IP Verse

Methods Of Making Heavy Chain Only Antibodies Using Transgenic Animals

Patent No. US10906970 (titled "Methods Of Making Heavy Chain Only Antibodies Using Transgenic Animals") was filed by Harbour Antibodies Bv on Apr 16, 2018.

What is this patent about?

’970 is related to the field of antibody engineering, specifically the generation of heavy chain-only antibodies in transgenic animals. Traditional antibodies consist of two heavy chains and two light chains. The production of fully human monoclonal antibodies for therapy is complex and expensive, relying on mammalian cell culture due to the intricate assembly and glycosylation requirements. This patent addresses the need for a more efficient method of producing functional antibodies, particularly for therapeutic applications.

The underlying idea behind ’970 is to engineer transgenic rodents, such as mice, to produce functional heavy chain-only antibodies in response to antigen challenge. This is achieved by introducing a heterologous heavy chain locus that lacks the C H 1 domain, which is normally responsible for binding to the light chain. By removing this domain, the transgenic animal is forced to produce antibodies consisting only of heavy chains, which can still bind to antigens.

The claims of ’970 focus on a method for producing soluble, antigen-specific heavy chain-only antibodies. This involves immunizing a transgenic rodent with a heterologous V H heavy chain locus. The locus includes a variable region with at least one V H gene segment, 20–40 D gene segments, at least one J gene segment, and a heavy chain constant region without a functional C H 1 domain. The V H , D, and J segments recombine to form a VDJ coding sequence, which, upon antigen challenge, produces a soluble, heavy chain-only antibody with a soluble, antigen-specific V H binding domain and a constant effector region lacking C H 1. The recombined locus is then cloned from an antibody-producing cell after affinity maturation, and the antibody is produced from this clone.

In practice, the transgenic rodent is immunized with an antigen, triggering an immune response that leads to the recombination of V, D, and J gene segments within the engineered heavy chain locus. Because the C H 1 domain is absent, only heavy chain-only antibodies are produced. These antibodies undergo affinity maturation through somatic mutation, resulting in high-affinity antigen binding. The B-cells producing these antibodies are then harvested, and their antibody genes are cloned and expressed to produce the desired heavy chain-only antibodies.

This approach differs from prior methods that rely on phage display or camelid antibodies. Phage display often yields antibodies with lower affinities, while camelid antibodies, although naturally occurring as heavy chain-only, can be immunogenic in humans. By using a fully human or humanized V H domain in a transgenic rodent, ’970 aims to generate high-affinity, fully human heavy chain-only antibodies that are suitable for therapeutic use, bypassing the limitations of traditional antibody production methods and offering a more efficient and potentially less immunogenic alternative.

How does this patent fit in bigger picture?

Technical landscape at the time

In the mid-2000s when ’970 was filed, antibody engineering at a time when bispecific antibodies were typically implemented using complex H2L2 complexes. At that time, manufacturing bispecific antibodies was non-trivial due to heterodimer redundancy and the need for engineered "knob and hole" heavy chains to prevent mispairing.

Novelty and Inventive Step

The examiner withdrew the rejection of claims 15 and 16 based on the inventor's declaration. The declaration asserted that, at the time of the invention, those skilled in the art would not have had a reasonable expectation of success in making the invention due to unpredictability in the art. Although the declaration was not from a disinterested party, the examiner could not refute its veracity, leading to the withdrawal of the rejection and allowance of the claims.

Claims

This patent contains 2 claims, with claims 1 and 2 being independent. The independent claims focus on methods for producing soluble, antigen-specific heavy chain only antibodies by immunizing a transgenic rodent with an antigen. There are no dependent claims.

Key Claim Terms New

Definitions of key terms used in the patent claims.

Term (Source)Support for SpecificationInterpretation
Affinity maturation via somatic mutation
(Claim 1, Claim 2)		“Nucleotide sequence analysis of antigen-specific mRNA encoding an antigen-specific heavy chain isolated from hybridomas derived from transgenic mice has demonstrated that heavy chain antibody diversity is primarily a function of VDJ recombination. Furthermore, the present inventors have shown that antibody diversity is generated in the CDR3 region of the functional antigen-binding domain of the heavy chain-only antibody with a more limited contribution from somatic mutations in the V H domains.”The process by which the affinity of the heavy chain-only antibody for its target antigen is increased through somatic mutations in the VDJ coding sequence after recombination.
Constant effector region
(Claim 1, Claim 2)		“According to this aspect of the invention, each heavy chain constant region essentially comprises at least one heavy chain constant region gene, which is expressed without a functional C H1 domain so that generation of heavy chain-only antibody can occur. Each heavy chain constant region may also comprise one or more additional heavy chain constant region exons, which are selected from the group consisting of Cδ, Cγ1-4, Cμ, Cε and Cα1-2 with the proviso that the additional heavy chain constant region genes also do not express a functional C H1 domain.”The constant region of the heavy chain-only antibody, derived from a Cγ or Cμ gene, that mediates effector functions but lacks a functional CH1 domain, ensuring that the antibody remains heavy chain-only and does not bind to a light chain.
Functional Ch1 domain
(Claim 1, Claim 2)		“For the production of heavy chain-only antibody, the heavy chain locus in the germline comprises gene segments encoding some or all of the possible constant regions. During maturation, a re-arranged V H binding domain is spliced onto the C H2 constant region-encoding segment, to provide a re-arranged gene encoding a heavy chain which lacks a C H1 domain and is therefore unable to associate with an immunoglobulin light chain.”The CH1 domain is a part of the heavy chain constant region that facilitates the interaction between the heavy and light chains in a typical antibody. In this invention, the CH1 domain is non-functional or absent to ensure the production of heavy chain-only antibodies.
Soluble, antigen-specific Vh binding domain
(Claim 1, Claim 2)		“Preferably, the V H domain as used herein remains in solution and is active in a physiological medium without the need for any other factor to maintain solubility. Preferably, the ability of the soluble V H domain to bind antigen has been improved by VDJ recombination and somatic mutation. There is no dependency on the presence or absence of the enlarged CDR3 loop peculiar to the camelid species.”The variable region of a heavy chain-only antibody that retains the ability to bind to a specific antigen and remains soluble in a physiological medium without requiring additional factors to maintain solubility. Its antigen-binding capability is improved through VDJ recombination and somatic mutation.
Vh Heavy chain locus
(Claim 1, Claim 2)		“A “V H heavy chain locus” in the context of the present invention relates to a minimal micro-locus encoding a V H domain comprising one or more V gene segments, one or more D gene segments and one or more J gene segments, operationally linked to one or more heavy chain effector regions (each devoid of a C H1 domain). Preferably, the primary source of antibody repertoire variability is the CDR3 region formed by the selection of D and J gene segments by the V-D and D-J junctions.”A genetic region in a transgenic rodent that includes V, D, and J gene segments capable of recombining to form a VDJ coding sequence, and a heavy chain constant region that does not encode a functional CH1 domain. This locus, when expressed after antigen challenge, produces a soluble, heavy chain-only antibody with a soluble, antigen-specific VH binding domain and a constant effector region lacking a functional CH1 domain.

Litigation Cases New

US Latest litigation cases involving this patent.

Case NumberFiling DateTitle
1:25-cv-13004Oct 14, 2025Harbour Antibodies BV v. Leveragen, Inc.
1:21-cv-01807Dec 23, 2021Harbour Antibodies BV et al v. Teneobio, Inc.

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US10906970

HARBOUR ANTIBODIES BV
Application Number
US15953622
Filing Date
Apr 16, 2018
Status
Expired
Expiry Date
Jul 22, 2025
External Links
Slate, USPTO, Google Patents