As to production of bi-specific antibodies see outline. 

Specific Types of BsAbs see outline

Introduction:

Most natural antibodies are bi or multivalent molecules comprising identical antigen binding sites. The exception are IgG4 molecules which are, due to an instable hinge region, capable of exchaning Fab arms (half-antibdoy association) This is a random process resulting in bivalent molecuels with two different specificites. Bispecific antibodies with defined specificities, however, are artificial molecules, per se not found in nature. (Kontermann, “The making of bispecific antibodies”, 9(2), 2017, 182-212; good discussion of the various formats of bi-specific antibodies)

The vast majority of immuoglobuilins are bivalent and monospecific molecules carrying the same specificity on both arms as they are composed of two identical heavy chain polypeptides and two identical light chain polypeptides. However, it was recognized that hybride hybridomas can be created by a fusion event between two hybrodimos. These “qudromas” express two different heavy and two different light chains and thus produce a variety of different antibody species resulting form the random pairing of the heavy and light chains. Among these different species, bispecific antibodies are generated, carrying a different specificity on each arm. Another naturally occurring exception is the immunoglobuilin of the IgG4 isotype that is able to undergo heavy cahin exchange due to a less stable dimerization mediated by the hinge region of that isotype. Fischer (US2014/0179547)

Specific Applications and Examples

Bi-specific antibodies against Two separate targets:

Beckmann, (US14/123,041 and US2014/0255405) discloses a method for the removal of soluble monomeric biomolecules form bodily fluds by using binding molecules  such as bispecific antibodies with at least two different specifities, either for two different epitopes on the monomeric biomolecule or for one epitope on the biomolecule and a second epitope on a second biomolecule, that exhibits at least two copies fo the seocnd epitope. By contacting a bodily fluid containing the soluble monomeric biomolecule, or alterntively the soluble monomeric biomolecule and the second biomolecule with the binding molcecule, aggregates are formed that result in the removal of the soluble monomeric biomolecule from the biodily fluid. Aggregation can be measured in a number of ways such as by immobilizing a first unlabeled version of the antibody in a sandwich ELISA, contacting the immobilized antibody with the soluble monomeric target, permitting the formation of the immobilized antibody and soluble biomolecule via first paratope (that part of the antibody that is required for specific binding) and first epitope interaction and contacting the complexes formed with a second verion of the antibody which is labeled where binding of the seocnd antibody via a second paratope to the second epitope on the immobilized target biomolecule can be detected by idntifying the present of the label. In one embodiment, the monomeric soluble target biomolcule is human GM-CSF ad the multimeric soluble target molcule is human TNF-alpha. 

Goldenberg (WO2006/063150) discloses an antigen-binding molecules in which two or more different single chain antibody or antibody fragment segments with teh same or different specificities are linked. The mutlispecific antgonist may be a mixture that contains at least two separate antibodies that bind to the different targets or the antagonist may be an antibody that is at least bispecific, in which different arms of the antibody react specifically with at least two different argets. There are certain dvantages when the multspecifci antgonist is an antibody that is bispecific, including rapid clearance from the blood. In one embodiment the first target is TNF-alpha and the second targt is a proinflammatory cytokines such as IL-6. 

Ghayur (WO2009/149189) discloses multivalent and multispecific binding proteins such as antibodies. which bind to two separate targets such as TNF and VEGF and TNF/IL6.

Miller (WO2011/084714) discloses bispecific epitopes which bind to TNF alpha and another molecule such as IL-6.

Anti-Cancer Bi-specific Antibodies

–Bi-secific Abs reactive with a trigger molecule on immune effector cell and surface antigen on a tumor target cell: have been described. (krosen, Advanced Drug Delivery Reviews 31 (1998) 105-129)

Cell specific targeting moeity and anti-cell proliferation moeity: Rosenblum (US2010/0068151) discloses a cehlator (chelatory moeity that binds to a cation)  conjugated to a cell specific targeting moeity such as an antibody and an anti-cell proliferation moeity such as gelonin, spaorin, ricin (moeity capable of reducing proliferation of a cell) which can specificaly target and damage hyperproliferative issue which occurs during angioenesis in tumor growth.