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CRO Services

Drug Development Expertise Empowering Research Services for Biologics

Lead Optimization

Comprehensive Antibody Engineering Platforms

Lead optimization represents a critical phase in biologics discovery. WuXi Biologics provides comprehensive lead identification and optimization services for antibody therapeutics, designed to address key challenges across the drug discovery and development stages.

 

Our scientific expertise encompasses a wide range of biologics, including monoclonal antibodies (mAbs), bispecific antibodies (bsAbs), and multispecific antibodies (msAbs), peptides, enzymes, soluble T-cell receptors (TCRs), cytokines, and other complex biomolecules. Our scientists also work in close collaboration with clients to improve lead developability, binding affinity, stability, and manufacturability, ensuring every candidate is fully optimized for CMC development and beyond.

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Antibody Humanization: Optimal, Structure-Based CDR Grafting

WuXi Biologics offers antibody humanization services utilizing best-fit CDR grafting guided by advanced structural modeling techniques. With a success rate exceeding 98% across more than 200 completed projects, our antibody humanization services cover a wide range of non-human antibodies for improved developability, including those derived from mouse, rat, hamster, rabbit, and chicken, as well as VHH single-domain antibodies from llama and alpaca.

Antibody Humanization Service Details:

Service Item

Description

Turnaround Time

 

Humanization

1. In silico CDR grafting

2. 3D model-guided design of back mutations

3. Humanized variants production

4. Affinity measurement (SPR/FACS) and lead selection

5. Optional: Developability assessment

4-6 weeks

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Humanization with PTM Risk Removal

2. 3D model-guided design of back mutations and PTM site mutations

3. Humanized & PTM-removal variants production

4. Affinity measurement (SPR/FACS) and lead selection

5. Combined lead production and affinity validation (SPR/FACS)

8-10 weeks

Case Study #1: Enhanced Binding Affinity and Developability Through Antibody Humanization

This case study highlights the effectiveness of our antibody humanization approach in reducing immunogenicity risks while simultaneously maintaining or improving binding affinity and key developability attributes, such as stability, expression, and manufacturability.

Figure A: The results demonstrate a median 1.4-fold increase in antigen-binding affinity. Key developability metrics, including Protein A titer in HEK293 cells, thermostability assessed by differential scanning fluorimetry (DSF), and T20 scores, further confirm the high quality and reliability of the humanization process.

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Affinity Maturation: Comprehensive Paratope Mapping to Identify Mutagenesis Hotspots

WuXi Biologics provides expert antibody affinity maturation services utilizing our validated parsimonious mutagenesis method for each antigen-antibody pair and multiformat screening assays (ELISA, SPR, FACS). We identify critical mutagenesis hotspots and generate focused mutant libraries. This targeted approach enables the efficient isolation of antibody variants with improved binding affinity and specificity.

Key Features of Our Affinity Optimization Services:

  • 1.5-4 months turnaround time
  • KD enhancement ranging from 10- to 10,000-fold, achieving pM levels
  • Minimize the risk of epitope shifts
  • Mitigation risks in PTMs, poly-reactivity, and aggregation
  • pH dependency by parallel screening

Affinity Maturation Service Details:

Service Item

Description

Turnaround Time

 

Antibody Paratope Mapping—Parsimonious Mutagenesis

1. Antibody reformatting and screening assay setup (ELISA)

2. Saturated mutagenesis screening of all CDR positions. (Optional: Screening at two different conditions)

3. Hits ranking (ELISA/FACS) and combinatorial library design

4. Library screening and hits ranking (ELISA/FACS)

5. IgG reformatting and affinity ranking (SPR/FACS)

6. Optional: Developability screening of combinatorials hits

3-5 months

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Block Mutagenesis

1. Antibody reformatting and screening assay setup (FACS)

2. Block mutagenesis library design and construction

3. Block mutagenesis library panning and screening (FACS)

4. Hit ranking (FACS) and block combination design

5. IgG reformatting and affinity ranking (FACS).

6. Optional: Developability screening of combinatorials hits

3-5 months

pH-Dependency Engineering

1. Antibody reformatting and screening assay setup (ELISA at two pH conditions)

2. His-scanning library design and construction

pH-dependency screening (ELISA/FACS)

3. Hit ranking (ELISA/FACS) and mutant combination design

4. IgG reformatting and pH-dependency ranking (ELISA/SPR/FACS)

2-3 months

Parsimonious Mutagenesis Affinity Maturation platform

Our parsimonious mutagenesis platform enables a 10- to 100-fold improvement in Koff  while minimizing the risk of epitope shift. This targeted approach also supports the elimination of liabilities (PTM, aggregation, and poly-reactivity) and facilitates the engineering of pH-sensitive binding profiles.

Case Study #1: Achieving a 456-Fold Increase in Antibody Affinity Through Parsimonious Mutagenesis

This case study illustrates the power of our targeted parsimonious mutagenesis approach, which enabled a 456-fold improvement in antibody binding affinity through precise identification and optimization of key paratope residues.

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Figure A: The parental antibody exhibited a baseline binding affinity with a KD of 6.66 × 10−8 M. After optimization via parsimonious mutagenesis. The KD was improved to 1.46×10−10 M, representing a 456-fold increase in binding affinity.

Block Mutagenesis Affinity Maturation Platform for Cell-Based Panning and Screening

Our block mutagenesis platform enables efficient affinity maturation through the construction of mutant libraries by randomizing overlapping five-amino-acid blocks across each CDR. With library sizes reaching up to 10⁸ variants, this approach supports affinity-based selection against cell surface targets via competitive, cell-based panning and screening, facilitating the identification of high-affinity antibody candidates.

High-Throughput (HTP) pH Engineering Platform

This platform enhances pH-dependent binding, thereby improving antibody-target selectivity and optimizing the in vivo pharmacokinetic (PK) profile.

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Fc Engineering: Strategic Design of Multiple Mutation Sets to Modulate Fc Effector Function

The Fc region is critical to antibody function, contributing not only to structural stability but also to immune effector activities, such as ADCC, CDC, ADCP, and antibody recycling. At WuXi Biologics, our Fc engineering platform employs rationally designed mutation sets to modulate Fc functions. This platform integrates comprehensive in vitro functional assays with in vivo PKPD studies, providing an end-to-end solution that reduces risk and enhances developability attributes across diverse therapeutic formats.

Key Features of our Fc Engineering Services:

  • Customize Fc function to modulate Fc effector activity and half-life, support bispecific assembly, and enable ADC conjugation
  • Support a range of modalities, including monoclonal antibodies (mAbs), bispecific antibodies (bsAbs), ADCs, and fusion proteins.
  • Comprehensive in vitro assays, such as Fc receptor binding (SPR), ADCC, CDC, and ADCP, combined with in vivo PKPD studies.

Fc Engineering Service Details:

 

Service Items

Turnaround Time

 

Fc Mutations Design and Production

3-4 weeks

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SPR Binding Characterization

1-2 weeks

In Vitro ADCC/CDC/ADCP Assays

2 weeks

Mouse PK

6-7 weeks

Rat PK

6-7 weeks

NHP PK

7-8 weeks

Case Study #1: Optimizing Fc Engineering for Enhanced Antibody Therapeutics

This case study highlights key engineering sites within the Fc region, categorized based on their functional impact: effector function modulation (red), half-life (blue), and Fc dimerization (green). These modifications could offer tailored solutions to required Fc functions in both therapeutic efficacy and pharmacokinetic properties.

Figure A: Fc engineering sites for Fc effector function (red), half-life (blue) and Fc dimerization (green).

Case Study #2: Modulating ADCC Effector Function via Fc Mutations

This study evaluated Fc-engineered IgG1 antibodies for enhanced or reduced ADCC function by measuring their binding affinity to human FcγRIIIa (F158 and V158) through SPR analysis. Mutations such as DE and DLE led to a significant increase in receptor binding, while LALA and N297A weakened interactions, highlighting their role in modulating ADCC effector function.

Table A: Binding affinities of Fc-engineered IgG1 variants to human FcγRIIIa (F158 and V158)

 

Ligand Analyte KD(M) ADCC effect
Human FcγRIIIa (V158) Wild type IgG1 antibody  7.55 × 10⁻⁷ +
IgG1 antibody with DE mutation 2.20 × 10⁻8 ++
IgG1 antibody with DLE mutation  1.56 × 10⁻⁸ ++
hIgG1 antibody with LALA mutation 2.89 × 10⁻⁵ –
hIgG1 antibody with N297A mutation No or weak binding –
Human FcγRIIIa (F158) Wild type IgG1 antibody  1.54 × 10⁻⁷ +
IgG1 antibody with DE mutation 9.54 × 10⁻⁹ ++
IgG1 antibody with DLE mutation  7.89 × 10⁻⁹ ++
hIgG1 antibody with LALA mutation 5.48 × 10⁻⁶ –
hIgG1 antibody with N297A mutation No or weak binding –

Figure A: SPR analysis of Fc-mutated IgG1 antibodies demonstrated that ADCC-enhancing mutations (DE, DLE) result in stronger binding to FcγRIIIa, while LALA and N297A mutations significantly reduce or eliminate receptor binding.

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