalent of each of these; i) an antigen relevant to inflammatory bowel disease and is derived from an antigen selected from one or more of the following groups: Flagellin, Fla-2, Fla-X, YIDX, Bacteroides integrase, or a fragment or equivalent of each of these; j) an antigen relevant to systemic lupus erythematosus and is derived from an antigen selected from one or more of the following groups: double-stranded DNA (ds), ribonucleoprotein (RNP), Smith (Sm), Sjogren's syndrome-related antigen A (SS-A) / Ro, Sjogren's syndrome-related antigen B (SS-B) / La, RO60, RO52, histones, or a fragment or equivalent of each of these; k) an antigen relevant to atherosclerosis and is derived from an antigen selected from one or more of the following groups: ApoB, ApoE or Petition 870250027877, dated 07 / 04 / 2025, page 146 / 384 137 / 299 a fragment or an equivalent of each of these; l) an antigen relevant to COPD and / or an antigen relevant to emphysema and is derived from elastin or a fragment or equivalent thereof; m) a psoriasis-relevant antigen and is derived from an antigen selected from one or more of the following groups: Cap18, ADMTSL5, ATL5, or a fragment or equivalent of each of these; n) an antigen relevant for autoimmune hepatitis and is derived from an antigen selected from one or more of the following groups: CYP2D6, SLA, or a fragment or equivalent of each of these; (o) an antigen relevant to uveitis and is derived from arrestin or a fragment or equivalent thereof; p) an antigen relevant to Sjögren's syndrome and is derived from an antigen selected from one or more of the following groups: (SSA) / Ro, (SS-B) / La, MR3, RO60, RO52, or a fragment or equivalent of each of these; q) a scleroderma-relevant antigen and is derived from an antigen selected from one or more of the following groups: CENP-C, TOP 1, RNA polymerase III, or a fragment or equivalent of each of these; r) an antigen relevant to antiphospholipid syndrome and is derived from APOH or a fragment or equivalent thereof; s) an antigen relevant to ANCA-associated vasculitis and is derived from an antigen selected from one or more of the following groups: MPO, PRTN3, or a fragment or equivalent of each of these; or t) an antigen relevant to stiff-person syndrome and is derived from GAD or a fragment or equivalent thereof. Antigens relevant to diabetes

[00255] Antigens relevant to diabetes include, without limitation, those derived from PPI, IGRP, GAD, islet cell autoantigen-2 (ICA2), and / or insulin. Autoreactive antigenic peptides relevant to diabetes include, without limitation, those derived from PPI, IGRP, GAD, islet cell autoantigen-2 (ICA2), and / or insulin. Petition 870250027877, dated 07 / 04 / 2025, page 147 / 384 138 / 299 limitation, those listed in Table 6 below, in addition to the peptides and proteins disclosed in US Publication 2005 / 0202032, which is incorporated into this descriptive report by reference in its entirety, as well as equivalents and / or combinations thereof, Table 6. Peptide hInsB10-18 HLVEALYLV hIGRP228-236 LNIDLLWSV hIGRP265-273 VLFGLGFAI IGRP206-214 VYLKTNVFL hIGRP206-214 VYLKTNLFL NRP-A7 VYLKTNLFL NRP-A7 KYNFLAN-KYNIV4 NRP-V7 KYNKANVFL YAI / Db FQDENYLYL INS B15-23 LYLVCGERG PPI76-90 (K88s) SLQPLALEGSLQSRG IGRP13-25 QHLQKDYRAYYTF GAD555-567 NFFRMVISNPAAT-GADSNPAAT-GADSN55555 IGRP23-35 YTFLNFMSNVGDP B24-C36 FFYTPKTRREAED PPI76-90 SLQPLALEGSLQKRG INS-I9 LYLVCGERI TUM KYQAVTTTL G6Pase KYCLITIFL Pro-insulinL2-10 ALWMRLLPLPL-PRO-INSULINA-LWLLL11 Petition 870250027877, of 07 / 04 / 2025, p. 148 / 384 139 / 299 ProinsulinBi0-i8 HLVEALYLV ProinsulinBi4-22 alylvcger ProinsulinBi5-24 lylvcgergf ProinsulinBi7-25 lvcgergff ProinsulinBi8-27 vcgergffyt Pro-insulinB2 0-27 GERGFFYT Pro-insulinB2i-2 9 ERGFFYTPK Pro-insulinB25-ci FYTPKTRRE Pro-insulinB27-c5 TPKTRREAEDL Pro-insulinac2 0-2 8 SLQPLALEG Pro-insulinc25-33 ALEGSLQKR Proinsulinac2 9-A5 SLQKRGIVEQ Proinsulin Ai-10 giveqcctsi Proinsulin A2-i0 iveqcctsi Proinsulin Ai2-2 0 slyqlenyc Relevant antigens for MS

[00256] The antigens of the disclosure include antigens related to multiple sclerosis. These antigens include, for example, those disclosed in U.S. Patent Application Publication No. 2012 / 0077686, and antigens derived from myelin basic protein, myelin-associated glycoprotein, myelin oligodendrocyte protein, proteolipid protein, myelin oligodendrocyte oligoprotein, myelin-associated oligodendrocyte basic protein, oligodendrocyte-specific protein, heat shock proteins, NOGO A oligodendrocyte-specific proteins, Po glycoprotein, peripheral myelin protein 22, or nucleotide 2'3'-cyclic 3'phosphodiesterase. In certain embodiments, the antigen is derived from myelin oligodendrocyte glycoprotein (MOG). Petition 870250027877, dated 07 / 04 / 2025, page 149 / 384 140 / 299

[00257] In further aspects, peptide antigens for the treatment of MS and MS-related disorders include, without limitation, those listed in Table 7, as well as equivalents and / or combinations of each of these: Table 7. Peptide MOG35-55 MEVGWYRSPFSRVVHLYRNGK MOG36-55 EVGWYRSPFSRVVHLYRNGK MAG287-295 SLLLELEEV MAG509-517 LMWAKIGPV MAG556-564 VLFSSDFRI MBP110-118 SLSRFSWGA MOG114-122 KVEDPFYWV MOG166-175 RTFDPHFLRV MOG172-180 FLRVPCWKI MOG179-188 KITLFVIVPV MOG188-196 VLGPLVALI MOG181-189 TLFVIVPVL MOG205-214 RLAGQFLEEL PLP80-88 FLYGALLLA MAG287-295 SLLLELEEV MAG509-517 LMWAKIGPV MAG556-564 VLFSSDFRI MOG97-109 TCFFRDHSYQEEA MOG97-109 (E107S) TCFFRDHSYQEEA MOG97-109 (E107S) TCFFRDHSYQSEA MBP89-101 VHFFKNIVTPRTP PLP175-192 YIYFNTWTTCQSIAFPSK PLP94-108 GAVRQIFGDYKTTIC Petition 870250027877, dated 07 / 04 / 2025, page 150 / 384 141 / 299 MBP86-98 PVVHFFKNIVTPR PLP54-68 NYQDYEYLINVIHAF PLP249-263 ATLVSLLTFMIAATY MOG156-170 LVLLAVLPVLLLQIT MOG201-215 FLRVPCWKITLFVIV MOG38-52 RHPIRALVGDEVELP MOG203-217 RVPCWKITLFVIVPV PLP250-264 TLVSLLTFMIATYN MPB13-32 KYLATASTMDHARHGFLPRH MPB83-99 ENPVVHFFKNIVTPRTP MPB111-129 LSRFSWGAEGQRPGFGYGG MPB146-170 AQGTLSKIFKLGGRDSRSGSPMARR MOG223-237 ALIICYNWLHRRLAG MOG6-20 IGPRHPIRALVGDEV PLP88-102 AEGFYTTGAVRQIFG PLP139-154 HCLGKWLGHPDKFVGI Antigens relevant to celiac disease (CD)

[00258] Antigens relevant to celiac disease include, without limitation, those derived from gliadin. In some embodiments, non-limiting types of gliadin include alpha / beta gliadin, γ-gliadin, or ω-gliadin. Other exemplary non-limiting antigens relevant to celiac disease include those listed in Table 8, as well as equivalents and / or combinations of each of these. Table 8. Peptide aGlia57-68 QLQPFPQPELPY aGlia62-72 PQPELPYPQPE aGlia217-229 SGEGSFQPSQQNP Relevant antigens for primary biliary cirrhosis (PBC) Petition 870250027877, dated 07 / 04 / 2025, page 151 / 384 142 / 299

[00259] Antigens relevant to primary biliary cirrhosis include, without limitation, those derived from PDC-E2. Non-limiting examples of exemplary antigens include those listed in Table 9, as well as equivalents and / or combinations of each of these. Table 9. Peptide PDC-E2122-135 GDLIAEVETDKATV PDC-E2249-262 GDLLAEIETDKATI PDC-E2249-263 GDLLAEIETDKATIG PDC-E2629-643 AQWLAEFRKYLEKPI PDC-E272-86 RLLLQLLGSPGRRYY PDC-E2353-367 GRVFVSPLAKKLAVE PDC-E2422-436 DIPISNIRRVIAQRL PDC-E2629-643 AQWLAEFRKYLEKPI PDC-E280-94 SPGRRYYSLPPHQKV PDC-E2353-367 GRVFVSPLAKKLAVE PDC-E2535-549 ETIANDVVSLATKAR Relevant antigens for pemphigus foliaceus (PF) and pemphigus vulgaris (PV)

[00260] Antigens relevant to PF and PV include, without limitation, those derived from desmoglein 3 (DG3) and / or desmoglein 1 (DG1). Non-limiting examples include those listed in Table 10, as well as equivalents and / or combinations of each of these. Table 10. Peptide DG1216-229 GEIRTMNNFLDREI DG397-111 FGIFVVDKNTGDINI DG3251-265 CECNIKVKDVNDNFP Petition 870250027877, dated 07 / 04 / 2025, page 152 / 384 143 / 299 DG3351-365 NKAEFHQSVISRYRV DG3453-467 DSTFIVNKTITAEVL DG3540-554 SITTLNATSALLRAQ DG3280-294 ILSSELLRFQVTDLD DG3326-340 EGILKVVKALDYEQL DG3367-381 STPVTIQVINVREGI DG313-27 AIFVVVILVHGELRI DG3323-337 RTNEGILKVVKALDY DG3438-452 DSKTAEIKFVKNMNR DG148-62 KREWIKFAAACREGE DG1206-222 MFIINNRTGEIRTMN DG1363-377 SQYKLKASAISVTVL DG13-17 WSFFRVVAMLFIFLV DG1192-206 SKIAFKIIRQEPSDS DG1326-340 TNVGILKVVKPLDYE DG11-15 MDWSFFRVVAMLFIF DG135-49 KNGTIKWHSIRRQKR DG1325-339 RTNVGILKVVKPLDY Antigens relevant to neuromyelitis optica spectrum disorder (NMO)

[00261] Antigens relevant to NMO include, without limitation, those derived from AQP4 or aquaporin 4. Non-limiting examples include those listed in Table 11, as well as equivalents and / or combinations of each of these. Table 11. Peptide AQP4129-143 GAGILYLVTPPSVVG AQP4284-298 RSQVETDDLILKPGV AQP463-76 EKPLPVDMVLISLC AQP4129-143 GAGILYLVTPPSVVG Petition 870250027877, dated 07 / 04 / 2025, page 153 / 384 144 / 299 AQP439-53 TAEFLAMLIFVLLSL Relevant antigens for arthritis

[00262] Antigens relevant to arthritis include, without limitation, those derived from heat shock proteins, immunoglobulin-binding protein, heterogeneous nuclear RNPs, annexin V, calpastatin, type II collagen, glucose-6-phosphate isomerase, human cartilage elongation factor gp39, mannose-binding lectin, citrullinated vimentin, type II collagen, fibrinogen, alpha enolase, anti-carbamylated protein (anti-CarP), peptidyl arginine deiminase type 4 (PAD4), BRAF, fibrinogen gamma chain, inter-alpha-trypsin H1 heavy chain inhibitor, alpha-1 antitrypsin, plasma protease C1 inhibitor, gelsolin, alpha 1-B glycoprotein, ceruloplasmin, inter-alpha-trypsin H4 heavy chain inhibitor, complement factor H, alpha 2 macroglobulin, serum amyloid, C-reactive protein, serum albumin, beta-chain of fibrinogen, serum transferrin, alpha 2HS glycoprotein, vimentin, Complement C3, or a fragment or equivalent of each of these. Relevant antigens for allergic asthma

[00263] Antigens relevant to allergic asthma include, without limitation, those derived from DERP-1 and DERP-2. Non-limiting examples include those listed in Table 12, as well as equivalents and / or combinations of each of these. Table 12. Peptide DERP-116-30 LRQMRTVTPIRMQGG DERP-1171-185 AVNIVGYSNAQGVDY DERP-1110-124 RFGISNYCQIYPPNV DERP-226-40 PCIIHRGKPFQLEAV DERP-2107-121 TVKVMGDDGVLACAI Antigens relevant to inflammatory bowel disease Petition 870250027877, dated 07 / 04 / 2025, page 154 / 384 145 / 299

[00264] Antigens relevant to inflammatory bowel disease include, without limitation, antigens relevant to Crohn's disease and antigens relevant to ulcerative colitis. In some embodiments, antigens relevant to inflammatory bowel disease include, without limitation, those derived from Bacteroides integrase, flagellin, flagellin 2 (Fla-2 / Fla-X), or uncharacterized E. coli protein (YIDX). Non-limiting examples include those listed in Table 13, as well as equivalents and / or combinations of each of these. Table 13. Bacteroides integrase antigen 183-197 EAINQGYMHADAYPF Bacteroides integrase antigen 146-160 KDLTYTFLRDFEQYL Bacteroides integrase antigen 175-189 RQLRTLVNEAINQGY Bacteroides integrase antigen 1-15 MDKIRYRLVYNRQNT Bacteroides integrase antigen 183-197 EAINQGYMHADAYPF Bacteroides integrase antigen 30-44 LNQRKIYLKTNVYLK Bacteroides integrase antigen 70-84 EYILYLQGIELGYWK Bacteroides integrase antigen 337-351 TCATLLIHQGVAITT Bacteroides integrase antigen 171-185 AKHMRQLRTLVNEAI IRYRLVYNRQNTLNR integrase antigen4-18 Petition 870250027877, dated 07 / 04 / 2025, page 155 / 384 146 / 299 bacteróides Antigeno256-270 de integrase de bacteróides ENFIRINGKRWLYFK F la-2 / Fla-X366-380 TGAAATYAIDSIADA F la-2 / Fla-Xi64-i78 NATFSMDQLKFGDTI F la-2 / Fla-X2 6i-275 DRTVVSSIGAYKLIQ Fla-2 / Fla-Xi-i5 MVVQHNLRAMNSNRM F la-2 / Fla-X5i-65 KMRKQIRGLSQASLN F la-2 / Fla-X2 69-2 83 GAYKLIQKELGLASS Fla-2 / Fla-X4-i8 QHNLRAMNSNRMLGI F la-2 / Fla-X27i-2 85 YKLIQKELGLASSIG YIDX78-92 ADDIVKMLNDPALNR YIDX93-107 HNIQVADDARFVLNA YIDX98-112 ADDARFVLNAGKKKF YIDX23-37 GCISYALVSHTAKGS YIDX78-92 ADDIVKMLNDPALNR YIDX195-209 LPVTVTLDIITAPLQ YIDX22-36 SGCISYALVSHTAKG YIDX80-94 DIVKMLNDPALNRHN YIDX101-115 ARFVLNAGKKKFTGT Antigens relevant to your system (SLE)

[00265] Antigens relevant to SLE include, without limitation, those derived from H4, H2B, H1', ​​dsDNA, RNP, Smith (Sm), Sjögren's Syndrome-Related Antigen A (SS-A) / Ro, Sjögren's Syndrome-Related Antigen B (SS-B) / La, and / or histones. In some embodiments, SS-A includes, without limitation, RO60 and RO52. In some embodiments, histones include, without limitation, H4, H2B, H1'. Non-limiting examples include those listed in Table 14, as well as equivalents and / or combinations of Petition 870250027877, dated 07 / 04 / 2025, page 156 / 384 147 / 299 each of these. Table 14. Peptide H471-94 TYTEHAKRKTVTAMDVVYALKRQG H474-88 E HAKRKTVTAMDVVY H476-90 AKRKTVTAMDVVYAL H475-89 HAKRKTVTAMDVVYA H478-92 RKTVTAMDVVYALKR H480-94 TVTAMDVVYALKRQ H2B10-24 PKKGSKKAVTKAQKK H2B16-30 KAVTKAQKKDGKKRK H1 '22-42 STDHPKYSDMIVAAIQAEKNR H1 '27-41 KYSDMIVAAIQAEKN Antigens relevant to atherosclerosis

[00266] Antigens relevant to atherosclerosis include, without limitation, those derived from Apolipoprotein B (ApoB) or Apolipoprotein E (ApoE). Non-limiting examples include those listed in Table 15, as well as equivalents and / or combinations of each of these. Table 15. Peptide ApoB3501-3516 SQEYSGSVANEANVY ApoB1952-1966 SHSLPYESSISTALE ApoB978-993 TGAYSNASSTESASY ApoB3498-3513 SFLSQEYSGSVANEA ApoB210A KTTKQSFDLSVKAQYKKNKH ApoB210B KTTKQSFDLSVKAQY ApoB210C TTKQSFDLSVKAQYK Antigens relevant to chronic obstructive pulmonary disease (COPD) and / or emphysema.

[00267] Antigens relevant to COPD and / or emphysema Petition 870250027877, dated 07 / 04 / 2025, page 157 / 384 148 / 299 include, without limitation, those derived from elastin. Non-limiting examples include those listed in Table 16, as well as equivalents and / or combinations of each of these. Table 16. Peptide Elastin 89-103 VAAKAQLRAAAGLGA Elastin55 8-572 KSAAKVAAKAQLRAA Elastin698-712 AAQFGLVGAAGLGGL Elastin566-580 KAQLRAAAGLGAGIP Elastin645-659 VP GALAAAKAAKYGA Antigens relevant to psoriasis

[00268] Antigens relevant to psoriasis include, without limitation, those listed in Table 17 below, as well as equivalents and / or combinations thereof. Other exemplary non-limiting antigens relevant to psoriasis may be derived from human Adamts-like protein 5 (ATL5), antimicrobial peptide cathelicidin (CAP18) and / or ADAMTS-like protein 5 (ADMTSL5). Table 17. Peptide Cap1864-78 RPTMDGDPDTPKPVS Cap1834-48 SYKEAVLRAIDGINQ Cap1847-61 NQRSSDANLYRLLDL Cap18151-165 KRIVQRIKDFLRNLV Petition 870250027877, dated 07 / 04 / 2025, page 158 / 384 149 / 299 Cap18149-163 EFKRIVQRIKDFLRN Cap18152-166 RIVQRIKDFLRNLVP Cap18131-145 RFALLGDFFRKSKEK Cap1824-38 QRIKDFLRNLVPRTE ADMTSL5245-259 DGRYVLNGHWVVSPP ADMTSL5267-281 THVVYTRDTGPQETL ADMTSL5372-386 RLLHYCGSDFVFQAR ADMTSL5289-303 HDLLLQVLLQEPNPG ADMTSL5396-410 ETRYEVRIQLVYKNR ADMTSL5433-447 HRDYLMAVQRLVSPD ADMTSL5142-156 EGHAFYHSFGRVLDG ADMTSL5236-250 RNHLALMGGDGRYVL ADMTSL5301-315 NPGIEFEFWLPRERY ADMTSL5203-217 VQRVFRDAGAFAGYW ADMTSL5404-418 QLVYKNRSPLRAREY Relevant antigens for autoimmune hepatitis

[00269] Antigens relevant to autoimmune hepatitis include, without limitation, those disclosed in Table 18 below, as well as equivalents and / or combinations thereof. Other exemplary non-limiting antigens relevant to autoimmune hepatitis may be derived from microsomal cytochrome P450IID6 (CYP2D6) and / or soluble liver antigen (SLA). Table 18. Peptide CYP2D6193-207 RRFEYDDPRFLRLLD CYP2D676-90 TPVVVLNGLAAVREA CYP2D6293-307 ENLRIVVADLFSAGM CYP2D6313-332 TLAWGLLLMILHPDVQRRVQ CYP2D6393-412 TTLITNLSSVLKDEAVWEKP CYP2D6199-213 DPRFLRLLDLAQEGL Petition 870250027877, dated 07 / 04 / 2025, page 159 / 384 150 / 299 CYP2D6450-464 RMELFLFFTSLLQHF CYP2D6301-315 DLFSAGMVTTSTTLA CYP2D6452-466 ​​ELFLFFTSLLQHFSF CYP2D659-73 DQLRRRFGDVFSLQL CYP2D6130-144 EQRRRFSVSTLRNLGL CYP2D6193-212 RRFEYDDPRFLRLLDLAQEG CYP2D6305-324 AGMVTTSTTLAWGLLLMILH CYP2D6131-145 QRRFSSVSTLRNLGLG CYP2D6216-230 ESGFLREVLNAVPVL CYP2D6238-252 GKVLRFQKAFLTQLD CYP2D6199-213 DPRFLRLLDLAQEGL CYP2D6235-252 GKVLRFQKAFLTQLD CYP2D6293-307 ENLRIVVADLFSAGM CYP2D6381-395 DIEVQGFRIPKGTTL CYP2D6429-443 KP EAFLPF SAGRRAC SLA334-348 YKKLLKERKEMFSYL SLA196-210 DELRTDLKAVEAKVQ SLA115-129 NKITNSLVLDIIKLA SLA373-386 NRLDRCLKAVRKER SLA186-197 LIQQGARVGRID SLA317-331 SPSLDVLITLLSLGS SLA171-185 DQKSCFKSMITAGFE SLA417-431 YTFRGFMSHTNNYPC SLA359-373 YNERLLHTPHNPISL SLA215-229 DCILCIHSTTSCFAP SLA111-125 SSLLNKITNSLVLDI SLA110-124 GSSLLNKITNSLVLD SLA299-313 NDSFIQEISKMYPGR SLA342-356 KEMFSYLSNQIKKLS Petition 870250027877, on 04 / 07 / 2025, page. 160 / 384 151 / 299 SLA49-63 STLELFLHELAIMDS SLA119-133 NSLVLDIIKLAGVHT SLA260-274 SKCMHLIQQGARVGR SLA26-40 RSHEHLIRLLLEKGK SLA86-100 RRHYRFIHGIGRSGD SLA331-345 SNGYKKLLKERKEMF Relevant antigens for uveitis

[00270] Antigens relevant to uveitis include, without limitation, those disclosed in Table 19 below, as well as equivalents and / or combinations thereof. Other exemplary antigens relevant to uveitis that are not limiting may be derived from arrestin, human retinal antigen S, and / or interphotoreceptor retinoid-binding protein (IRBP). Table 19. Peptide Arrestinai99-213 QFFMSDKPLHLAVSLN Arrestin77-9i DVIGLTFRRDLYFSR Arrestin250-264 NVVLYSSDYYVKPVA Arrestinai72-186 S SVRL LIRKVQHAP L Arrestin354-368 EVPFRLMHPQPEDPA Arrestin239-253 KKIKAFVEQVANVVL Arrestinai02-ii6 STPTKLQESLLKKLG Arrestina59-73 KKVYVTLTCAFRYGQ Arrestina280-294 KTLTLLPLLANNRER Arrestina29i-306 NRERRGIALDGKIKHE Arrestinai95-209 EAAWQFFMSDKPLHL Arrestina200-214 QFFMSDKPLHLAVSL Relevant antigens for Sjögren's syndrome

[00271] Antigens relevant to Sjögren's syndrome include, without limitation, those disclosed in Table 20 below, as well as equivalents and / or combinations thereof. Other antigens Petition 870250027877, dated 07 / 04 / 2025, pp. 161 / 384 152 / 299 relevant to Sjogren's syndrome, non-limiting examples may be derived from (SS-A) / Ro, (SS-B) / La, RO60, RO52, and / or muscarinic receptor 3 (MR3). Table 20. Peptídeo RO60127-141 TFIQFKKDLKESMKC RO60523-537 DTGALDVIRNFTLDM RO60243-257 EVIHLIEEHRLVREH RO60484-498 REYRKKMDIPAKLIV RO60347-361 EEILKALDAAFYKTF RO60369-383 KRFFLLAVDVSASMNQ RO60426-440 TDMTLQQVLMAMSQI RO60267-281 EVWKALLQEMPLTAL RO60178-192 SHKDLLRLSHLKPSS RO60358-372 YKTFKTVEPTGKRFL RO60221-235 ETEKLLKYLEAVEKV RO60318-332 RIHPFHILIALETYK RO60407-421 EKDS YVVAF S DEMVP RO60459-473 TPADVFIVFTDNETF RO6051-65 QKLGLENAEALIRLI RO60312-326 KLLKKARIHPFHILI LA241-255 DDQTCREDLHILFSN LA101-115 TDEYKNDVKNRSVYI LA153-167 SIFVVFDSIESAKKF LA178-192 TDLLILFKDDYFAKK LA19-33 HQIEYYFGDFNLPRD LA37-51 KEQIKLDEGWVPLEI LA133-147 DKGQVLNIQMRRTLH LA50-64 EIMIKFNRLNRLTTD Petition 870250027877, 04 / 07 / 2025, pág. 162 / 384 153 / 299 LA32-46 RDKFLKEQIKLDEGW LA153-167 SIFVVFDSIESAKKF LA83-97 SEDKTKIRRSPSKPL LA136-150 QVLNIQMRRTLHKAF LA297-311 RNKEVTWEVLEGEVE LA59-73 NRLTTDFNVIVEALS LA151-165 KGSIFVVFDSIESAK LA86-100 KTKIRRSPSKPLPEV LA154-168 IFVVFDSIESAKKFV Antigens relevant to scleroderma

[00272] Relevant antigens for scleroderma include, without limitation, those disclosed in Table 21 below, as well as equivalents and / or combinations thereof. Non-limiting exemplary scleroderma-relevant antigens may be derived from centromere C autoantigen protein (CENPC), DNA topoisomerase I (TOP1), and / or RNA polymerase III. Table 21. Peptide TOP1346-360 KERIANFKIEPPGLF TOP1420-434 QGSIKYIMLNPSSRI TOP1750-764 QREKFAWAIDMADED TOP1419-433 IQGSIKYIMLNPSSR TOP1591-605 YNASITLQQQLKELT TOP1695-709 EQLMKLEVQATDREE TOP1305-319 SQYFKAQTEARKQMS TOP1346-360 KERIANFKIEPPGLF TOP1419-433 IQGSIKYIMLNPSSR TOP1425-439 YIMLNPSSRIKGEKD TOP1614-628 KILSYNRANRAVAIL CENP-C297-311 KLIEDEFIIDESDQS Petition 870250027877, dated 07 / 04 / 2025, page 163 / 384 154 / 299 CENP-C857-871 KVYKTLDTPFFSTGK CENP-C887-901 QDILVFYVNFGDLLC CENP-C212-226 KVMLKKIEIDNKVSD CENP-C643-657 EDNIMTAQNVPLKPQ CENP-C832-846 TREIILMDLVRPQDT CENP-C167-181 TSVSQNVIPSSAQKR CENP-C246-260 RIRDSEYEIQRQAKK CENP-C846-860 TYQFFVKHGELKVYK CENP-C149-163 DEEFYLSVGSPSVLL CENP-C833-847 REIILMDLVRPQDTY CENP-C847-861 YQFFVKHGELKVYKT Antigens relevant to antiphospholipid syndrome

[00273] Antigens relevant to antiphospholipid syndrome include, without limitation, those disclosed in Table 22 below, as well as equivalents and / or combinations thereof. Non-limiting exemplary antigens relevant to antiphospholipid syndrome may be derived from beta-2 glycoprotein 1 (BG2P1 or APOH). Table 22. Peptide APOH235-249 HDGYSLDGPEEIECT APOH306-320 KCSYTEDAQCIDGTI APOH237-251 GYSLDGPEEIECTKL APOH295-309 KVSFFCKNKEKKCSY APOH28-42 DLPFSTVVPLKTFYE APOH173-187 ECLPQHAMFGNDTIT APOH264-278 CKVPVKKATVVYQGE APOH295-309 KVSFFCKNKEKKCSY APOH49-63 YSCKPGYVSRGGMRK APOH269-283 KKATVVYQGERVKIQ Petition 870250027877, dated 07 / 04 / 2025, page 164 / 384 155 / 299 APOH295-309 KVSFFCKNKEKKCSY APOH321-355 EVPKCFKEHSSLAFW APOH322-336 VPKCFKEHSSLAFWK APOH324-338 KCFKEHSSLAFWKTD Antigens relevant to ANCA-associated vasculitis

[00274] Antigens relevant to ANCA-associated vasculitis include, without limitation, those disclosed in Table 23 below, as well as equivalents and / or combinations thereof. Non-limiting examples of antigens relevant to ANCA-associated vasculitis may be derived from myeloperoxidase (MPO), proteinase (PRTN3), or bacterial permeability-enhancing factor (BPI). Table 23. Peptide MPO506-520 QPFMFRLDNRYQPME MPO302-316 RIKNQADCIPFFRSC MPO7-21 SSLRCMVDLGPCWAG MPO689-703 QQRQALAQISLPRII MPO248-262 RSLMFMQWGQLLDHD MPO444-458 QEARKIVGAMVQIIT MPO513-527 DNRYQPMEPNPRVPL MPO97-111 ELLSYFKQPVAATRT MPO616-630 QLGTVLRNLKLARKL MPO462-476 YLPLVLGPTAMRKYL MPO617-631 LGTVLRNLKLARKLM MPO714-728 KNNIFMSNSYPRDFV PRTN344-58 SLQMRGNPGSHFCGG PRTN3234-248 TRVALYVDWIRSTLR PRTN359-73 TLIHPSFVLTAAHCL PRTN3117-131 NDVLLIQLSSPANLS Petition 870250027877, dated 07 / 04 / 2025, page 165 / 384 156 / 299 PRTN3164-178 DPPAQVLQELNVTVV PRTN371-85 HCLRDIPQRLVNVVL PRTN3241-255 DWIRSTLRRVEAKGR PRTN359-73 TLIHPSFVLTAAHCL PRTN3183-197 RPHNICTFVPRRKAG PRTN362-76 HPSFVLTAAHCLRDI PRTN3118-132 DVLLIQLSSPANLSA PRTN3239-253 YVDWIRSTLRRVEAK Antigens relevant to stiff-person syndrome

[00275] Relevant antigens for stiff-person syndrome include, without limitation, those disclosed in Table 24 below, as well as equivalents and / or combinations thereof. Non-limiting exemplary antigens relevant to stiff-person syndrome may be derived from glutamate decarboxylase (GAD). In some embodiments, GAD includes, without limitation, GAD65. Table 24. Peptide GAD212-226 EYVTLKKMREIIGWP GAD555-569 NFFRMVISNPAATHQ GAD297-311 DSVILIKCDERGKMI

[00276] It is contemplated that, in the compositions of the revelation, there is between approximately 0.001 mg and approximately 10 mg of total protein per mL in the composition. Thus, the protein concentration in a composition can be approximately, at least approximately, or at most approximately 0.001, 0.010, 0.050, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 0.50, 100 pg / mL or mg / mL or more (or any derivable range between these values). Of these, approximately, at least approximately, or at most approximately 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, Petition 870250027877, dated 07 / 04 / 2025, pp. 166 / 384 157 / 299 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% can be formed by peptide / MHC / nanoparticle complex.

[00277] The present disclosure contemplates the administration of a peptide / MHC / nanoparticle complex to effect diagnosis, treatment or preventive therapy against the development of a disease or condition associated with autoimmune responses or cancer.

[00278] Furthermore, U.S. Patent No. 4,554,101 (Hopp), which is incorporated into this descriptive report by reference, teaches the identification and preparation of epitopes from primary amino acid sequences based on hydrophilicity. By means of the methods disclosed in Hopp, those skilled in the art would be able to identify potential epitopes from within an amino acid sequence and confirm their immunogenicity. Several scientific publications have also been devoted to the prediction of secondary structure and the identification of epitopes from amino acid sequence analyses (Chou and Fasman, 1974a,b; 1978a,b; 1979). Any of these may be used, if desired, to supplement the teachings of Hopp in U.S. Patent No. 4,554,101. Other antigenic components

[00279] Different peptide molecules can be used as antigens or antigenic fragments in complex with MHC molecules. These molecules include, but are not limited to, carbohydrates, lipids, small molecules, and the like. Carbohydrates are the main components of the outer surface of a variety of cells. Certain carbohydrates are characteristic of different stages of differentiation, and very often these carbohydrates are recognized by specific antibodies. The expression of distinct carbohydrates Petition 870250027877, dated 07 / 04 / 2025, page 167 / 384 158 / 299 may be restricted to specific cell types. Autoantibody responses to endometrial and serum antigens have been shown to be a common feature of endometriosis. A serum autoantibody response in endometriosis to several previously identified antigens, including Heremans Schmidt glycoprotein 2 and carbonic anhydrase, which is specific for a carbohydrate epitope, has been described. Exemplary, non-limiting antigen-MHC complexes

[00280] In certain modalities, specific combinations of antigen and MHC can be optimized for the treatment of a specific disease. Non-limiting examples include, without limitation, the following: For the treatment of type I diabetes, the pMHC complex antigen may be derived from an antigen of the following groups: PPI76-90 (k88s), IGRP13-25, GAD555-567, GAD555-567 (557I), IGRP23-35, B24-C36, PPI76-90, or a fragment or equivalent of each of these, and the pMHC complex MHC comprises all or part of a polypeptide of the following groups: HLA-DRB1*0401 / DRA, HLA-DRB1*0301 / DRA, or a fragment or equivalent of each of these.

[00281] In some embodiments, the pMHC complex antigen comprises: a) an antigen relevant to diabetes and is derived from an antigen selected from one or more of the following groups: preproinsulin (PPI), glucose-6-phosphatase-specific (IGRP), glutamate decarboxylase (GAD), islet cell autoantigen-2 (ICA2), insulin, proinsulin, or a fragment or equivalent of each of these; b) a multiple sclerosis-relevant antigen and is derived from an antigen selected from one or more of the following groups: myelin basic protein, myelin-associated glycoprotein, myelin oligodendrocyte protein, proteolipid protein, myelin oligodendrocyte oligoprotein, myelin-associated oligodendrocyte basic protein, protein Petition 870250027877, dated 07 / 04 / 2025, page 168 / 384 159 / 299 oligodendrocyte-specific, heat shock proteins, oligodendrocyte-specific proteins, NOGO A, Po glycoprotein, peripheral myelin protein 22, 2'3'-cyclic nucleotide 3'phosphodiesterase, or a fragment or equivalent of each of these; c) an antigen relevant to celiac disease and is derived from gliadin or a fragment or equivalent thereof; d) an antigen relevant to primary biliary cirrhosis and is derived from PDC-E2 or a fragment or equivalent thereof; (e) an antigen relevant to pemphigus foliaceus and / or an antigen relevant to pemphigus vulgaris and is derived from an antigen selected from one or more of the following groups: DG1, DG3, or a fragment or equivalent of each of these; f) an antigen relevant to a neuromyelitis optica spectrum disorder and is derived from AQP4 or a fragment or equivalent thereof; (g) an antigen relevant to arthritis and is derived from an antigen selected from one or more of the following groups: heat shock proteins, immunoglobulin-binding protein, heterogeneous nuclear RNPs, annexin V, calpastatin, type II collagen, glucose-6-phosphate isomerase, human cartilage elongation factor gp39, mannose-binding lectin, citrullinated vimentin, type II collagen, fibrinogen, alpha enolase, anti-carbamylated protein (anti-CarP), peptidyl arginine deiminase type 4 (PAD4), BRAF, fibrinogen gamma chain, inter-alpha-trypsin H1 heavy chain inhibitor, alpha-1 antitrypsin, plasma protease C1 inhibitor, gelsolin, alpha 1-B glycoprotein, ceruloplasmin, inter-alpha-trypsin H4 heavy chain inhibitor, complement factor H, alpha 2 macroglobulin, serum amyloid, protein C-reactive protein, serum albumin, beta-chain fibrinogen, serum transferrin, alpha 2 HS glycoprotein, vimentin, Complement C3,or a fragment or an equivalent of each of these; Petition 870250027877, dated 07 / 04 / 2025, page 169 / 384 160 / 299 h) an antigen relevant to allergic asthma and is derived from an antigen selected from one or more of the following groups: DERP-1, DERP-2, or a fragment or equivalent of each of these; i) an antigen relevant to inflammatory bowel disease and is derived from an antigen selected from one or more of the following groups: Flagellin, Fla-2, Fla-X, YIDX, Bacteroides integrase, or a fragment or equivalent of each of these; j) an antigen relevant to systemic lupus erythematosus and is derived from an antigen selected from one or more of the following groups: (ds)double-stranded DNA, ribonucleoprotein (RNP), Smith (Sm), Sjogren's syndrome-related antigen A (SS-A) / Ro, Sjogren's syndrome-related antigen B (SS-B) / La, RO60, RO52, histones, or a fragment or equivalent of each of these; k) an antigen relevant to atherosclerosis and is derived from an antigen selected from one or more of the following groups: ApoB, ApoE, or a fragment or equivalent of each of these; l) an antigen relevant to COPD and / or an antigen relevant to emphysema and is derived from elastin or a fragment or equivalent thereof; m) a psoriasis-relevant antigen and is derived from an antigen selected from one or more of the following groups: Cap18, ADMTSL5, ATL5, or a fragment or equivalent of each of these; n) an antigen relevant for autoimmune hepatitis and is derived from an antigen selected from one or more of the following groups: CYP2D6, SLA, or a fragment or equivalent of each of these; (o) an antigen relevant to uveitis and is derived from arrestin or a fragment or equivalent thereof; p) an antigen relevant to Sjögren's syndrome and is derived from an antigen selected from one or more of the following groups: (SSA) / Ro, (SS-B) / La, MR3, RO60, RO52, or a fragment or equivalent of each of these; q) an antigen relevant to scleroderma and is derived Petition 870250027877, dated 07 / 04 / 2025, page 170 / 384 161 / 299 of an antigen selected from one or more of the following groups: CENP-C, TOP 1, RNA polymerase III, or a fragment or equivalent of each of these; r) an antigen relevant to antiphospholipid syndrome and is derived from APOH or a fragment or equivalent thereof; s) an antigen relevant to ANCA-associated vasculitis and is derived from an antigen selected from one or more of the following groups: MPO, PRTN3, or a fragment or equivalent of each of these; or t) an antigen relevant to stiff-person syndrome and is derived from GAD or a fragment or equivalent thereof.

[00282] In some embodiments, the MHC protein of the pMHC complex comprises all or part of a classical class I MHC protein, a non-classical class I MHC protein, a classical class II MHC protein, a non-classical class II MHC protein, MHC dimers (Fc fusions), MHC tetramers, or a polymeric form of an MHC protein, wherein the MHC protein optionally comprises a knob-in-hole based MHC-alpha-Fc / MHC-beta-Fc heterodimer or multimer.

[00283] In some embodiments, the MHC protein of the pMHC complex comprises all or part of a polypeptide from the following groups: HLA DR, HLA DQ, HLA DP, HLA-A, HLA-B, HLA-C, HLA-E, HLAF, HLA-G, CD1d, or a fragment or equivalent of each of these.

[00284] In some embodiments, the MHC protein of the pMHC complex comprises all or part of a polypeptide from the group: HLA-DR, HLA-DQ, HLA-DP, or a fragment or an equivalent of each of these.

[00285] In some embodiments, the MHC protein of the pMHC complex comprises all or part of a polypeptide from the group: HLA-DRB1 / DRA, HLA-DRB3 / DRA, HLA-DRB4 / DRA, HLA-DRB5 / DRA, HLA-DQA1 / HLA-DQB1, HLA-DPB1 / HLA-DPA1, or a fragment or equivalent of each of these. Petition 870250027877, dated 07 / 04 / 2025, pp. 171 / 384 162 / 299

[00286] In certain respects, the pMHC complex comprises: a) a diabetes-relevant antigen derived from an antigen selected from one or more of the following groups: hInsB10-18, hIGRP228236, hIGRP265-273, IGRP206-214, hIGRP206-214, NRP-A7, NRP-I4, NRP-V7, YAI / Db, INS B15-23, PPI76-90 (K88S), IGRP13-25, GAD555-567, GAD555-567(557I), IGRP23-35, B24-C36, PPI76-90, INS-I9, TUM, G6Pase, ProinsulinL2-10, ProinsulinL3-11, ProinsulinL6-14, ProinsulinB5-14, Proinsulin B10-18, Proinsulin B14-22, Proinsulin B15-24, Proinsulin B17-25, Proinsulin B18-27, Proinsulin B20-27, Proinsulin B21-29, Proinsulin B25-C1, Proinsulin B27-C5, Proinsulin C20-28, Proinsulin C25-33, Proinsulin C29-A5, Proinsulin A1-10, Proinsulin A2-10, Proinsulin A12-20, or a fragment or equivalent of each of these; b) a multiple sclerosis-relevant antigen derived from an antigen selected from one or more of the following groups: MOG35-55, MOG3655, MAG287-295, MAG509-517, MAG556-564, MBP110-118, MOG114-122, MOG166-175, MOG172-180, MOG179-188, MOG188-196, MOG181-189, MOG205-214, PLP80-88, MAG287-295, MAG509-517, MAG556-564, MOG97-109 MOG97-109(E107S), MBP89-101, PLP175-192, PLP94108, MBP86-98, PLP54-68, PLP249-263, MOG156-170, MOG201-215, MOG38-52, MOG203217, PLP250-264, MPB13-32, MPB83-99, MPB111-129, MPB146-170, MOG223-237, MOG620, PLP88-102, PLP139-154, or a fragment or equivalent of each of these; c) a celiac disease relevant antigen derived from an antigen selected from one or more of the following groups: aGlia57-68, aGlia6272, aGlia217-229, or a fragment or equivalent of each of these; d) an antigen relevant to primary biliary cirrhosis derived from an antigen selected from one or more of the following groups: PDCE2122-135, PDC-E2249-262, PDC-E2249-263, PDC-E2629-643, PDC-E272-86, PDCE2353-367, PDC-E2422-436, PDC-E2629-643, PDC-E280-94, PDC-E2353-367, PDCE2535-549, or a fragment or equivalent of each of these; (e) a pemphigus foliaceus relevant antigen and / or a pemphigus vulgaris relevant antigen, each of which is Petition 870250027877, dated 07 / 04 / 2025, page 172 / 384 163 / 299 derived from an antigen selected from one or more of the following groups: DG1216-229, DG397-111, DG3251-265, DG3441-455, DG3351-365, DG3453-467, DG3540-554, DG3280-294, DG3326-340, DG3367-381, DG313-27, DG3323-337, DG3438-452, DG14862, DG1206-222, DG1363-377, DG13-17, DG1192-206, DG1326-340, DG11-15, DG135-49, DG1325-339, or a fragment or equivalent of each of these; f) an antigen relevant to a neuromyelitis optica spectrum disorder derived from an antigen selected from one or more of the following groups: AQP4129-143, AQP4284-298, AQP463-76, AQP4129-143, AQP439-53, or a fragment or equivalent of each of these; (g) an antigen relevant to allergic asthma derived from an antigen selected from one or more of the following groups: DERP-116-30, DERP-1171-185, DERP-1110-124, DERP-226-40, DERP-2107-121, or a fragment or equivalent of each of these; h) an antigen relevant to inflammatory bowel disease derived from an antigen selected from one or more of the following groups: Bacteroides integrase antigen 183-197, Bacteroides integrase antigen 146-160, Bacteroides integrase antigen 175-189, Bacteroides integrase antigen 1-15, Bacteroides integrase antigen 183-197, Bacteroides integrase antigen 30-44, Bacteroides integrase antigen 70-84, Bacteroides integrase antigen 337-351, Bacteroides integrase antigen 171-185, Bacteroides integrase antigen 4-18, Bacteroides integrase antigen 256-270, Fla-2 / Fla-X 366-380, Fla2 / Fla-X 164-178, Fla-2 / Fla-X261-275, Fla-2 / Fla-X1-15, Fla-2 / Fla-X51-65, Fla-2 / Fla-X269-283, Fla-2 / Fla-X4-18, Fla-2 / Fla-X271-285, YIDX78-92, YIDX93-107, YIDX98-112, YIDX23-37, YIDX78-92, YIDX195-209, YIDX22-36, YIDX8094, YIDX101-115, or a fragment or equivalent of each of these; i) a systemic lupus erythematosus relevant antigen derived from an antigen selected from one or more of the following groups: H471-94, H474-88, H476-90, H475-89, H478-92, H480-94, H2B10-24, H2B1630, H1z22-42, H1z27-41, or a fragment or equivalent of each of these; Petition 870250027877, dated 07 / 04 / 2025, pp. 173 / 384 164 / 299 j) an antigen relevant to atherosclerosis derived from an antigen selected from one or more of the following groups: ApoB3501-3516, ApoB1952-1966, ApoB978-993, ApoB3498-3513, ApoB210A, ApoB210B, ApoB210C, or a fragment or equivalent of each of these; k) a COPD-relevant antigen and / or an emphysema-relevant antigen, each of which is derived from an antigen selected from one or more of the following groups: elastin89-103, elastin698-712, elastin8-22, elastin94-108, elastin13-27, elastin695-709, elastin563-577, elastin558-572, elastin698-712, elastin566-580, elastin645-659, or a fragment or equivalent of each of these; l) a psoriasis-relevant antigen derived from an antigen selected from one or more of the following groups: Cap1864-78, Cap183448, Cap1847-61, Cap18151-165, Cap18149-163, Cap18152-166, Cap18131-145, Cap1824-38, ADMTSL5245-259, ADMTSL5267-281, ADMTSL5372-386, ADMTSL5289-303, ADMTSL5396-410, ADMTSL5433-447, ADMTSL5142-156, ADMTSL5236-250, ADMTSL5301315, ADMTSL5203-217, ADMTSL5404-418, or a fragment or equivalent of each of these; m) an antigen relevant to autoimmune hepatitis derived from an antigen selected from one or more of the following groups: (CYP2D6)193207, CYP2D676-90, CYP2D6293-307, CYP2D6313-332, CYP2D6393-412, CYP2D6199-213, CYP2D6450-464, CYP2D6301-315, CYP2D6452-466, CYP2D659-73, CYP2D6130-144, CYP2D6193-212, CYP2D6305-324, CYP2D6131-145, CYP2D6216-230, CYP2D6238-252, CYP2D6199-213, CYP2D6235-252, CYP2D6293-307, CYP2D6381-395, CYP2D6429-443, SLA334-348, SLA196-210, SLA115-129, SLA373-386, SLA186-197, SLA317-331, SLA171- 185, SLA417-431, SLA359-373, SLA215-229, SLA111-125, SLA110-124, SLA299-313, SLA342-356, SLA49-63, SLA119-133, SLA260-274, SLA26-40, SLA86-100, SLA331-345, or a fragment or equivalent of each of these; n) a uveitis-relevant antigen derived from an antigen selected from one or more of the following groups: arrestin 199-213, arrestin 77-91, arrestin 250-264, arrestin 172-186, arrestin 354-368, arrestin 239-253, arrestin 102-116, arrestin 59-73, arrestin 280-294, arrestin 291-306, arrestin 195-209, arrestin 200-214, or a fragment Petition 870250027877, dated 07 / 04 / 2025, pp. 174 / 384 165 / 299 or an equivalent of each of these; o) an antigen relevant to Sjögren's syndrome derived from an antigen selected from one or more of the following groups: RO60127-141, RO60523-537, RO60243-257, RO60484-498, RO60347-361, RO60369-383, RO60426-440, RO60267-281, RO60178-192, RO60358-372, RO60221-235, RO60318-332, RO60407-421, RO60459-473, RO6051-65, RO60312-326, LA241-255, LA101-115, LA153-167, LA178-192, LA19-33, LA37-51, LA133-147, LA50-64, LA32-46, LA153-167, LA83-97, LA136-150, LA297-311, LA59-73, LA151-165, LA86-100, LA154-168, or a fragment or equivalent of each of these; p) a scleroderma-relevant antigen derived from an antigen selected from one or more of the following groups: TOP1346-360, TOP1420434, TOP1750-764, TOP1419-433, TOP1591-605, TOP1695-709, TOP1305-319, TOP1346- 360, TOP1419-433, TOP1425-439, TOP1614-628, CENP-C297-311, CENP-C857-871, CENP-C887-901, CENP-C212-226, CENP-C643-657, CENP-C832-846, CENP-C167-181, CENP-C246-260, CENP-C846-860, CENP-C149-163, CENP-C833-847, CENP-C847-861, or a fragment or equivalent of each of these; q) an antigen relevant to antiphospholipid syndrome derived from an antigen selected from one or more of the following groups: APOH235-249, APOH306-320, APOH237-251, APOH295-309, APOH28-42, APOH173-187, APOH264-278, APOH295-309, APOH49-63, APOH269-283, APOH295-309, APOH321-355, APOH322-336, APOH324-338, or a fragment or equivalent of each of these; r) an antigen relevant for ANCA-associated vasculitis derived from an antigen selected from one or more of the following groups: MPO506-520, MPO302-316, MPO7-21, MPO689-703, MPO248-262, MPO444-458, MPO513-527, MPO97-111, MPO616-630, MPO462-476, MPO617-631, MPO714-728, PRTN344-58, PRTN3234-248, PRTN359-73, PRTN3117-131, PRTN3164-178, PRTN371-85, PRTN3241-255, PRTN359-73, PRTN3183-197, PRTN362-76, PRTN3118-132, PRTN3239-253, or a fragment or equivalent of each of these; or s) an antigen relevant to stiff-person syndrome derived from an antigen selected from one or more of the following groups: GAD212-226, GAD555-569, GAD297-311, or a fragment or equivalent of each of these. Petition 870250027877, dated 07 / 04 / 2025, page 175 / 384 166 / 299

[00287] In certain respects, the pMHC complex comprises: a) a diabetes-relevant antigen derived from an antigen selected from one or more of the following groups: hInsB10-18, hIGRP228236, hIGRP265-273, IGRP206-214, hIGRP206-214, NRP-A7, NRP-I4, NRP-V7, YAI / Db, INS B15-23, PPI76-90 (K88S), IGRP13-25, GAD555-567, GAD555-567(557I), IGRP23-35, B24-C36, PPI76-90, INS-I9, TUM, G6Pase, ProinsulinL2-10, ProinsulinL3-11, ProinsulinL6-14, ProinsulinB5-14, Proinsulin B10-18, Proinsulin B14-22, Proinsulin B15-24, Proinsulin B17-25, Proinsulin B18-27, Proinsulin B20-27, Proinsulin B21-29, Proinsulin B25-C1, Proinsulin B27-C5, Proinsulin C20-28, Proinsulin C25-33, Proinsulin C29-A5, Proinsulin A1-10, Proinsulin A2-10, Proinsulin A12-20, or a fragment or equivalent of each of these, and the MHC protein of the pMHC complex comprises all or part of HLA-DR or a fragment or equivalent thereof; b) a multiple sclerosis-relevant antigen derived from an antigen selected from one or more of the following groups: MOG35-55, MOG3655, MAG287-295, MAG509-517, MAG556-564, MBP110-118, MOG114-122, MOG166-175, MOG172-180, MOG179-188, MOG188-196, MOG181-189, MOG205-214, PLP80-88, MAG287-295, MAG509-517, MAG556-564, MOG97-109 MOG97-109(E107S), MBP89-101, PLP175-192, PLP94108, MBP86-98, PLP54-68, PLP249-263, MOG156-170, MOG201-215, MOG38-52, MOG203-217, PLP250-264, MPB13-32, MPB83-99, MPB111-129, MPB146-170, MOG223-237, MOG620, PLP88-102, PLP139-154, or a fragment or equivalent of each of these, and the MHC protein of the pMHC complex comprises all or part of HLA-DR or a fragment or equivalent thereof; c) a celiac disease-relevant antigen derived from an antigen selected from one or more of the following groups: aGlia57-68, aGlia6272, aGlia217-229, or a fragment or equivalent of each of these, and the MHC protein of the pMHC complex comprises all or part of HLA-DQ or a fragment or equivalent thereof; d) an antigen relevant for primary biliary cirrhosis derived from an antigen selected from one or more of the following groups: PDCE2122-135, PDC-E2249-262, PDC-E2249-263, PDC-E2629-643, PDC-E272-86, PDC Petition 870250027877, dated 07 / 04 / 2025, page 176 / 384 167 / 299 E2353-367, PDC-E2422-436, PDC-E2629-643, PDC-E280-94, PDC-E2353-367, PDCE2535-549, or a fragment or an equivalent of each of these, and the MHC protein of the pMHC complex comprises all or part of HLADR or a fragment of an equivalent thereof; (e) a pemphigus foliaceus relevant antigen and / or a pemphigus vulgaris relevant antigen, each of which is derived from an antigen selected from one or more of the following groups: DG1216-229, DG397-111, DG3251-265, DG3441-455, DG3351-365, DG3453-467, DG3540-554, DG3280-294, DG3326-340, DG3367-381, DG313-27, DG3323-337, DG3438-452, DG14862, DG1206-222, DG1363-377, DG13-17, DG1192-206, DG1326-340, DG11-15, DG135-49, DG1325-339, or a fragment or equivalent of each of these, and the MHC protein of the pMHC complex comprises all or part of HLADR or a fragment or equivalent thereof; f) an antigen relevant to a neuromyelitis optica spectrum disorder derived from an antigen selected from one or more of the following groups: AQP4129-143, AQP4284-298, AQP463-76, AQP4129-143, AQP439-53, or a fragment or equivalent of each of these, and the MHC protein of the pMHC complex comprises all or part of HLA-DR or a fragment or equivalent thereof; (g) an antigen relevant to allergic asthma derived from an antigen selected from one or more of the following groups: DERP-116-30, DERP-1171-185, DERP-1110-124, DERP-226-40, DERP-2107-121, or a fragment or equivalent of each of these, and the MHC protein of the pMHC complex comprises all or part of a polypeptide from the following groups: HLA-DR, HLA-DP, or a fragment or equivalent of each of these; h) an antigen relevant to inflammatory bowel disease derived from an antigen selected from one or more of the following groups: Bacteroides integrase antigen 183-197, Bacteroides integrase antigen 146-160, Bacteroides integrase antigen 175-189, Bacteroides integrase antigen 1-15, Bacteroides integrase antigen 183-197, Bacteroides integrase antigen 30-44, Bacteroides integrase antigen 70-84, Bacteroides integrase antigen 337-351, integrase antigen Petition 870250027877, dated 07 / 04 / 2025, page 177 / 384 168 / 299 of bacteroidsi7i-i85, bacteroids integrase antigen4-i8, bacteroids integrase antigen256-270, Fla-2 / Fla-X366-380, Fla2 / Fl...

Claims

1. A complex, characterized in that it comprises a nanoparticle core coupled, via a polyethylene glycol (PEG) ligand that is less than 5 kilodaltons in molecular weight, to a plurality of antigen-MHC class II (pMHCII) complexes, wherein the nanoparticle core comprises iron or iron oxide, and has a diameter of 5 nm to 25 nm; wherein the pMHCII complexes are coupled via a carboxy-terminal cysteine ​​to a maleimide-functionalized end of the PEG ligand, wherein the maleimide-functionalized end comprises an alkoxy, wherein the alkoxy comprises C1 to C3 alkyl; and wherein the PEG ligand further comprises a non-maleimide-functionalized end, wherein the non-maleimide-functionalized end is covalently coupled to the nanoparticle core; and where the number of coupled pMHCIIs per nanoparticle surface area is from 0.4 pMHC / 100 nm2 to 5 pMHC / 100 nm2,wherein the complex differentiates an activated T cell or a memory T cell into an IL-10-producing TR1 cell, and further wherein the pMHCII complex is selected from: PPI76-90(k88s)-HLA-DRB1*04 01 / DRA, IGRP-13-DRB1-DRB1*04 01 / DRA, 01 / DRA, GAD555-567-HLA-DRB1*0401 / DRA, GAD555-567(557i) -HLA-DRB1*0401 / DRA, IGRP23-35-HLA-DRB1*0401 / DRA, B24-C36-HLA-DRB1*0401 / DRA, B24-C36-HLA-DRB1*01 / 01 / DRA PPI76-90HLA-DRB1*0401 / DRA; or MBP86-98-HLA-DRB1*1501 / DRA, MBP89-1o1-HLA-DRB5*O1O1 / DRA, MOG3852-HLA-DRB4*0101 / DRA, MOG97-109(e107s)-HLA-DRB1*01 / DRA, 01 / DRA MOG203-217HLA-DRB3*0101 / DRA, PLP54-68-HLA-DRB3*0101 / DRA, PLP94-108-HLADRB1*0301 / DRA, PLP250-264-HLA-DRB4*0101 / DRA, MPB132-HRB3*0101 / DRA*RAD MPB83-99-HLA-DRB5*0101 / DRA, MPB111-129-HLADRB5*0101 / DRA, MPB146-170-HLA-DRB5*0101 / DRA, MOG223-237-HLADRB3*0202 / DRA, MOGLA6-HRA-DRB5*0101 / DRA PLP88-102-HLADRB3*0202 / DRA, and PLP139-154-HLA-DRB5*0101 / DRA; or Petition 870260040806, of 30 / 04 / 2026, p. 11 / 26 2 / 7 aGlia57-68-HLA-DQA1*0501 / HLA-DQB1*0201,aGlia62-72- HLADQA1*0501 / HLA-DQB1*0201, aGlia217-229- HLA-DQA1*0501 / HLADQB1*0302, e aGlia217-229-HLA-DQA1*03 / HLA-DQB1*0302; ou DG1216-229-HLA-DRB1*0101 / DRA, DG1216-229-HLA-DRB1*0102 / DRA, DG397-iii-HLA-DRB1*04 02 / DRA, DG3251-265-HLA-DRB1*04 02 / DRA, DG3251-265HLA-DRB1*0401 / DRA, DG3441-455-HLA-DRB1*0402 / DRA, DG3351-365-HLADRB3*0202 / DRA, DG3453-467-HLA-DRB3*0202 / DRA, DG3540-554-HLADRB3*0202 / DRA, DG3280-294-HLA-DRB4*0101 / DRA, DG3326-340-HLADRB4*0101 / DRA, DG3367-381-HLA-DRB4*0101 / DRA, DG313-27-HLADRB5*0101 / DRA, DG3323-337-HLA-DRB5*0101 / DRA, DG3438-452-HLADRB5*0101 / DRA, DG148-62-HLA-DRB3*0202 / DRA, DG1206-222-HLADRB3*0202 / DRA, DG1363-377-HLA-DRB3*0202 / DRA, DG13-17-HLADRB4*0101 / DRA DG1192-206-HLA-DRB4*0101 / DRA, DG1326-340-HLADRB4*0101 / DRA, DGii-15-HLA-DRB5*0101 / DRA, DG135-49-HLADRB5*0101 / DRA, e DG1325-339-HLA-DRB5*0101 / DRA; ou AQP4129-143-HLA-DRB1*0101 / DRA, AQP4284-298-HLA-DRB1*0301 / DRA, AQP463-76-HLA-DRB1*0301 / DRA, AQP4129-143-HLA-DRB1*0401 / DRA,e AQP439-53-HLA-DRB1*1501 / DRA; ou DERP-116-30-HLA-DRB1*0101 / DRA, DERP-116-30 -HLADRB1*1501 / DRA, DERP1171-185 — HLA-DRB1*1501 / DRA, DERP-Iiio-124 —HLADPB1*0401 / DRA, DERP-226-40 -HLA-DRB1*0101 / DRA; DERP-226-40-HLADRB1*1501 / DRA, and DERP-2107-121—HLA-DRB1*0301 / DRA; ou elastin89-103-HLA-DRB3*0101 / DRA, elastin698-712-HLADRB5*0101 / DRA, elastin8-22-HLA-DRB5*0101 / DRA, elastin94-108-HLADRB5*0101 / DRA, elastin13-27-HLA-DRB4*0101 / DRA, elastin695-709HLA-DRB4*0101 / DRA, elastin563-577-HLA-DRB4*0101 / DRA, elastin558572-HLA-DRB4*0101 / DRA, elastin566-580-HLA-DRB3*0202 / DRA, e elastin645-659-HLA-DRB3*0202 / DRA; or Cap1864-78-HLA-DRB3*0101 / DRA, Cap1834-48-HLA-DRB3*0101 / DRA, Cap1 847-61-HLA-DRB3*0101 / DRA, Cap18151-165-HLA -DRB4*0101 / DRA, Cap1 8149-163-HLA-DRB5*0101 / DRA, Cap1 8152-166-HLA-DRB5*0101 / DRA, Cap18131-145-HLA-DRB5*0101 / DRA, Cap1 824-38-HLA-DRB3*02 02 / DRA, ADMTSL5245-259-HLA-DRB3*0101 / DRA, ADMTSL5267-281-HLA-DRB3*0101 / DRA, Petition 870260040806, dated 30 / 04 / 2026,pág. 12 / 26 3 / 7 ADMTSL5372-386-HLA-DRB3*0101 / DRA, ADMTSL5396-4io-HLA-DRB4*O1O1 / DRA, ADMTSL5i42-i56-HLA-DRB5*0101 / DRA, ADMTSL5301-315-HLA-DRB5*0101 / DRA, ADMTSL5404-418-HLA-DRB3*02 02 / DRA ADMTSL5289-303-HLA-DRB4*0101 / DRA ADMTSL5433-447-HLA-DRB4*0101 / DRA ADMTSL5203-217-HLA-DRB3*02 02 / DRA e ADMTSL5433-447-HLA-DRB3*02 02 / DR ou CYP2D6193-207-HLA-DRB1*0301 / DRA, CYP2D676-90-HLADRB1*0301 / DRA, CYP2D6293-307-HLA-DRB1*0 301 / DRA, CYP2D6313-332-HLADRB1*0301 / DRA, CYP2D6393-412-HLA-DRB1*0 301 / DRA, CYP2D6199-213-HLADRB1*0401 / DRA, CYP2D6450-464-HLA-DRB1*0401 / DRA, CYP2D6301-315-HLADRB1*0401 / DRA, CYP2D6452-466-HLA-DRB1*0701 / DRA, CYP2D659-73-HLADRB1*0701 / DRA, CYP2D6130-144-HLA-DRB1*0701 / DRA, CYP2D6193-212-HLADRB1*0701 / DRA, CYP2D6305-324-HLA-DRB1*0701 / DRA, CYP2D6131-145-HLADRB3*0202 / DRA, CYP2D6216-230-HLA-DRB3*0202 / DRA CYP2D6238-252-HLADRB3*0202 / DRA, CYP2D6199-213-HLA-DRB4*0101 / DRA, CYP2D6235-252-HLADRB4*0101 / DRA, CYP2D6293-307-HLA-DRB4*0101 / DRA,CYP2D6238-252-HLADRB5*0101 / DRA, CYP2D6381-395-HLA-DRB5*0101 / DRA, CYP2D6429-443-HLADRB5*0101 / DRA, SLA334-348-HLA-DRB1*0 301 / DRA, SLA196-210-HLADRB1*0301 / DRA, SLA115-129-HLA-DRB1*0 301 / DRA, SLA373-386-HLADRB1*0301 / DRA, SLA186-197-HLA-DRB1*0 301 / DRA, SLA317-331-HLADRB1*0401 / DRA SLA171-185-HLA-DRB1*0401 / DRA, SLA417-431-HLADRB1*0401 / DRA, SLA359-373-HLA-DRB1*0701 / DRA, SLA215-229-HLADRB1*0701 / DRA, SLAiii-i25-HLA-DRB1*0701 / DRA, SLA110-124-HLADRB3*0202 / DRA, SLA299-313-HLA-DRB3*0202 / DRA, SLA342-356-HLADRB3*0202 / DRA, SLA49-63-HLA-DRB4*0101 / DRA, SLA119-133-HLADRB4*0101 / DRA SLA260-274-HLA-DRB4*0101 / DRA, SLA26-40-HLADRB5*0101 / DRA, SLA86-ioo-HLA-DRB5*O1O1 / DRA, e SLA331-345-HLADRB5*0101 / DRA; ou arrestina199-213-HLA-DRB3*0101 / DRA, arrestina77-91-HLADRB3*0101 / DRA, arrestina250-264-HLA-DRB3*0101 / DRA, arrestina172-186HLA-DRB4*0101 / DRA, arrestina354-368-HLA-DRB4*0101 / DRA, arrestina239-253-HLA-DRB4*0101 / DRA, arrestina102-116-HLADRB5*0101 / DRA, arrestina59-73-HLA-DRB5*0101arrestina280-294-HLA Petition 870260040806, de 30 / 04 / 2026, pag. 13 / 26 4 / 7 DRB5*0101, arrestina29i-306-HLA-DRB1*0 301 / DRA, arrestinai95-209-HLADRB3*0202 / DRA, arrestina199-213-HLA-DRB3*0202 / DRA, e arrestina200214-HLA-DRB3*0202 / DRA; ou RO60127-141-HLA-DRB1*0301 / DRA, RO60243-257-HLA-DRB1*03 01 / DRA, RO60347-361-HLA-DRB3*0101 / DRA, RO60426-440-HLA-DRB4*0101 / DRA, RO60178-192-HLA-DRB4*0101 / DRA, RO60358-372-HLA-DRB4*0101 / DRA, RO60221-235-HLA-DRB4*0101 / DRA, RO60318-332-HLA-DRB4*0101 / DRA, RO60523-537-HLA-DRB1*03 01 / DRA, RO60484-498-HLA-DRB3*0101 / DRA, RO60369-383-HLA-DRB3*0101 / DRA, RO60267-281-HLA-DRB4*0101 / DRA, RO60358-372-HLA-DRB5*0101 / DRA, RO60221-235-HLA-DRB5*0101 / DRA, RO60318-332-HLA-DRB5*0101 / DRA, RO60407-421-HLA-DRB4*0101 / DRA, RO60407-421-HLA-DQA1*0501 / HLA-DQB1*0201, RO60459-473-HLADRB4*0101 / DRA, RO6Ü459-473-HLA-DQA1*0501 / HLA-DQB1*02Ü1, RO60318-332HLA-DQA1*0501 / HLA-DQB1*0201, RO6051-65-HLA-DRB3*02 02 / DRA, RO60312326-HLA-DRB3*02 02 / DRA, RO60347-361-HLA-DRB3*02 02 / DRA,LA241-255-HLADRB1*0301 / DRA, DRB1*0301 / DRA, DRB3*0101 / DRA, DRB4*0101 / DRA, DRB4*0101 / DRA, DRB5*0101 / DRA, LA101-115-HLA-DRB1*0301 / DRA, LAi53-167-HLALA178-192-HLA-DRB3*0101 / DRA, LA19-33-HLALA37-51-HLA-DRB3*0101 / DRA, LA133-147-HLALA50-64-HLA-DRB4*0101 / DRA, LA32-46-HLALA153-167-HLA-DRB5*0101 / DRA, LA83-97-HLALA136-150-HLA-DRB5*0101 / DRA, LA297-311-HLADQA1*0501 / HLA-DQB1*02 01, LA59-73-HLA-DQA1*0501 / HLA-DQB1*02 01, LA59-73-HLA-DRB4*0101 / DRA, LA151-165-HLA-DQA1*0501 / HLA-DQB1*0201, LA151-165-HLA-DRB4*0101 / DRA, LA297-311-HLA-DRB4*0101 / DRA, LA50-64HLA-DRB3*0202 / DRA LA86-100-HLA-DRB3*0202 / DRA, e LA154-168-HLADRB3*0202 / DRA; ou TOP1346-360-HLA-DRB3*0101 / DRA, TOP1420-434-HLA-DRB3*0101 / DRA, TOP1750-764-HLA-DRB3*0101 / DRA, TOP1419-433-HLA-DRB4*0101 / DRA, TOP1591-605-HLA-DRB4*0101 / DRA, TOP1695-709-HLA-DRB4*0101 / DRA, TOP1305-319-HLA-DRB5*0101 / DRA, TOP1346-360-HLA-DRB5*0101 / DRA, TOP1419-433-HLA-DRB5*0101 / DRA TOP1420-434-HLA-DRB3*02 02 / DRA, TOP1425-439-HLA-DRB3*02 02 / DRA, TOP1614-628-HLA-DRB3*02 02 / DRA,CENPC297-311-HLA-DRB3*0101 / DRA, CENP-C857-871-HLA-DRB3*0101 / DRA, CENPpetição 870260040806, on 04 / 30 / 2026, p. 14 / 26 5 / 7 C887-90i-HLA-DRB3*0101 / DRA, CENP-C212-226-HLA-DRB4*0101 / DRA, CENPC643-657-HLA-DRB4*0101 / DRA, CENP-C832-846-HLA-DRB4*0101 / DRA, cenpC167-181-HLA-DRB5*0101 / DRA, CENP-C246-260-HLA-DRB5*0101 / DRA, CENPC846-860-HLA-DRB5*0101 / DRA, CENP-C149-163-HLA-DRB3*02 02 / DRA, CENPC833-847-HLA-DRB3*0202 / DRA, e CENP-C847-861-HLA-DRB3*02 02 / DRA; au APOH235-249-HLA-DRB3*0101 / DRA, APOH306-320-HLA-DRB3*0101 / DRA, APOH237-251-HLA-DRB3*0101 / DRA, APOH295-309-HLA-DRB3*0101 / DRA, APOH2842-HLA-DRB4*0101 / DRA, APOH173-187-HLA-DRB4*0101 / DRA, APOH264-278HLA-DRB4*0101 / DRA, APOH295-309-HLA-DRB4*0101 / DRA, APOH49-63-HLADRB5*0101 / DRA, APOH269-283-HLA-DRB5*0101 / DRA, APOH295-309-HLADRB5*0101 / DRA, APOH321-355-HLA-DRB3*0202 / DRA, APOH322-336-HLADRB3*0202 / DRA, e APOH324-338-HLA-DRB3*0202 / DRA; ou MPO50 6-520-HLA-DRB3*0101 / DRA, MPO302-316-HLA-DRB3*0101 / DRA, MPO7-21-HLA-DRB3*0101 / DRA, MPO689-703-HLA-DRB4*0101 / DRA,MPO248-262HLA-DRB4*0101 / DRA, MPO444-458-HLA-DRB4*0101 / DRA, MPO513-527-HLADRB5*0101 / DRA, MPO97-111-HLA-DRB5*0101 / DRA, MPO616-630-HLADRB5*0101 / DRA, MPO462-476-HLA-DRB3*02 02 / DRA, MPO617-631-HLADRB3*0202 / DRA, MPO714-728-HLA-DRB3*0202 / DRA, PRTN344-58-HLADRB3*0101 / DRA, PRTN3234-248-HLA-DRB3*0101 / DRA, PRTN359-73-HLA DRB3*0101 / DRA, PRTN359-73-HLA-DRB5*0101 / DRA, PRTN3117-131-HLADRB4*0101 / DRA, PRTN3164-178-HLA-DRB4*0101 / DRA, PRTN371-85-HLADRB4*0101 / DRA, PRTN3241-255-HLA-DRB5*0101 / DRA, PRTN3183-197-HLADRB5*0101 / DRA, PRTN362-76-HLA-DRB3*0202 / DRA, PRTN3118-132-HLADRB3*0202 / DRA, and PRTN3239-253-HLA-DRB3*0202 / DRA; or GAD212-226-HLA-DRB1*0801 / DRA, GAD555-569-HLA-DRB1*0801 / DRA, and GAD297-311-HLA-DRB1*03 01 / DRA., 2. The complex of claim 1, wherein the number of coupled pMHCIIs per nanoparticle surface area is from 0.4 pMHC / 100 nm2 to 1.3 pMHC / 100 nm2.

3. Complex, according to claim 1, characterized in that the number of coupled pMHCIIs per nanoparticle surface area is from 0.5 pMHC / 100 nm2 to 0.9 pMHC / 100 nm2.

4. Complex, according to claim 1, characterized in that the diameter of the nanoparticle core is from 15 nm to 25 nm.

5. Complex, according to claim 1, characterized in that the pMHCIIs are covalently coupled to the nanoparticle core through the formation of a carbon-sulfur bond between the thiol group (-SH) of the cysteine ​​residue added to the carboxy terminus of the pMHCIIs and maleimide.

6. Complex, according to claim 1, characterized in that the IL-10-producing TR1 cell expresses CD49b.

7. Pharmaceutical composition, characterized in that it comprises the complex, as defined in claim 1, and a biocompatible excipient.

8. Use of the complex, as defined in any one of claims 1 to 6, characterized by being in the manufacture of a medicament for the treatment of prediabetes, multiple sclerosis, allergic asthma, cirrhosis, neuromyelitis optica spectrum disorder (Devic's disease, NMO), autoimmune encephalitis, autoantibody-mediated neurological syndromes, stiff-person syndrome, paraneoplastic disease, other diseases of the central and peripheral nervous systems, pemphigus vulgaris, arthritis, rheumatoid arthritis, systemic lupus erythematosus (SLE), celiac disease, psoriasis, alopecia areata, acquired thrombocytopenic purpura, autoimmune cardiomyopathy, idiopathic dilated cardiomyopathy (IDCM), myasthenia gravis, uveitis, ankylosing spondylitis, Graves' disease, Hashimoto's thyroiditis, immune-mediated myopathies, antiphospholipid syndrome (ANCA+), atherosclerosis, scleroderma, autoimmune hepatitis, dermatomyositis, chronic obstructive pulmonary disease, spinal cord injury, traumatic injury,Tobacco-induced lung destruction, chronic obstructive pulmonary disease (COPD), pulmonary emphysema, sclerosing cholangitis, peripheral neuropathy, narcolepsy, Goodpasture's syndrome, Kawasaki disease, autoimmune uveitis, colitis, emphysema, pemphigus, pemphigus foliaceus, Sjögren's syndrome, ANCA-associated vasculitis, relevant antigen for primary sclerosing cholangitis, adipose tissue inflammation / type II diabetes, or obesity associated with adipose tissue inflammation / insulin resistance.

9. Use of the pharmaceutical composition, as defined in claim 7, characterized by being in the manufacture of a medicament for the treatment of prediabetes, multiple sclerosis, allergic asthma, cirrhosis, neuromyelitis optica spectrum disorder (Devic's disease, NMO), autoimmune encephalitis, autoantibody-mediated neurological syndromes, stiff-person syndrome, paraneoplastic disease, other diseases of the central and peripheral nervous systems, pemphigus vulgaris, arthritis, rheumatoid arthritis, systemic lupus erythematosus (SLE), celiac disease, psoriasis, alopecia areata, acquired thrombocytopenic purpura, autoimmune cardiomyopathy, idiopathic dilated cardiomyopathy (IDCM), myasthenia gravis, uveitis, ankylosing spondylitis, Graves' disease, Hashimoto's thyroiditis, immune-mediated myopathies, antiphospholipid syndrome (ANCA+), atherosclerosis, scleroderma, autoimmune hepatitis, dermatomyositis, chronic obstructive pulmonary disease, spinal cord injury, traumatic injury,Tobacco-induced lung destruction, chronic obstructive pulmonary disease (COPD), pulmonary emphysema, sclerosing cholangitis, peripheral neuropathy, narcolepsy, Goodpasture's syndrome, Kawasaki disease, autoimmune uveitis, colitis, emphysema, pemphigus, pemphigus foliaceus, Sjögren's syndrome, ANCA-associated vasculitis, antigen relevant to primary sclerosing cholangitis, adipose tissue inflammation / type II diabetes, or obesity associated with adipose tissue inflammation / insulin resistance.

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