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Design of high-affinity binders to immune modulating receptors for cancer immunotherapy

Yang, Wei, Hicks, Derrick R., Ghosh, Agnidipta, Schwartze, Tristin A., Conventry, Brian, Goreshnik, Inna, Allen, Aza, Halabiya, Samer F., Kim, Chan Johng, Hinck, Cynthia S., Lee, David S., Bera, Asim K., Li, Zhe, Wang, Yujia, Schlichthaerle, Thomas, Cao, Longxing, Huang, Buwei, Garrett, Sarah, Gerben, Stacey R., Rettie, Stephen, Heine, Piper, Murray, Analisa, Edman, Natasha, Carter, Lauren, Stewart, Lance, Almo, Steven C., Hinck, Andrew P., Baker, David·2025·Nature Communications
DOI 10.1038/s41467-025-57192-zPMC PMC11865580
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Abstract

Immune receptors have emerged as critical therapeutic targets for cancer immunotherapy. Designed protein binders can have high affinity, modularity, and stability and hence could be attractive components of protein therapeutics directed against these receptors, but traditional Rosetta based protein binder methods using small globular scaffolds have difficulty achieving high affinity on convex targets. Here we describe the development of helical concave scaffolds tailored to the convex target sites typically involved in immune receptor interactions. We employed these scaffolds to design proteins that bind to TGFβRII, CTLA-4, and PD-L1, achieving low nanomolar to picomolar affinities and potent biological activity following experimental optimization. Co-crystal structures of the TGFβRII and CTLA-4 binders in complex with their respective receptors closely match the design models. These designs should have considerable utility for downstream therapeutic applications.

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Fig. 1 Design of 5HCS scaffolds to target convex interfaces on immunoglobulin-like targets. a Convex interfaces on Ig fold immune receptors. Receptors and corresponding partners are shown in purple and green cartoons, respectively. spherical surfaces fitted from interfacial heavy atoms on receptors are shown as blue transparent spheres. i, CTLA-4/CD86 complex, PDB ID: 1I85; ii, TGFβRII/TGFβ−3 complex, PDB ID: 1KTZ; iii, PD-1/PD-L1 complex, PDB ID: 3BIK;iv, TIGIT/CD112 complex, PDB ID: 5V52; v, LAG3/LAG3-antibody complex, PDB ID: 7TZH. b Design workflow. Column 1: 5HCS concave scaffolds with a wide range of curvatures were designed with three helices (blue) forming the concave surfaces (Cbeta labeled as spheres) and two helices (orange) buttressing at the backside. Column 2: Docking of 5HCS scaffolds to target binding sites. Column 3: Following docking, the interface sequencing is optimized for high-affinity binding.
Fig. 1 Design of 5HCS scaffolds to target convex interfaces on immunoglobulin-like targets. a Convex interfaces on Ig fold immune receptors. Receptors and corresponding partners are shown in purple and green cartoons, respectively. spherical surfaces fitted from interfacial heavy atoms on receptors are shown as blue transparent spheres. i, CTLA-4/CD86 complex, PDB ID: 1I85; ii, TGFβRII/TGFβ−3 complex, PDB ID: 1KTZ; iii, PD-1/PD-L1 complex, PDB ID: 3BIK;iv, TIGIT/CD112 complex, PDB ID: 5V52; v, LAG3/LAG3-antibody complex, PDB ID: 7TZH. b Design workflow. Column 1: 5HCS concave scaffolds with a wide range of curvatures were designed with three helices (blue) forming the concave surfaces (Cbeta labeled as spheres) and two helices (orange) buttressing at the backside. Column 2: Docking of 5HCS scaffolds to target binding sites. Column 3: Following docking, the interface sequencing is optimized for high-affinity binding.CC BY · PubMed Central
Fig. 2 Concave 5HCS binder to TGFβRII. a Left: Design model of 5HCS_TGFBR2_1 (cartoon) binding to TGFβRII (PDB ID: 1KTZ). 5HCS_TGFBR2_1 is colored by Shannon entropy from the site saturation mutagenesis results at each position in blue (low entropy, conserved) to red (high entropy, not conserved). Right: Biolayer interferometry characterization of 5HCS_TGFBR2_1. Biotinylated TGFβRII were loaded to Streptavidin (SA) tips and incubated with 2.7 nM, 0.9 nM, and 0.3 nM of 5HCS_TGFBR2_1 to measure the binding affinity. The binding responses are shown in solid lines and fitted curves are shown in dotted lines. b Circular dichroism spectra from 25 °C to 95 °C for 5HCS_TGFBR2_1. c Crystal structure of 5HCS_TGFBR2_1 in complex with TGFβRII. Left are top and side views of the crystal (blue and gray) superimposed on the design models (green and white). In the middle, TGFβRII is shown in surface view and colored by electrostatic potential (using ChimeraX; red negative, blue positive). On the right, detailed interactions between 5HCS_TGFBR2_1 (blue, green) and TGFβRII (gray, white) are shown. d Heat map of the log enrichments for the 5HCS_TGFBR2_1 SSM library selected with 1.6 nM TGFβRII at representative positions. Enriched mutations are shown in red and depleted in blue. The annotated amino acid in each column indicates the residue from the parent sequence. e Dose-dependent inhibition of TGF-β3 (10 pM) signaling in HEK293 cells. The mean values were calculated from triplicates for the cell signaling inhibition assays measured in parallel, and error bars represent standard deviations. IC50 values were fitted using four-parameter logistic regression by Python scripts. Source data (a, b, e) are provided in the Source Data file.
Fig. 2 Concave 5HCS binder to TGFβRII. a Left: Design model of 5HCS_TGFBR2_1 (cartoon) binding to TGFβRII (PDB ID: 1KTZ). 5HCS_TGFBR2_1 is colored by Shannon entropy from the site saturation mutagenesis results at each position in blue (low entropy, conserved) to red (high entropy, not conserved). Right: Biolayer interferometry characterization of 5HCS_TGFBR2_1. Biotinylated TGFβRII were loaded to Streptavidin (SA) tips and incubated with 2.7 nM, 0.9 nM, and 0.3 nM of 5HCS_TGFBR2_1 to measure the binding affinity. The binding responses are shown in solid lines and fitted curves are shown in dotted lines. b Circular dichroism spectra from 25 °C to 95 °C for 5HCS_TGFBR2_1. c Crystal structure of 5HCS_TGFBR2_1 in complex with TGFβRII. Left are top and side views of the crystal (blue and gray) superimposed on the design models (green and white). In the middle, TGFβRII is shown in surface view and colored by electrostatic potential (using ChimeraX; red negative, blue positive). On the right, detailed interactions between 5HCS_TGFBR2_1 (blue, green) and TGFβRII (gray, white) are shown. d Heat map of the log enrichments for the 5HCS_TGFBR2_1 SSM library selected with 1.6 nM TGFβRII at representative positions. Enriched mutations are shown in red and depleted in blue. The annotated amino acid in each column indicates the residue from the parent sequence. e Dose-dependent inhibition of TGF-β3 (10 pM) signaling in HEK293 cells. The mean values were calculated from triplicates for the cell signaling inhibition assays measured in parallel, and error bars represent standard deviations. IC50 values were fitted using four-parameter logistic regression by Python scripts. Source data (a, b, e) are provided in the Source Data file.CC BY · PubMed Central
Fig. 3 Designed 5HCS CTLA-4 binder. a Left: Model of 5HCS_CTLA4_1 (cartoon) binding to CTLA-4 (PDB ID:1l85) colored by Shannon entropy from site saturation mutagenesis results. Right: Log enrichments for the 5HCS_CTLA4_1 SSM library selected with 10 nM CTLA-4 at representative positions. The annotated amino acid in each column indicates the residue from the parent sequence. b Biolayer interferometry characterization of 5HCS_CTLA4_1. Biotinylated CTLA-4 was loaded to Streptavidin (SA) tips, and these were incubated with 2.7 nM, 0.9 nM, and 0.3 nM of 5HCS_CTLA4_1 to measure the binding affinity. c Crystal structure of 5HCS_CTLA4_1 in complex with CTLA-4. Color schemes are the same as Fig. 2c. Designed interactions between 5HCS_CTLA4_1 (green) and CTLA-4 (white). d Circular dichroism spectra from 25 °C to 95 °C for 5HCS_CTLA4_1. Color schemes and experimental details are as in Fig. 2b. e Increase of TCR activation induced signal (via NFAT pathway) from engineered CTLA-4 effector cells lines by 5HCS_CTLA4_1 (green), lpilimumab (gold), and 5HCS_CTLA4_1_c6 (blue) is shown. EC50 values were fitted using four-parameter logistic regression by Python scripts. Source data (b, d, e) are provided in the Source Data file.
Fig. 3 Designed 5HCS CTLA-4 binder. a Left: Model of 5HCS_CTLA4_1 (cartoon) binding to CTLA-4 (PDB ID:1l85) colored by Shannon entropy from site saturation mutagenesis results. Right: Log enrichments for the 5HCS_CTLA4_1 SSM library selected with 10 nM CTLA-4 at representative positions. The annotated amino acid in each column indicates the residue from the parent sequence. b Biolayer interferometry characterization of 5HCS_CTLA4_1. Biotinylated CTLA-4 was loaded to Streptavidin (SA) tips, and these were incubated with 2.7 nM, 0.9 nM, and 0.3 nM of 5HCS_CTLA4_1 to measure the binding affinity. c Crystal structure of 5HCS_CTLA4_1 in complex with CTLA-4. Color schemes are the same as Fig. 2c. Designed interactions between 5HCS_CTLA4_1 (green) and CTLA-4 (white). d Circular dichroism spectra from 25 °C to 95 °C for 5HCS_CTLA4_1. Color schemes and experimental details are as in Fig. 2b. e Increase of TCR activation induced signal (via NFAT pathway) from engineered CTLA-4 effector cells lines by 5HCS_CTLA4_1 (green), lpilimumab (gold), and 5HCS_CTLA4_1_c6 (blue) is shown. EC50 values were fitted using four-parameter logistic regression by Python scripts. Source data (b, d, e) are provided in the Source Data file.CC BY · PubMed Central
Fig. 4 Designed 5HCS binder to PD-L1. a Biophysical Characterization of 5HCS_PDL1_1. Left: Model of 5HCS_PDL1_1 (cartoon) binding to PD-L1 (PDB ID: 3BIK), with 5HCS_PDL1_1 colored by Shannon entropy from site saturation mutagenesis results. Middle: Biolayer interferometry characterization of 5HCS_PDL1_1. Biotinylated PD-L1 was loaded to Streptavidin (SA) tips, and these were incubated with 8 nM, 2.7 nM, and 0.9 nM of 5HCS_PDL1_1 to measure the binding affinity. Right: Circular dichroism spectra from 25 °C to 95 °C for 5HCS_PDL1_1. b Heat map representing the log enrichments for the 5HCS_PDL1_1 SSM library selected with 6 nM PD-L1 at representative positions. The annotated amino acid in each column indicates the residue from the parent sequence. c Unbound crystal structure of 5HCS_PDL1_1 and designed interactions between 5HCS_PDL1_1 (green) and PD-L1 (white). Color schemes are the same as Fig. 2. d WT A431 (green) and PD-L1 KO A431 (gold) cell lines were stained with fluorophore-labeled 5HCS_PDL1_1 and anti-PD-L1 antibody respectively and then analyzed through FACS. The comparison between anti-PD-L1 vs. A431 WT and Unstain A431 WT resulted in a significance level with p = 2.874 × 10−4. The 5HCS_PDL1_1 vs. A431 and Unstain A431 WT comparison yielded a significant p-value of p = 4.269 × 10−2. A431 WT samples were tested in two wells, and A431 KO samples in four wells, with 5000 cells per well, ensuring reproducibility and statistical reliability. ns, no significance, *P < 0.05, and ***P < 0.001. (t test independent samples with Bonferroni correction). Bars, mean ± SEM. e The increase of TCR activation induced signal (via NFAT pathway) from engineered PD-1 effector cell lines by 5HCS_PDL1_1 (green), control antibody (gold) is shown. The mean values were calculated from triplicates for the cell signaling inhibition assays measured in parallel, and error bars represent standard deviations. Color schemes and experimental details are as in Fig. 3. Source data (a, d, e) are provided in the Source Data file.
Fig. 4 Designed 5HCS binder to PD-L1. a Biophysical Characterization of 5HCS_PDL1_1. Left: Model of 5HCS_PDL1_1 (cartoon) binding to PD-L1 (PDB ID: 3BIK), with 5HCS_PDL1_1 colored by Shannon entropy from site saturation mutagenesis results. Middle: Biolayer interferometry characterization of 5HCS_PDL1_1. Biotinylated PD-L1 was loaded to Streptavidin (SA) tips, and these were incubated with 8 nM, 2.7 nM, and 0.9 nM of 5HCS_PDL1_1 to measure the binding affinity. Right: Circular dichroism spectra from 25 °C to 95 °C for 5HCS_PDL1_1. b Heat map representing the log enrichments for the 5HCS_PDL1_1 SSM library selected with 6 nM PD-L1 at representative positions. The annotated amino acid in each column indicates the residue from the parent sequence. c Unbound crystal structure of 5HCS_PDL1_1 and designed interactions between 5HCS_PDL1_1 (green) and PD-L1 (white). Color schemes are the same as Fig. 2. d WT A431 (green) and PD-L1 KO A431 (gold) cell lines were stained with fluorophore-labeled 5HCS_PDL1_1 and anti-PD-L1 antibody respectively and then analyzed through FACS. The comparison between anti-PD-L1 vs. A431 WT and Unstain A431 WT resulted in a significance level with p = 2.874 × 10−4. The 5HCS_PDL1_1 vs. A431 and Unstain A431 WT comparison yielded a significant p-value of p = 4.269 × 10−2. A431 WT samples were tested in two wells, and A431 KO samples in four wells, with 5000 cells per well, ensuring reproducibility and statistical reliability. ns, no significance, *P < 0.05, and ***P < 0.001. (t test independent samples with Bonferroni correction). Bars, mean ± SEM. e The increase of TCR activation induced signal (via NFAT pathway) from engineered PD-1 effector cell lines by 5HCS_PDL1_1 (green), control antibody (gold) is shown. The mean values were calculated from triplicates for the cell signaling inhibition assays measured in parallel, and error bars represent standard deviations. Color schemes and experimental details are as in Fig. 3. Source data (a, d, e) are provided in the Source Data file.CC BY · PubMed Central

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Authors
Yang, W., Hicks, D. R., Ghosh, A., Schwartze, T. A., Conventry, B., Goreshnik, I., Allen, A., Halabiya, S. F., Kim, C. J., Hinck, C. S., Lee, D. S., Bera, A. K., Li, Z., Wang, Y., Schlichthaerle, T., Cao, L., Huang, B., Garrett, S., Gerben, S. R., Rettie, S., Heine, P., Murray, A., Edman, N., Carter, L., Stewart, L., Almo, S. C., Hinck, A. P., & Baker, D.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-02-26
Volume
16
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-025-57192-z
PMC
PMC11865580
Cited by
40
References
11
Language
en
Licence
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (R01AG063845, U19AG065156)
  • United States Department of Defense | Defense Advanced Research Projects Agency (HR001120S0052, HR001117S0003)
  • Gates Ventures;Audacious Project;Open Philanthropy Project Improving Protein Design Fund;Howard Hughes Medical Institute

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