Slide 1: Leveraging Evolutionary Distance for the Discovery of Ultralong CDRH3 Antibodies with Broad Epitope Coverage
1 Leveraging Evolutionary Distance for the Discovery of Ultralong CDRH3 Antibodies with Broad Epitope Coverage AETC: Tuesday, December 16, 2025 Scientific Briefing #5: 12:35-1:05pm
Slide 2: OmniAb Enables Innovative Antibody Therapeutics
2 OmniAb Enables Innovative Antibody Therapeutics AS OF 9/30/2025 Overview Clinical and Commercial-Stage Partner Pipeline(1) Phase Phase 1 Phase 1 1/1b Phase 1/2 1/2 Phase 2 Phase 3 Registration Approved 1/1b 104 Zhikang Hongyi Cessation Zhikang Hongyi Gloria Merck KGaA Genmab Hanall, Harbour, Immun
Slide 3: OmniAb Technologies
3 OmniAb Technologies TECHNOLOGY OFFERINGS ADDRESSES THE MOST CRITICAL CHALLENGES OF ANTIBODY DISCOVERY Create Screen Deliver Create Diverse Repertoires of Screen Millions of Cells to Find Further Characterize, Select and Optimize High-Quality Antibodies Potential Therapeutic Candidates the Right Th
Slide 4: Alternative Antibody Formats are Found in Nature
4 Alternative Antibody Formats are Found in Nature AROSE INDEPENDENTLY DURING EVOLUTION Human Chicken Camelid Cow Proportion Conventional Antibody Heavy-Chain Only Standard Ultralong (UL) (Heavy x Light) (no light chain) CDRH3 CDRH3 Flajnik et al. PLOS Biology 2011
Slide 5: Ultralong CDRH3s Create Novel Binding Domains
5 Ultralong CDRH3s Create Novel Binding Domains CDRH3 HIV gp120 knob glycans Human Cow Novel structure may enable targeting epitopes unreachable by standard antibodies VL VH Stanfield et al, Sci Adv 2020
Slide 6: Binding Domains of Antibody-Based Biologics
6 Binding Domains of Antibody-Based Biologics Fv VHH, VNAR Ultralong CDRH3 25 kDa 15 kDa 4-6 kDa Species OmniAb Platforms Cow antibody “knob” or "picobody™" is the smallest independent antigen binding domain
Slide 7: Chicken Platforms - Powered by Evolution
7 Chicken Platforms - Powered by Evolution GREATER EVOLUTIONARY DISTANCE YIELDS GREATER IMMUNOGENICITY AND MORE ANTIBODY DIVERSITY PRIMORDIAL TARGET GENE HUMAN ORTHOLOG MAMMALIAN LINEAGE Early form of gene prior to avian/mammalian 300 MILLION ~95 MILLION evolutionary split YEARS AGO YEARS AGO AVIAN
Slide 8: The Chicken Advantage - Chickens Can "See More"
8 The Chicken Advantage - Chickens Can "See More" DIFFERENTIAL RECOGNITION: CHICKEN ORTHOLOGS ARE MORE DISPARATE THAN MAMMALIAN 95% identity 65% identity vs. vs. Example of a highly Amino acid differences conserved multi-spanning relative to human are transmembrane protein highlighted (SLC2A4) Chick
Slide 9: Why Use a Transgenic Chicken to Produce UL CDRH3s?
9 Why Use a Transgenic Chicken to Produce UL CDRH3s? EVOLUTIONARY DISTANCE, PRACTICAL EFFICIENCIES, AND WORKFLOW OPTIONALITY HUMAN ORTHOLOG OF THERAPEUTIC TARGET PROTEIN BOVINE ORTHOLOG CHICKEN ORTHOLOG (Cow) (Chicken) • Mammalian host • Evolutionarily distant host • Bovine framework • Human framewo
Slide 10: OmniUltra - The Ultralong CDRH3 Transgenic Chicken
10 OmniUltra™ - The Ultralong CDRH3 Transgenic Chicken VL AND ULTRALONG VH TRANSGENES DESIGNED WITH HUMAN V FRAMEWORKS Ultralong CDRH3 (knob): antigen-binding VH L1 H2 L3 L2 H1 Stabilized human VL VH/VL framework to support stalk-knob Constant Regions: chicken CH, human CL
Slide 11: OmniUltra Transgene Design
11 OmniUltra™ Transgene Design CHICKENS ENGINEERED FOR GENE CONVERSION OF ULTRALONG SEQUENCES Functional V knob UL CDRH3 stalk Pseudogenes Pseudogenes Functional V etc. (16 total) Stanfield, et al. (2016) Science Immunology: 1(1) Stanfield, et al. (2020) Sci Adv: 6
Slide 12: Immunogenicity Assessment of Transgene Design
12 Immunogenicity Assessment of Transgene Design EPIVAX ANALYSIS OF POTENTIAL PSEUDOGENES OmniUltra™ pseudogenes predicted to have low immunogenic potential
Slide 13: B Cell Development is Robust in OmniUltra
13 B Cell Development is Robust in OmniUltra NORMAL B AND T CELL FREQUENCIES IN PBMC B-cells IgM TCR1 TCR2/3 WT Chicken Robust B cell populations are produced in OmniUltra™ transgenic birds
Slide 14: Total Serum Antibody Titers
14 Total Serum Antibody Titers OmniUltra™ chickens express IgM and IgY antibodies Naïve birds at 6 weeks of age
Slide 15: Ultralong CDRH3 Produced in OmniUltra
15 Ultralong CDRH3 Produced in OmniUltra WESTERN BLOT OF SERUM IMMUNOGLOBULIN WT OmniUltra™ UL CDRH3: ~4-6 kDa UL IgY (63 kDa) WT IgY (58 kDa) IgY Light chain (25 kDa) WT IgM UL IgM (66 kDa) WT IgM (61 kDa) Ultralong CDRH3 is produced in class-switched serumNaïve immunoglobulin birds at 6 weeks of a
Slide 16: Naïve Repertoire Diversified by Gene Conversion
16 Naïve Repertoire Diversified by Gene Conversion NGS ANALYSIS OF NAÏVE REPERTOIRE # Total CDRH3 # CDRH3 w/ germline seq # CDRH3 w/ gene conversion # CDRH3 w/ pseudogene ID 346,458 20,790 (6%) 325,668 (94%) 320,167 (92%) All pseudogenes participate in gene conversion of ultralong CDRH3 repertoire
Slide 17: OmniUltra Immune Response
17 OmniUltra Immune Response BROAD ARRAY OF TARGETS ASSESSED Target Target Type NKp46 Immune Engager CD98 Brain Delivery BDNF Pain Modulator EGFR B7-H3 Tumor Target CD38 PSMA OmniAb Partner Target 1 Confidential OmniAb Partner Target 2 Confidential OmniAb Partner Target 3 Confidential OmniUltra chic
Slide 18: Ultralong CDRH3s Are Diversified by Gene Conversion
18 Ultralong CDRH3s Are Diversified by Gene Conversion SEQUENCE ANALYSIS OF ANTIGEN-SELECTED CLONES Stalk Knob Stalk Pseudogene Position Gene conversion mainly focused on knob region in antigen-specific ultralong antibodies
Slide 19: Ultralong CDRH3 Bind to Therapeutic Targets on Cells
19 Ultralong CDRH3 Bind to Therapeutic Targets on Cells FLOW CYTOMETRY OF ANTIGEN-SPECIFIC CLONES Ultralong CDRH3 IgG antibodies bind to native protein structure
Slide 20: Ultralong CDRH3 Can Internalize
20 Ultralong CDRH3 Can Internalize PSMA CLONES INTERNALIZE IN LNCaP CELLS 5 min 30 min 60 min 60 min Negative Control Clone 1 5 min 30 min 60 min 60 min Rosopatamab Clone 2 Ultralong CDRH3 IgG antibodies have potential application for ADCs
Slide 21: Ultralong CDRH3 Binding Affinity
21 Ultralong CDRH3 Binding Affinity NATIVE KNOB ON GERMLINED VH MAINTAINS BINDING AFFINITY Ultralong CDRH3 IgG clones cover a broad range of binding affinity, depending on the target
Slide 22: Epitope Coverage of Ultralong Antibodies
22 Epitope Coverage of Ultralong Antibodies NKp46 EGFR B7-H3 Novel bin OmniUltra - 1 unique epitope bin not represented by any other repertoire tested OmniUltra - 2 epitope bins OmniUltra - 4 epitope bins (including a novel bin) OmniUltra, n=5 OmniTaur (cow), n=2 OmniUltra, n=22 OmniUltra, n=50 Benc
Slide 23: OmniUltra chickens are engineered to express ultralong CDRH3 in the context of human V frameworks
23 • OmniUltra chickens are engineered to express ultralong CDRH3 in the context of human V frameworks • Like wild-type chickens, OmniUltra chickens produce robust immune titers to a variety of human targets • Pseudogenes participate in gene conversion of ultralong CDRH3 • Ultralong CDRH3 cover the
Slide 24: Acknowledgements
24 Acknowledgements
Slide 25: Poster 126: Development of OmniUltra: A transgenic chicken system
25 Poster 126: Development of OmniUltra™: A transgenic chicken system for the generation of ultralong CDRH3 antibodies, mini-proteins, and structured proteins Poster 139: Empowering the efficient discovery of ultra-long CDRH3 antibodies with high-throughput xPloration® workflows Booth 300