Production Of Heavy Chain Only Antibodies In Transgenic Mammals
Patent No. US10993420 (titled "Production Of Heavy Chain Only Antibodies In Transgenic Mammals") was filed by Harbour Antibodies Bv on Mar 14, 2014.
What is this patent about?
’420 is related to the field of antibody engineering, specifically the generation of heavy chain-only antibodies (HCAb) in transgenic animals. Traditional antibody structures consist of both heavy and light chains, but certain species like camelids naturally produce functional antibodies composed only of heavy chains. This patent addresses the challenge of efficiently generating high-affinity, human-like HCAb in transgenic mammals, particularly mice, for therapeutic and diagnostic applications.
The underlying idea behind ’420 is to optimize the composition of the heterologous immunoglobulin heavy chain locus introduced into the transgenic animal. The key inventive insight is that restricting the diversity of the variable heavy chain (VH) gene segments within this locus, specifically by focusing on the VH3 subclass , leads to a more efficient production of soluble and high-affinity HCAb. This is because VH3 domains exhibit better intrinsic solubility compared to other VH subclasses, reducing non-productive rearrangements during B cell development.
The claims of ’420 focus on a method for producing VH heavy chain-only antibodies in a transgenic non-human mammal. The method involves expressing a transgene with a heterologous VH heavy chain locus that includes human VH gene segments, but *not* all subclasses. Critically, the locus must include three or more human VH3 gene segments (or a combination of VH3 and VH4), along with D and J gene segments, and a constant heavy chain region lacking the CH1 domain . The method concludes with isolating the resulting VH heavy chain-only antibody.
In practice, the transgenic animal, typically a mouse, is engineered with a modified heavy chain locus containing a specific arrangement of human VH3 gene segments, D segments, J segments, and a constant region. The absence of the CH1 domain is crucial because it prevents the heavy chain from binding to a light chain, ensuring the production of HCAb. After immunization with an antigen, the animal's B cells undergo maturation, generating a diverse repertoire of HCAb through VDJ recombination and somatic hypermutation. The resulting antibodies can then be isolated using standard techniques like hybridoma technology or phage display.
This approach differentiates itself from prior art by recognizing the importance of VH domain solubility in HCAb production. Previous attempts to create transgenic animals with a broader range of VH gene segments often resulted in lower B cell numbers and antibody titers due to the presence of less soluble VH domains. By focusing on the VH3 subclass, ’420 promotes more efficient B cell development and a higher yield of soluble, high-affinity HCAb . This allows for the generation of human-like antibodies without the need to immunize large numbers of animals or rely on camelid-derived VHH domains, which can be immunogenic in humans.
How does this patent fit in bigger picture?
Technical landscape at the time
In the early 2010s when ’420 was filed, transgenic animal models were commonly used for antibody development, at a time when generating fully human antibodies required engineering of the animal's immunoglobulin loci. At this time, creating heavy chain-only antibodies with high affinity and solubility presented technical challenges, when systems commonly relied on traditional hybridoma technology or phage display for antibody generation.
Novelty and Inventive Step
Claims were rejected under pre-AIA 35 U.S.C. 102(e) as being anticipated by prior art. The applicant traversed these rejections, but the examiner maintained the rejections. Claims were also rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, for lack of enablement. This action was made final. No claims were allowed.
Claims
This patent contains 21 claims, with independent claims numbered 1, 3, and 13. The independent claims generally focus on methods for producing VH heavy chain-only antibodies in transgenic non-human mammals by expressing a heterologous VH heavy chain locus and isolating the resulting antibodies. The dependent claims generally specify details and variations of the methods described in the independent claims.
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Date
Description
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US10993420
- Application Number
- US14211243
- Filing Date
- Mar 14, 2014
- Status
- Granted
- Expiry Date
- Mar 31, 2035
- External Links
- Slate, USPTO, Google Patents